@article {pmid39966464, year = {2025}, author = {Ramasamy, VS and Nathan, ABP and Choi, MC and Kim, SH and Ohn, T}, title = {Aβ42 induces stress granule formation via PACT/PKR pathway.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {5829}, pmid = {39966464}, issn = {2045-2322}, abstract = {Stress granule (SG) formation has been linked to several neurodegenerative disorders, such as Alzheimer's disease (AD). Amyloid-β42 (Aβ42) is a key player in the pathogenesis of AD and is known to trigger various stress-related signaling pathways. However, the impact of Aβ on SG formation has not been fully understood. The primary aim of this study is to analyze the SG-inducing properties of Aβ42 and to uncover the molecular mechanisms underlying this process. Our results revealed that exposure to 20 μM Aβ42 led to a significant SG formation in neuroblastoma-derived (SH-SY5Y) and glioma-derived (U87) cell lines. Interestingly, we observed elevated levels of p-eIF2α, while overall protein translation levels remained unchanged. Monomeric and oligomeric forms of Aβ42 exhibited a 4-5 times stronger ability to induce SG formation compared to fibrillar forms. Additionally, treatment with familial mutants of Aβ42 (Dutch and Flemish) showed distinct effects on SG induction. Moreover, our findings using eIF2α kinases knockout (KO) cell lines demonstrated that Aβ-induced SG formation is primarily dependent on Protein Kinase R (PKR). Subsequent proximity ligation assay (PLA) analysis revealed a close proximity of PACT and PKR in Aβ-treated cells and in AD mouse hippocampus. Taken together, our study suggests that Aβ42 promotes SG formation through PKR kinase activation, which in turn requires PACT involvement.}, } @article {pmid39966100, year = {2025}, author = {Lobyntseva, A and Ganaiem, M and Ivashko-Pachima, Y and Barnstable, CJ and Weisinger, B and Parabucki, A and Segal, Y and Shohami, E and Gozes, I}, title = {Extremely Low-Frequency and Low-Intensity Electromagnetic Field Technology (ELF-EMF) Sculpts Microtubules.}, journal = {The European journal of neuroscience}, volume = {61}, number = {4}, pages = {e70023}, doi = {10.1111/ejn.70023}, pmid = {39966100}, issn = {1460-9568}, support = {//BrainQ Technologies Ltd./ ; }, mesh = {*Microtubules/metabolism ; *tau Proteins/metabolism ; *Electromagnetic Fields ; Cell Line, Tumor ; Humans ; Zinc/metabolism ; Phosphorylation ; Animals ; Tubulin/metabolism ; Neurons/metabolism/radiation effects ; Magnetic Field Therapy/methods ; Mice ; }, abstract = {Aberrant microtubule dynamics coupled with a reduction in Tau-microtubule interaction are at the core of neuronal injuries resulting in microtubule disruption and aggregates of abnormally phosphorylated Tau. These pathological Tau aggregates define tauopathies such as Alzheimer's disease (AD), as well as the pathological sequelae following traumatic brain injury (TBI), stroke and spinal cord injury (SCI). We hypothesized that differential applications of extremely low-frequency and low-intensity electromagnetic field (ELF-EMF) will change microtubule function. To examine our hypothesis, we pre-applied ELF-EMF to a neuroblastoma neuronal cell line later exposed to 4 h of zinc intoxication, modelling Tau-microtubule dissociation. ELF-EMF (40 Hz and 1 G; multiple exposure schedules) enhanced microtubule dynamics and increased Tau-microtubule interaction in the face of zinc toxicity. Complementing these preconditioning neuroprotective effects, concomitant 1 h treatment protocols comparing 3.9 or 40 Hz and 1 G exposure, indicated effects on Tau phosphorylation accentuated with 40 Hz and reduction in beta tubulin isotypes, depending on electromagnetic frequencies, most pronounced at 3.9 Hz. Our results discovered ELF-EMF modulation on the microtubule cytoskeleton essential for brain health.}, } @article {pmid39965691, year = {2025}, author = {Prabakaran, A and Rakshit, D and Patel, I and Susanna, KJ and Mishra, A and Radhakrishnanand, P and Sarma, P and Alexander, A}, title = {Chitosan-coated nanostructured lipid carriers for intranasal delivery of sinapic acid in Aβ1-42 induced C57BL/6 mice for Alzheimer's disease treatment.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {141136}, doi = {10.1016/j.ijbiomac.2025.141136}, pmid = {39965691}, issn = {1879-0003}, abstract = {Sinapic acid (SA) is a plant-derived antioxidant that exhibits neuroprotective activity. However, its poor bioavailability in the brain limits its therapeutic application in treating Alzheimer's disease (AD). Therefore, the present study hypothesizes that coating nanostructured lipid carriers (NLCs) with a biological macromolecule like chitosan (CH-SA-NLCs) could enhance the delivery of SA for AD treatment. Further, the CH-SA-NLCs were spherical with sizes below 200 nm, confirmed by AFM, SEM, and TEM and achieved a sustained drug release of 76.5 % in pH 6.5 simulated nasal fluid over 24 h. Also, the histopathology study confirmed the safety of CH-SA-NLCs, validating its suitability for intranasal administration. Not only the in vitro sustained drug release closely correlated with in vivo pharmacokinetics of CH-SA-NLCs (i.n.), demonstrating a 1.7-fold increase in SA's half-life compared to plain SA (i.v.) in plasma but also CH-SA-NLCs (i.n.) achieved a superior AUC0-∞ of 7676.32 ± 2738.55 ng/g*h with a 2.6-fold improved drug targeting efficiency of SA in the brain of BALB/c mice. These improvements resulted in significant neuroprotective effects and decreased oxidative stress and inflammatory levels in Aβ1-42-induced mice. Overall, the study highlights safe and effective intranasal delivery of SA via chitosan-coated nanocarrier as a promising AD treatment strategy.}, } @article {pmid39965199, year = {2025}, author = {Frederiksen, KS and Hahn-Pedersen, J and Crawford, R and Morrison, R and Jeppesen, R and Doward, L and Weidner, W}, title = {Traversing Shifting Sands-the Challenges of Caring for Someone With Alzheimer's Disease and the Impact on Care Partners: Social Media Content Analysis.}, journal = {Journal of medical Internet research}, volume = {27}, number = {}, pages = {e55468}, doi = {10.2196/55468}, pmid = {39965199}, issn = {1438-8871}, mesh = {*Alzheimer Disease/psychology ; Humans ; *Social Media ; *Caregivers/psychology ; *Quality of Life/psychology ; }, abstract = {BACKGROUND: Social media data provide a valuable opportunity to explore the effects that Alzheimer disease (AD) has on care partners, including the aspects of providing care that have the greatest impacts on their lives and well-being and their priorities for their loved ones' treatment.

OBJECTIVE: The objective of this social media review was to gain insight into the impact of caring for someone with AD, focusing particularly on impacts on psychological and emotional well-being, social functioning, daily life and ability to work, health-related quality of life, social functioning, and relationships.

METHODS: We reviewed social media posts from 4 sources-YouTube (Google), Alzheimer's Association, Alzheimer Society of Canada, and Dementia UK-to gain insights into the impact of AD on care partners. English-language posts uploaded between May 2011 and May 2021 that discussed the impact of AD on care partners were included and analyzed thematically.

RESULTS: Of the 279 posts identified, 55 posts, shared by 70 contributors (4 people living with AD and 66 care partners or family members), met the review criteria. The top 3 reported or observed impacts of AD discussed by contributors were psychological and emotional well-being (53/70, 76%), social life and relationships (37/70, 53%), and care partner overall health-related quality of life (27/70, 39%). An important theme that emerged was the emotional distress and sadness (24/70, 34%) associated with the care partners' experience of "living bereavement" or "anticipatory grief." Contributors also reported impacts on care partners' daily life (9/70, 13%) and work and employment (8/70, 11%). Care partners' emotional distress was also exacerbated by loved ones' AD-related symptoms (eg, altered behavior and memory loss). Caregiving had long-term consequences for care partners, including diminished personal well-being, family and personal sacrifices, loss of employment, and unanticipated financial burdens.

CONCLUSIONS: Insights from social media emphasized the psychological, emotional, professional, and financial impacts on individuals providing informal care for a person with AD and the need for improved care partner support. A comprehensive understanding of care partners' experiences is needed to capture the true impact of AD.}, } @article {pmid39963928, year = {2025}, author = {Lomas, C and Dubey, RC and Perez-Alvarez, G and Lopez Hernandez, Y and Atmar, A and Arias, AY and Vashist, A and Aggarwal, S and Manickam, P and Lakshmana, MK and Vashist, A}, title = {Recent advances in nanotherapeutics for HIV-associated neurocognitive disorders and substance use disorders.}, journal = {Nanomedicine (London, England)}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/17435889.2025.2461984}, pmid = {39963928}, issn = {1748-6963}, abstract = {Substance use disorders (SUD) and HIV-associated neurocognitive disorders (HAND) work synergistically as a significant cause of cognitive decline in adults and adolescents globally. Current therapies continue to be limited due to difficulties crossing the blood-brain barrier (BBB) leading to limited precision and effectiveness, neurotoxicity, and lack of co-treatment options for both HAND and SUD. Nanoparticle-based therapeutics have several advantages over conventional therapies including more precise targeting, the ability to cross the BBB, and high biocompatibility which decreases toxicity and optimizes sustainability. These advantages extend to other neurological disorders such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). This review summarizes recent advances in nanotechnology for application to HAND, SUD, and co-treatment, as well as other neurological disorders. This review also highlights the potential challenges these therapies face in clinical translation and long-term safety.}, } @article {pmid39963471, year = {2025}, author = {Wright, AL and Weible, AP and Estes, OB and Wehr, M}, title = {Ketamine does not rescue plaque load or gap detection in the 5XFAD mouse model of Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1505908}, pmid = {39963471}, issn = {1663-4365}, abstract = {Ketamine has received growing attention for its effects on neuroplasticity and neuroinflammation, and as a treatment for depression and other mental health disorders. Recent evidence suggests that early sensory and behavioral deficits in Alzheimer's disease could be caused by synaptic disruption that occurs before irreversible neuropathology. This raises the possibility that ketamine could slow down or prevent network disruption and the ensuing sensory and behavioral deficits in Alzheimer's. Here we tested this idea in the 5XFAD mouse model of Alzheimer's, using either an acute single injection of ketamine, or chronic daily injections over 15 weeks. We tested the effects of ketamine on both amyloid plaque load and on a behavioral auditory gap detection task that is an early Alzheimer's biomarker in both mice and humans. We found that ketamine had no effect on plaque load, nor any effect on gap detection, for either acute or chronic dosing. Chronic ketamine facilitated startle responses specifically in 5XFAD mice, but this could simply be related to experience-dependent effects on stress or habituation rather than any rescue effect of ketamine on Alzheimer's-related deficits. We did find robust correlations between gap detection deficits and plaque load in auditory cortex and in the caudal pontine reticular nucleus, demonstrating that the behavioral deficits seen in 5XFAD mice are directly related to amyloid accumulation in these brain regions, and confirming the validity of gap detection as an early biomarker of Alzheimer's. Ketamine, however, had no effect on the strength of these correlations. We conclude that ketamine has no beneficial effect on the development of behavioral gap detection deficits or plaque load in the 5XFAD Alzheimer's mouse model, following either an acute single dose or a chronic daily dose regimen.}, } @article {pmid39963432, year = {2025}, author = {Dhariwal, R and Jain, M and Mir, YR and Singh, A and Jain, B and Kumar, P and Tariq, M and Verma, D and Deshmukh, K and Yadav, VK and Malik, T}, title = {Targeted drug delivery in neurodegenerative diseases: the role of nanotechnology.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1522223}, pmid = {39963432}, issn = {2296-858X}, abstract = {Neurodegenerative diseases, characterized by progressive neuronal loss and cognitive impairments, pose a significant global health challenge. This study explores the potential of nanotherapeutics as a promising approach to enhance drug delivery across physiological barriers, particularly the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (B-CSFB). By employing nanoparticles, this research aims to address critical challenges in the diagnosis and treatment of conditions such as Alzheimer's, Parkinson's, and Huntington's diseases. The multifactorial nature of these disorders necessitates innovative solutions that leverage nanomedicine to improve drug solubility, circulation time, and targeted delivery while minimizing off-target effects. The findings underscore the importance of advancing nanomedicine applications to develop effective therapeutic strategies that can alleviate the burden of neurodegenerative diseases on individuals and healthcare systems.}, } @article {pmid39963073, year = {2025}, author = {Li, B and Wang, L and Xiao, Y and Wang, Y and Wang, Y and Peng, Y and Zhang, A and Tang, Z and Qi, X}, title = {Gastrodin Ameliorates Tau Pathology and BBB Dysfunction in 3xTg-AD Transgenic Mice by Regulating the ADRA1/NF-κB/NLRP3 Pathway to Reduce Neuroinflammation.}, journal = {Phytotherapy research : PTR}, volume = {}, number = {}, pages = {}, doi = {10.1002/ptr.8461}, pmid = {39963073}, issn = {1099-1573}, support = {82260263//Chinese National Natural Science Foundation/ ; Qiankehe Platform Talents-GCC[2023]035//Guizhou Provincial Science and Technology Program Project/ ; Qiankehe Platform Talents-CXTD[2023]003//Guizhou Provincial Science and Technology Program Project/ ; Qiankehe Support [2023] General 232//Guizhou Provincial Science and Technology Program Project/ ; Qiankehe Basic-[2024] Youth 228//Guizhou Provincial Science and Technology Program Project/ ; QianJiaoji [2024]92//Guizhou Provincial Department of Education Youth Science and Technology Talent Project/ ; gzwkj2022-187//Science and Technology Fund Project of the Guizhou Provincial Health Commission/ ; }, abstract = {BACKGROUND AND AIM: Gastrodin, an active compound derived from the traditional Chinese herbal medicine Gastrodia, demonstrates a variety of pharmacological effects, particularly in the enhancement of neural functions. Thus, the aim of this study is to explore the therapeutic effects of gastrodin on Alzheimer's disease (AD) and its underlying molecular mechanisms.

EXPERIMENTAL PROCEDURE: Cognitive function was assessed via Morris water maze and Y-maze tests. Tau pathology, neuroinflammation, and BBB dysfunction were analyzed using various techniques, including Western blot, immunohistochemistry, and ELISA. ADRA1 overexpression was induced by lentiviral infection, and gastrodin's impact on NF-κB p65, NLRP3, IL-1β, and IL-18 levels was evaluated.

KEY RESULTS: In the in vivo experiment, gastrodin enhanced learning and spatial memory in 3xTg-AD mice, as well as reducing p-Tau protein expression in the hippocampus and cortex. Gastrodin inhibited the ADRA1/NF-κB/NLRP3 pathway, which decreased glial cell activation and inflammatory cytokines IL-1β and IL-18, improving neuron and BBB function. In the in vitro experiment, gastrodin inhibited the activation of the NF-κB/NLRP3 pathway due to ADRA1 overexpression and prevented the Aβ42-induced increase in ADRA1/NF-κB/NLRP3 protein expression in SH-SY5Y cells. It also reduced IL-1β and IL-18 cytokine release, restoring tight junction protein expression in bEnd.3 cells.

CONCLUSIONS AND IMPLICATIONS: gastrodin ameliorates learning and memory abilities by alleviating neuroinflammation and tau pathology, restoring the structure and function of neurons and BBB, suggesting that gastrodin may serve as an effective drug for the treatment of AD.}, } @article {pmid39962970, year = {2025}, author = {Fiala, M and Hammock, BD and Hwang, SH and Whitelegge, J and Paul, K and Kaczor-Urbanowicz, KE and Urbanowicz, A and Kesari, S}, title = {Inhibitors of soluble epoxide hydrolase and cGAS/STING repair defects in amyloid-β clearance underlying vascular complications of Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877241305965}, doi = {10.1177/13872877241305965}, pmid = {39962970}, issn = {1875-8908}, abstract = {BACKGROUND: Alzheimer's disease (AD) and its monoclonal antibody therapies are associated with brain vasculitis and amyloid-related imaging abnormalities. The naturally-formed epoxides (EpFAs) of polyunsaturated fatty acids (PUFAs), such as 11,12-epoxyeicosatetraenoic acid (EEQ), are anti-inflammatory and pro-resolution mediators, which are increased by dietary supplementation with ω-3 PUFAs. EpFAs are, however, enzymatically hydrolyzed by soluble epoxide hydrolase (sEH) in AD patients' macrophages in vivo and in vitro.

OBJECTIVE: To repair amyloid-β 1-42 (Aβ) degradation by AD macrophages using the inhibitors of a) soluble epoxide hydrolase (sEHIs), termed TPPU and EC5026, together with EpFAs, or b) STING pathway termed H-151.

METHODS: Immunobiology, immunochemistry, RNA sequencing, and confocal microscopy were used.

RESULTS: In AD brain (examined postmortem), monocyte/macrophages upload Aβ in plaques and transfer it without degradation into brain microvessels, suffer apoptotis, and release Aβ, inducing vasculitis. The EpFAs of epoxyeicosatetraenoic acid (EEQ), along with the inhibitors TPPU and H-151, decrease inflammatory cytokines and regulate macrophage unfolded protein response to endoplasmic reticulum stress. Treatment of AD macrophages by TPPU with EEQ or by STING inhibitor H-151 increased uploading of Aβ after 2 hours and increased degradation of Aβ after 24 hours.

CONCLUSIONS: The sEHI inhibitor EC5026 and the STING inhibitor H-151 increased macrophage uptake and degradation of Aβ. EC5026 administration was safe in normal volunteers. EC5026 together with ω-3 PUFA supplementation are indicated for in a clinical trial in patients with mild cognitive impairment.}, } @article {pmid39962563, year = {2025}, author = {Sarti, P and Varrasi, S and Guerrera, CS and Platania, GA and Furneri, G and Torre, V and Boccaccio, FM and Rivi, V and Tascedda, S and Pirrone, C and Santagati, M and Blom, JMC and Castellano, S and Caraci, F}, title = {Exploring apathy components and their relationship in cognitive decline: insights from a network cross-sectional study.}, journal = {BMC psychology}, volume = {13}, number = {1}, pages = {129}, pmid = {39962563}, issn = {2050-7283}, mesh = {Humans ; *Apathy ; Male ; Female ; *Cognitive Dysfunction/psychology ; Cross-Sectional Studies ; Aged ; *Alzheimer Disease/psychology ; Aged, 80 and over ; Neuropsychological Tests ; Middle Aged ; Disease Progression ; }, abstract = {BACKGROUND: Apathy worsens with age and cognitive decline, particularly in Alzheimer's, leading to functional and cognitive deterioration. Comprehending its broad impact is vital for customized, preventive treatments.

METHODS: The study examined 214 adults divided in three groups-Mild Cognitive Impairment, mild Alzheimer's, and controls-using neuropsychological tests and questionnaires, with statistical and network analysis to explore apathy's links with other group variables related to demographics and treatment.

RESULTS: Notable differences were observed among the groups' performance of administered tests. While inferential statistics failed to return a predictive model of apathy in mild Alzheimer's, networks and cluster analyses indicate that the demographic variables analysed have different importance at different times of disease progression and that cognitive apathy is particularly prominent in AD-related decline.

CONCLUSIONS: Network analysis revealed insights into dementia risk differentiation, notably the impact of sex and demographic factors, beyond the scope of traditional statistics. It highlighted cognitive apathy as a key area for personalized intervention strategies more than behavioural and emotional, emphasizing the importance of short-term goals and not taking away the person's autonomy when not strictly necessary.}, } @article {pmid39963030, year = {2024}, author = {Wieczorek, I and Strosznajder, RP}, title = {S1P receptor modulators affect the toxicity of amyloid β oligomers in microglial and neuronal cells.}, journal = {Folia neuropathologica}, volume = {62}, number = {4}, pages = {348-361}, doi = {10.5114/fn.2024.145758}, pmid = {39963030}, issn = {1509-572X}, mesh = {*Microglia/drug effects/metabolism ; *Amyloid beta-Peptides/toxicity/metabolism ; *Neurons/drug effects/metabolism ; Animals ; Cell Survival/drug effects ; Sphingosine 1 Phosphate Receptor Modulators/pharmacology ; Mice ; Receptors, Lysosphingolipid/metabolism ; Alzheimer Disease/metabolism ; }, abstract = {A large body of evidence has shown that the amyloid b peptide oligomers (Abo) are predominantly responsible for the neurodegeneration/cognitive impairments in Alzheimer's disease (AD). Abo cause mitochondrial dysfunctions leading to an imbalance between pro- and antiapoptotic proteins and finally to neuronal apoptosis. Further, Abo trigger overactivation of microglia followed by enhanced release of proinflammatory cytokines, which exacerbates neurotoxicity of Abo. The above-mentioned alterations are accompanied by disturbed metabolism of prosurvival bioactive sphingolipid, sphingosine-1-phosphate (S1P), and S1P-dependent signalling via specific receptors (S1PR1-5). In the present study, we investigated for the first time the influence of selective - ponesimod (S1PR1), CYM5541 (S1PR3), CYM50308 (S1PR4), A971432 (S1PR4), siponimod (S1PR1,5) - and nonselective - phosphorylated fingolimod/pFTY720 (S1PR1,3-5) - S1P receptor modulators on cell viability, mitochondrial membrane potential (MMP) and expression of genes encoding S1P receptors, pro- and antiapoptotic proteins and proinflammatory cytokines in hippocampal neuronal (HT22) and in microglial (BV2) cell lines treated with 1 µM Abo for 24 hours. A significant reduction in the MMP, cell viability and mRNA levels of Bcl2 and Il18 together with increased Il6 expression was observed in HT22 cells after Abo administration. CYM50308 and A971432 restored the Bcl2 mRNA level to control values (those of Abo-untreated cells) and pFTY720 markedly reduced the Il6 expression. In BV2 cells, Abo induced a significant decrease in the MMP, cell viability and expression of S1pr1, Bad, Bcl2, Tnf and Il18, which was not counteracted by any of the modulators used. In turn, mRNA levels of Il1b, Il6, were markedly increased in microglia after Abo treatment and the administration of studied compounds tended to exacerbate the proinflammatory effect of Abo. In conclusion, the toxic effect of Abo is more pronounced in microglia. S1P receptor modulators may to some extent mitigate proapoptotic and proinflammatory effects of Abo in HT22 cells. In contrast, the same compounds tend to enhance Abo-induced inflammatory changes in BV2 cells.}, } @article {pmid39961913, year = {2025}, author = {Cava, C and Castiglioni, I}, title = {Drug repositioning based on mutual information for the treatment of Alzheimer's disease patients.}, journal = {Medical & biological engineering & computing}, volume = {}, number = {}, pages = {}, pmid = {39961913}, issn = {1741-0444}, abstract = {Computational drug repositioning approaches should be investigated for the identification of new treatments for Alzheimer's patients as a huge amount of omics data has been produced during pre-clinical and clinical studies. Here, we investigated a gene network in Alzheimer's patients to detect a proper therapeutic target. We screened the targets of different drugs (34,006 compounds) using data available in the Connectivity Map database. Then, we analyzed transcriptome profiles of Alzheimer's patients to discover a network of gene-drugs based on mutual information, representing an index of dependence among genes. This study identified a network consisting of 25 genes and compounds and interconnected biological processes using computational approaches. The results also highlight the diagnostic role of the 25 genes since we obtained good classification performances using a neural network model. We also suggest 12 repurposable drugs (like KU-60019, AM-630, CP55940, enflurane, ginkgolide B, linopirdine, apremilast, ibudilast, pentoxifylline, roflumilast, acitretin, and tamibarotene) interacting with 6 genes (ATM, CNR1, GLRB, KCNQ2, PDE4B, and RARA), that we linked to retrograde endocannabinoid signaling, synaptic vesicle cycle, morphine addiction, and homologous recombination.}, } @article {pmid39961726, year = {2025}, author = {Simpson, I}, title = {Therapeutic delivery - industry update covering October 2024.}, journal = {Therapeutic delivery}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/20415990.2025.2463312}, pmid = {39961726}, issn = {2041-6008}, abstract = {This Industry Update covers the period from 1[st] October through to 31 October 2024 and is based on information sourced from company press releases, scientific literature, patents, and various news websites. This month saw two biotech company acquisitions being made by larger biopharma companies with Modifi Biosciences, a company focussing on the development of novel small molecule anticancer therapeutics, being acquired Merck, and AbbVie acquiring Aliada Therapeutics, which focuses on the treatment of central nervous system disorders. Elektrofi and Archon Biosciences both announced new investments, respectively, to support the development of novel high concentration subcutaneous drug delivery technology and for the development Antibody cages for therapeutic applications. GSK and Cambridge University announced a new five-year collaboration focusing on kidney and respiratory disease, and Aeropump and Resyca announced the launch of a new soft mist nasal delivery system that they have been jointly developing. UCB gained FDA approval for a higher dose of its injectable drug, BIMZELX for the treatment of autoimmune disorders, and AbbVie FDA approval for a continuous infusion treatment for Parkinson's Disease. Eisai announced it has completed its submission to the FDA for a subcutaneous version of its already approved therapy for Alzheimer's Disease. Clinical research updates included Johnson and Johnson announcing termination of a Phase III trial evaluating an implanted combination device for the treatment of bladder cancer, and Lilly announced positive results for modified dosing regimen for its approved Alzheimer's drug, Kisunla (donanemab).In October, the PDA held its annual Universe of Prefilled Syringes conference at which several updates on developments in injectable drug delivery were made. Scientific updates relating to therapeutic delivery included: a controlled drug delivery technology that enables a complete course of antibiotics to be delivered; a new lipid-based delivery system that improves the safety and efficacy of gene therapies; and the use of tiny controllable robots to enable targeted drug delivery of multiple therapeutics.}, } @article {pmid39960625, year = {2025}, author = {Ni, R and Jiang, J and Wang, F and Min, J}, title = {Treating incurable non-communicable diseases by targeting iron metabolism and ferroptosis.}, journal = {Science China. Life sciences}, volume = {}, number = {}, pages = {}, pmid = {39960625}, issn = {1869-1889}, abstract = {Both iron metabolism and ferroptosis (an iron-dependent form of programmed cell death) have been connected to the development and progression of many currently incurable non-communicable diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, metabolic dysfunction-associated steatohepatitis, heart failure, and both treatment-relapsed and refractory cancers, such as pancreatic ductal adenocarcinoma and triple-negative breast cancer. Thus, understanding the relationship between iron and these diseases can pave the way for the development of novel therapeutic strategies. Here, we summarize the latest evidence supporting the pathological roles of dysregulated iron metabolism and ferroptosis in a wide range of preclinical animal models of these currently incurable non-communicable diseases. We also summarize the feasibility of targeting iron metabolism and ferroptosis for the prevention and treatment of iron- and ferroptosis-related diseases that currently have limited treatment options. In addition, we provide our perspectives on the challenges and promises regarding the translational potential of targeting dysregulated iron metabolism and ferroptosis to treat diseases, highlighting the future roadmap for developing iron- and ferroptosis-targeted therapeutics.}, } @article {pmid39960601, year = {2025}, author = {Padmakumar, L and Menon, RN and Gopala, S and Vilanilam, GC}, title = {MTH1 in the disorders of the central nervous system: scope beyond brain tumors and challenges.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {39960601}, issn = {2240-2993}, abstract = {Human MutT homolog 1 (MTH1) plays a crucial role in sanitizing oxidized DNA precursors by enzymatically hydrolyzing oxidized nucleotides. The absence of MTH1 activity in the cells results in the accumulation of oxidized nucleotides within the nucleus and mitochondria, leading to mutations, abnormal proteins, and neurodegeneration (in the central nervous system). It has garnered interest as a potential target for anticancer treatment through targeted inhibitor molecules but remains largely understudied in other neurological disorders. This review explores the understanding of MTH1 expression in glioma and its potential role in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease concerning disease mechanism and prognosis. Neurodegeneration, activation of glial cells, and mitochondrial dysfunction are common mechanisms involved in the progression of these diseases. This review also tries to identify the unexplored associations and research gaps that can reveal novel applications of the enzyme in epilepsy, in which MTH1 is studied less. The influence of the ROS environment and cell type on MTH1 expression and function is crucial to be studied for elucidating its role in a multitude of CNS pathologies. The involvement of microglial cell-mediated inflammatory responses through ROS production in epileptogenesis in mouse models highlights the interplay between oxidative stress and neuroinflammation in epilepsy. The possible existence of a similar association between MTH1 expression and pathogenesis of the discussed neurological disorders in vivo demands further exploration preclinically and in patient samples.}, } @article {pmid39960561, year = {2025}, author = {Rajabian, A and Kioumarsi Darbandi, Z and Aliyari, M and Saberi, R and Amirahmadi, S and Amini, H and Salmani, H and Youseflee, P and Hosseini, M}, title = {Pioglitazone improves learning and memory in a rat model of cholinergic dysfunction induced by scopolamine, the roles of oxidative stress and neuroinflammation.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {39960561}, issn = {1432-1912}, abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by progressive cognitive decline. Among various experimental models, scopolamine-induced amnesia is widely used to mimic memory dysfunction. Pioglitazone (PG), a thiazolidinedione derivative, has recently demonstrated neuroprotective potential in neurodegenerative conditions. This study aimed to evaluate the potential benefits of PG in mitigating scopolamine-induced cholinergic dysfunction and the associated memory and learning deficits in male Wistar rats. Fifty male Wistar rats were randomly assigned to five groups: (1) Control, (2) Scopolamine, and (3-5) three treatment groups receiving daily injections of PG at doses of 20, 40, or 60 mg/kg for three weeks in addition to scopolamine administration. Cognitive impairment was induced using scopolamine in all groups except the control. Cognitive function was assessed using the Morris water maze (MWM) and passive avoidance (PA) tests. Biochemical analyses were conducted to measure malondialdehyde (MDA), superoxide dismutase (SOD), total thiol levels, and acetylcholinesterase (AChE) activity in the cortex and hippocampus. Additionally, mRNA expression levels of inflammatory markers (TNF-α, IL-1β, IL-6) were evaluated in the hippocampus. Scopolamine induced cognitive impairment, increased MDA levels and AChE activity, decreased SOD activity and thiol levels, and elevated mRNA expression of inflammatory cytokines. PG significantly reversed these effects by enhancing performance in the MWM and PA tests, reducing MDA levels and AChE activity, and increasing SOD activity and total thiol concentration. Additionally, PG downregulated TNF-α, IL-1β, and IL-6 expression in brain tissue. The present behavioral and neurochemical findings suggest that PG ameliorates scopolamine-induced memory impairment by reducing oxidative stress and neuroinflammation while enhancing cholinergic function.}, } @article {pmid39959708, year = {2025}, author = {Shukla, R and Mishra, K and Singh, S}, title = {Exploring therapeutic potential of Bacopa monnieri bioactive compounds against Alzheimer's and Parkinson's diseases.}, journal = {3 Biotech}, volume = {15}, number = {3}, pages = {61}, pmid = {39959708}, issn = {2190-572X}, abstract = {UNLABELLED: Parkinson's disease (PD) and Alzheimer's disease (AD) consist of progressive illnesses of central nervous system that primarily affect the elderly and are characterized by movement symptoms, memory decline, and cognitive impairment. A number of variables, including the lack of a novel treatment, a steady rise in the patient population, and the high expense of care and treatment, have contributed to the growing significance of these diseases. In recent decades, we have gained a better understanding of the causes of diseases, but complex mechanisms of neuronal loss, combined with physiological factors that are incompatible, pose challenges in describing the pathogenic processes and devising effective treatments. Currently, there are no known treatments for most of these diseases, rendering them incurable. Therefore, there is a pressing need for therapeutic interventions that have the potential to effectively treat neurodegeneration. This study aimed to evaluate the efficacy of the ayurvedic herb Bacopa monnieri bioactive components against the therapeutic targets HTR1A, HTR1B, HTR2A, HTR2C, HTR7, alpha-synuclein, amyloid beta, and tau protein of Alzheimer's and Parkinson's illnesses. The docking analysis revealed the promising binding affinity with Quercetin, Apigenin, and Luteolin and Molecular mechanics/generalized Born surface area (MM/GBSA) further confirmed the stability of the complexes. In vitro investigation indicated that Quercetin is the most effective for treating AD and PD due to its considerable inhibition of alpha-synuclein production, whereas Luteolin is the favorable one for preventing both diseases by mitigating effects during Rotenone treatment. The future implications and constraints of the current study suggest that further validation in Invivo models of Alzheimer's and Parkinson's diseases is necessary to investigate the effects of Quercetin and Apigenin in the treatment of these conditions, as well as Luteolin and Quercetin for their prevention.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04224-6.}, } @article {pmid39959287, year = {2025}, author = {Leibold, NS and Kotiya, D and Verma, N and Despa, F}, title = {Detection of Amylin-β-amyloid Hetero-Oligomers by Enzyme-Linked Immunosorbent Assay.}, journal = {Bio-protocol}, volume = {15}, number = {3}, pages = {e5179}, pmid = {39959287}, issn = {2331-8325}, abstract = {Amylin is an amyloidogenic neuroendocrine hormone co-synthesized and co-secreted with insulin from the pancreas. It readily crosses the blood-brain barrier and synergistically forms mixed amyloid plaques with β-amyloid (Aβ) in brain parenchyma. Parenchymal amylin-Aβ plaques are found in both sporadic and early-onset familial Alzheimer's disease (AD), yet their (patho)physiological role remains elusive, particularly due to a lack of detection modalities for these mixed plaques. Previously, we developed an enzyme-linked immunosorbent assay (ELISA) capable of detecting amylin-Aβ hetero-oligomers in brain lysate and blood using a polyclonal anti-amylin antibody to capture hetero-oligomers and a monoclonal anti-Aβ mid-domain detection antibody combination. This combination allows for the recognition of distinct amylin epitopes, which remain accessible after amylin-Aβ oligomerization has begun, and precise detection of Aβ epitopes available after oligomer formation. The utility of this assay is evidenced in our previous report, wherein differences in hetero-oligomer content in brain tissue from patients with and without AD and patients with and without diabetes were distinguished. Additionally, using AD model rats, we provided evidence that our assay can be employed for the detection of amylin-Aβ in blood. This assay and protocol are important innovations in the field of AD research because they meet an unmet need to detect mixed amyloid plaques that, if targeted therapeutically, could reduce AD progression and severity. Key features • Detects amylin-Aβ hetero-oligomers in blood from patients with Alzheimer's disease. • Enables simultaneous, high-throughput analysis of hetero-oligomer content of brain and blood tissue. • Allows exploration into the amylin-Aβ interaction during AD pathogenesis, potentially leading to novel treatment mechanisms by controlling the amylin-Aβ interaction.}, } @article {pmid39958500, year = {2025}, author = {Moon, WJ}, title = {[Preface for Special Issue on Alzheimer's Disease: New Diagnostic Criteria, Treatment, and the Role of Neuroimaging].}, journal = {Journal of the Korean Society of Radiology}, volume = {86}, number = {1}, pages = {4-5}, pmid = {39958500}, issn = {2951-0805}, } @article {pmid39958499, year = {2025}, author = {Jeong, SY and Suh, CH and Lim, JS and Choi, Y and Kim, HS and Kim, SJ and Lee, JH}, title = {Anti-Amyloid Imaging Abnormality in the Era of Anti-Amyloid Beta Monoclonal Antibodies: Recent Updates for the Radiologist.}, journal = {Journal of the Korean Society of Radiology}, volume = {86}, number = {1}, pages = {17-33}, pmid = {39958499}, issn = {2951-0805}, abstract = {Lecanemab and donanemab have received full U.S. Food and Drug Administration (FDA) approval, and subsequently, lecanemab has been approved by the Korean FDA and it has recently entered commercial use in Korea. This has increased interest in anti-amyloid immunotherapy for Alzheimer's disease. Anti-amyloid immunotherapy has shown potential to modify the progression of the disease by specifically binding to amyloid β, a key pathological product in Alzheimer's disease, and eliminating accumulated amyloid plaques in the brain. However, this treatment can be accompanied by a side-effect, amyloid-related imaging abnormalities (ARIA), which requires periodic monitoring by MRI. It is crucial to detect ARIA and accurately assess the severity by radiology. The role of the radiologist is important in this context, requiring proficiency in basic knowledge of ARIA, and in diagnosing/evaluating ARIA. This review aims to comprehensively cover aspects of ARIA, including its definition, pathophysiology, incidence, risk factors, assessment of severity by radiology, differential diagnosis, and management.}, } @article {pmid39958494, year = {2025}, author = {Yim, Y and Moon, WJ}, title = {[Diagnosis and Treatment of Alzheimer's Disease: Current Update].}, journal = {Journal of the Korean Society of Radiology}, volume = {86}, number = {1}, pages = {6-16}, pmid = {39958494}, issn = {2951-0805}, abstract = {Alzheimer's disease, one of the most common causes of dementia, places a significant socioeconomic burden on aging societies. Encouragingly, extensive research on this neurocognitive disorder has finally uncovered the underpinnings of its pathophysiology, igniting a new era of treatment possibilities. Furthermore, the advent of amyloid PET imaging has allowed diagnosis of the amyloid pathology, the underlying cause of Alzheimer's disease. Notwithstanding the initial setback with aducanumab, the subsequent full FDA approval of two anti-amyloid antibody drugs (Lecanemab and Donanemab) has revolutionized the treatment landscape. These disease-modifying drugs are designed to target and remove beta-amyloid. This review covers the updated diagnostic criteria for Alzheimer's disease and discusses recent developments in treatment strategies, including these new disease-modifying drugs.}, } @article {pmid39958493, year = {2025}, author = {Kim, J and Kim, E and Park, M and Bae, YJ and Suh, CH and You, SH and Yim, Y and Lee, HJ and Choi, JW and Oh, SW and Moon, WJ and , }, title = {[Amyloid-Related Imaging Abnormalities in Anti-Amyloid Monoclonal Antibody Therapy for Alzheimer's Disease: Expert Recommendation for Standard MRI Protocol].}, journal = {Journal of the Korean Society of Radiology}, volume = {86}, number = {1}, pages = {34-44}, pmid = {39958493}, issn = {2951-0805}, abstract = {The introduction of anti-amyloid therapies for Alzheimer's disease (AD), such as lecanemab (Lequembi[®]), which was recently approved in Korea, necessitates careful monitoring for amyloid-related imaging abnormalities (ARIA) using brain MRI. To optimize ARIA monitoring in Korean clinical settings, the Korean Society of Neuroradiology (KSNR) and the Age and Neurodegeneration Imaging (ANDI) Study Group proposed MRI protocol recommendations on essential MR sequences, MRI acquisition parameters, timing and condition of MRI examinations, and essential details to provide a scientific basis for maximizing the safety and efficacy of AD treatment. A customized, standardized MRI protocol focusing on Korea's healthcare environment can improve ARIA management and ensure patient safety through early detection of potential anti-amyloid therapy side effects, thereby enhancing treatment quality.}, } @article {pmid39958092, year = {2025}, author = {Szczerba, M and Hejnosz, A and Majewski, G and Grodzka, O and Domitrz, I}, title = {Asthma as a Modifiable Risk Factor for Dementia and Neurodegeneration: A Systematic Review.}, journal = {Cureus}, volume = {17}, number = {1}, pages = {e77540}, pmid = {39958092}, issn = {2168-8184}, abstract = {Asthma remains a significant health concern, with increasing incidence rates and a notable annual mortality rate. Although the pathophysiology of asthma and its impact on the respiratory system are well understood, leading to effective symptom control, the broader effects of chronic localized airway inflammation on the rest of the body remain less clear. One potential consequence of this persistent state is an elevated risk of developing dementia across various etiologies, including Alzheimer's disease (AD). This systematic review aims to elucidate the underlying mechanisms driving this association, with a particular focus on identifying neurodegeneration markers detectable through laboratory and imaging studies. Additionally, it examines the impact of asthma treatments on this potential risk, exploring their possible contributory role in the pathogenesis of dementia. Such insights should inform the development of personalized treatment strategies for asthma patients, aimed at preventing or delaying the onset of dementia. However, further research is necessary to understand the underlying mechanisms of the connection fully and crucial to integrate it with routine clinical practice.}, } @article {pmid39957765, year = {2025}, author = {Meng, W and Chao, W and Kaiwei, Z and Sijia, M and Jiajia, S and Shijie, X}, title = {Bioactive compounds from Chinese herbal plants for neurological health: mechanisms, pathways, and functional food applications.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1537363}, pmid = {39957765}, issn = {2296-861X}, abstract = {Neurological disorders pose significant global public health challenges, with a rising prevalence and complex pathophysiological mechanisms that impose substantial social and economic burdens. Traditional Chinese Medicine (TCM), with its holistic approach and multi-target effects, has gained increasing attention in the treatment of neurological diseases. This review explores bioactive compounds derived from Chinese herbal plants, focusing on their mechanisms of action, underlying pathways, and potential applications in functional food development. The review highlights the neuroprotective properties of flavonoids, alkaloids, polysaccharides, and polyphenols found in key TCM herbs such as Scutellaria baicalensis, Salvia miltiorrhiza, Ligusticum chuanxiong, and Gastrodia elata. These compounds have demonstrated significant anti-inflammatory, antioxidant, and neurogenic effects, making them promising candidates for the prevention and treatment of neurological conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), and depression. Furthermore, the synergistic effects of TCM formulations targeting multiple signaling pathways offer advantages over single-target therapies, especially in combating neurodegenerative diseases. The review also discusses the challenges and future directions for integrating these bioactive compounds into functional foods and dietary supplements, aiming to improve neurological health and enhance clinical outcomes. Ultimately, this work aims to provide valuable insights into the potential of TCM-based interventions for promoting neurological well-being and addressing the global burden of neurological disorders.}, } @article {pmid39957504, year = {2025}, author = {Jiang, X and Zheng, Y and Sun, H and Dang, Y and Yin, M and Xiao, M and Wu, T}, title = {Fecal Microbiota Transplantation Improves Cognitive Function of a Mouse Model of Alzheimer's Disease.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {2}, pages = {e70259}, doi = {10.1111/cns.70259}, pmid = {39957504}, issn = {1755-5949}, support = {81971237//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Alzheimer Disease/therapy ; *Fecal Microbiota Transplantation ; Mice ; *Disease Models, Animal ; *Mice, Transgenic ; *Gastrointestinal Microbiome/physiology ; Cognition/physiology ; Amyloid beta-Peptides/metabolism ; Presenilin-1/genetics ; Male ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: A growing body of evidence suggests a link between the gut microbiota and Alzheimer's disease (AD), although the underlying mechanisms remain elusive. This study aimed to investigate the impact of fecal microbiota transplantation (FMT) on cognitive function in a mouse model of AD.

METHODS: Four-month-old 5 × FAD (familial Alzheimer's disease) mice underwent antibiotic treatment to deplete their native gut microbiota. Subsequently, they received FMT either weekly or every other day. After 8 weeks, cognitive function and β-amyloid (Aβ) load were assessed through behavioral testing and pathological analysis, respectively. The composition of the gut microbiota was analyzed using 16S rRNA sequencing.

RESULTS: Initial weekly FMT failed to alleviate memory deficits or reduce brain Aβ pathology in 5 × FAD mice. In contrast, FMT administered every other day effectively restored gut dysbiosis in 5 × FAD mice and decreased Aβ pathology and lipopolysaccharide levels in the colon and hippocampus. Mechanistically, FMT reduced the expression of amyloid β precursor protein, β-site APP cleaving enzyme 1, and presenilin-1, potentially by inhibiting the Toll-like receptor 4/inhibitor of kappa B kinase β/nuclear factor kappa-B signaling pathway. However, the cognitive benefits of FMT on 5 × FAD mice diminished over time.

CONCLUSION: These findings demonstrate the dose- and time-dependent efficacy of FMT in mitigating AD-like pathology, underscoring the potential of targeting the gut microbiota for AD treatment.}, } @article {pmid39957048, year = {2025}, author = {Kandeda, AK and Mezui, C and Kengni, S and Baldagai, N and Mabou, ST}, title = {Kalanchoe crenata Haw. (Crassulacea) Decreases Hippocampal Neuron Loss and Improves Memory and Executive Function in Aged Rats: Implications for Anti-Inflammatory and Antioxidant Mechanisms.}, journal = {Brain and behavior}, volume = {15}, number = {2}, pages = {e70261}, doi = {10.1002/brb3.70261}, pmid = {39957048}, issn = {2162-3279}, mesh = {Animals ; Rats ; *Plant Extracts/pharmacology/administration & dosage ; *Hippocampus/drug effects ; Male ; *Antioxidants/pharmacology/administration & dosage ; *Executive Function/drug effects/physiology ; *Rats, Wistar ; *Memory Disorders/drug therapy ; *Kalanchoe/chemistry ; *Galactose/pharmacology ; Neurons/drug effects ; Anti-Inflammatory Agents/pharmacology/administration & dosage ; Memory/drug effects ; Maze Learning/drug effects ; Oxidative Stress/drug effects ; Aging/drug effects/physiology ; Disease Models, Animal ; }, abstract = {INTRODUCTION: Alzheimer's disease is a neurodegenerative disease that alters learning and memory processes. Kalanchoe crenata (Crassulaceae) has long been used in Cameroonian traditional medicine to treat hypertension, malaria, and dementia. The present study aims to evaluate the anti-amnesic effect of an aqueous extract of K. crenata in D-galactose-treated rats and possible mechanisms of action.

METHODS: Memory impairment was induced in rats by subcutaneous injection of D-galactose (350 mg/kg) once daily for 30 days. At the end of the procedure, the animals were assessed for memory impairment using Morris water maze and object recognition tasks. Animals with memory impairment were divided into six groups of eight rats each and treated once daily for 24 days as follows: the negative control group received per os distilled water (10 mL/kg); the positive control group received donepezil (2 mg/kg, p.o.); and three test groups received the extract of K. crenata (62, 124, and 248 mg/kg, p.o.). A group of eight rats was added and served as a control group. After completion of the procedure, the memory deficit in rats was reassessed by the object recognition test on Day 15 of the treatment, the Morris water maze test on Day 18, and the open-field test on Day 24. At the end of behavioral experiments, the animals were sacrificed and some biochemical parameters in the hippocampus were estimated. In addition, histological analysis of the hippocampus was performed.

RESULTS: K. crenata significantly decreased the time to reach the platform and increased the time spent in the target quadrant of the Morris water maze. It also increased the discrimination index during the object recognition test. The extract significantly reversed D-galactose-induced oxidative stress and inflammation. This was confirmed by the attenuation of neuronal loss.

CONCLUSION: These findings suggest that K. crenata extract possesses an anti-amnesic-like effect probably mediated by antioxidant and anti-inflammatory mechanisms.}, } @article {pmid39956886, year = {2025}, author = {Almutary, AG and Begum, MY and Siddiqua, A and Gupta, S and Chauhan, P and Wadhwa, K and Singh, G and Iqbal, D and Padmapriya, G and Kumar, S and Kedia, N and Verma, R and Kumar, R and Sinha, A and Dheepak, B and Abomughaid, MM and Jha, NK}, title = {Unlocking the Neuroprotective Potential of Silymarin: A Promising Ally in Safeguarding the Brain from Alzheimer's Disease and Other Neurological Disorders.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39956886}, issn = {1559-1182}, abstract = {Medicinal plants and their phytochemicals have been extensively employed worldwide for centuries to address a diverse range of ailments, boasting a history that spans several decades. These plants are considered the source of numerous medicinal compounds. For instance, silymarin is a polyphenolic flavonoid extract obtained from the milk thistle plant or Silybum marianum which has been shown to have significant neuroprotective effects and great therapeutic benefits. Neurodegenerative diseases (NDs) are a class of neurological diseases that have become more prevalent in recent years, and although treatment is available, there is no complete cure developed yet. Silymarin utilizes a range of molecular mechanisms, including modulation of MAPK, AMPK, NF-κB, mTOR, and PI3K/Akt pathways, along with various receptors, enzymes, and growth factors. These mechanisms collectively contribute to its protective effects against NDs such as Alzheimer's disease, Parkinson's disease, and depression. Despite its safety and efficacy, silymarin faces challenges related to bioavailability and aqueous solubility, hindering its development as a clinical drug. This review highlights the molecular mechanisms underlying silymarin's neuroprotective effects, suggesting its potential as a promising therapeutic strategy for NDs.}, } @article {pmid39956674, year = {2025}, author = {Hammers, DB and Musema, J and Eloyan, A and Thangarajah, M and Taurone, A and La Joie, R and Touroutoglou, A and Vemuri, P and Kramer, J and Aisen, P and Dage, JL and Nudelman, KN and Kirby, K and Atri, A and Clark, D and Day, GS and Duara, R and Graff-Radford, NR and Grant, I and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, JC and Mendez, MF and Womack, K and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, SJ and Turner, RS and Wingo, TS and Wolk, DA and Carrillo, MC and Rabinovici, GD and Dickerson, BC and Apostolova, LG and , }, title = {Characterizing and validating 12-month reliable cognitive change in Early-Onset Alzheimer's Disease for use in clinical trials.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100075}, doi = {10.1016/j.tjpad.2025.100075}, pmid = {39956674}, issn = {2426-0266}, abstract = {BACKGROUND: As literature suggests that Early-Onset Alzheimer's Disease (EOAD) and late-onset AD may differ in important ways, need exists for randomized clinical trials for treatments tailored to EOAD. Accurately measuring reliable cognitive change in individual patients with EOAD will have great value for these trials.

OBJECTIVES: The current study sought to characterize and validate 12-month reliable change from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) neuropsychological battery.

DESIGN: Standardized regression-based (SRB) prediction equations were developed from age-matched cognitively intact participants within LEADS, and applied to clinically impaired participants from LEADS.

SETTING: Participants were recruited from outpatient academic medical centers.

PARTICIPANTS: Participants were enrolled in LEADS and diagnosed with amyloid-positive EOAD (n = 189) and amyloid-negative early-onset cognitive impairment not related to AD (EOnonAD; n = 43).

MEASUREMENT: 12-month reliable change (Z-scores) was compared between groups across cognitive domain composites, and distributions of individual participant trajectories were examined. Prediction of Z-scores by common AD biomarkers was also considered.

RESULTS: Both EOAD and EOnonAD displayed significantly lower 12-month follow-up scores than were predicted based on SRB equations, with declines more pronounced for EOAD across several domains. AD biomarkers of cerebral β-amyloid, tau, and EOAD-specific atrophy were predictive of 12-month change scores.

CONCLUSIONS: The current results support including EOAD patients in longitudinal clinical trials, and generate evidence of validation for using 12-month reliable cognitive change as a clinical outcome metric in clinical trials in EOAD cohorts like LEADS. Doing so will enhance the success of EOAD trials and permit a better understanding of individual responses to treatment.}, } @article {pmid39956324, year = {2025}, author = {Hussain, N and Khan, MM and Sharma, A and Singh, RK and Khan, RH}, title = {Beyond plaques and tangles: the role of Immune Cell Dysfunction in Alzheimer's disease.}, journal = {Neurochemistry international}, volume = {}, number = {}, pages = {105947}, doi = {10.1016/j.neuint.2025.105947}, pmid = {39956324}, issn = {1872-9754}, abstract = {The interplay between immune cell dysfunction and associated neuroinflammation plays a critical role in the pathogenesis of Alzheimer's disease. Neuroinflammation, orchestrated by microglia and peripheral immune cells, exacerbates synaptic dysfunction and neurodegeneration in AD. Emerging evidence suggests a systemic immune response in AD, challenging traditional views of neurocentric pathology. Therapeutic strategies targeting neuroinflammation hold promise, yet translating preclinical findings into clinical success remains elusive. This article presents recent advances in AD scientific studies, highlighting the pivotal role of immune cell dysfunction and signaling pathways in disease progression. We also discussed therapeutic studies targeting immune cell dysregulation, as treatment methods. This advocates for a paradigm shift towards holistic approaches that integrate peripheral and central immune responses, fostering a comprehensive understanding of AD pathophysiology and paving the way for transformative interventions.}, } @article {pmid39955261, year = {2025}, author = {Cline, EN and Antwi-Berko, D and Sundell, K and Johnson, E and Hyland, M and Zhang, H and Vanderstichele, H and Kaplow, J and Dean, RA and Stoops, E and Vanmechelen, E and Koel-Simmelink, MJA and Teunissen, CE and Sethuraman, G and Feaster, T and Siemers, E and Jerecic, J}, title = {Biofluid biomarker changes following treatment with sabirnetug (ACU193) in INTERCEPT-AD, a phase 1 trial in early Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100082}, doi = {10.1016/j.tjpad.2025.100082}, pmid = {39955261}, issn = {2426-0266}, abstract = {OBJECTIVE: Sabirnetug (ACU193) is a humanized monoclonal antibody selective for soluble amyloid beta oligomers (AβOs), synaptotoxins that are early and persistent triggers of Alzheimer's disease (AD). Sabirnetug pharmacodynamics were examined in the INTERCEPT-AD phase 1 study in mild cognitive impairment and mild dementia due to AD (NCT04931459) using biofluid biomarkers associated with Aβ and tau pathology, synaptic dysfunction, neuroinflammation, and neurodegeneration.

METHODS: INTERCEPT-AD was a randomized, first-in-human study of sabirnetug versus placebo administered as a single (SAD; 2, 10, 25, 60 mg/kg) or multiple (MAD; three doses of 10 or 60 mg/kg every 4 weeks [Q4W] or 25 mg/kg Q2W) ascending doses. Biomarkers were measured pre-/post-dose in CSF and EDTA-plasma. Correlations of biomarker changes versus dose, exposure duration, and target engagement were determined.

RESULTS: In MAD cohorts, CSF pTau181 decreased significantly (60 mg/kg Q4W, p = 0.049). VAMP2 decreased significantly at all doses (p ≤ 0.041); neurogranin decreased significantly at 60 mg/kg Q4W (p = 0.037). Aβ1-42/Aβ1-40 trended upward with sabirnetug dose. Aβ1-42/Aβ1-40 and neurogranin changes correlated with sabirnetug-AβO target engagement (p ≤ 0.01). Decreases in tTau, VAMP2, and neurogranin correlated with exposure duration (p ≤ 0.007). Plasma pTau181, pTau217, GFAP, and NfL trended lower.

DISCUSSION: Following three sabirnetug doses, changes in CSF and plasma biomarkers were observed. The CSF biomarker response increased with increasing dose and exposure duration, consistent with previous reports that sabirnetug reaches the central compartment and engages its AβO target. The ongoing phase 2 ALTITUDE-AD study (NCT06335173) will test whether sabirnetug's pharmacodynamic effects can be substantiated with a larger sample size and longer treatment duration.}, } @article {pmid39954841, year = {2025}, author = {Sripetchwandee, J and Kongkaew, A and Kumfu, S and Chattipakorn, N and Chattipakorn, SC}, title = {Modulating Mitochondrial Dynamics Preserves Cognitive Performance via Ameliorating Iron-Mediated Brain Toxicity in Iron-Overload Rats.}, journal = {European journal of pharmacology}, volume = {}, number = {}, pages = {177379}, doi = {10.1016/j.ejphar.2025.177379}, pmid = {39954841}, issn = {1879-0712}, abstract = {This study aimed to demonstrate the pharmacological efficacy of mitochondrial dynamics modulators, including the fission inhibitor Mdivi-1 and the fusion promoter M1, on parameters in brain and cognitive performance in rats with iron overload condition. Forty male Wistar rats were randomly categorized into two groups to receive either 10% dextrose in normal saline (control, n = 8) or iron dextran (100 mg/kg, Fe group, n = 32) via intraperitoneal injection for six weeks. During the fifth week of injection, rats in the Fe group were further categorized into four groups (n = 8 each) to subcutaneously injected with 1) vehicle (10% DMSO in normal saline), 2) deferoxamine (DFO) (25 mg/kg), 3) Mdivi-1 (1.2 mg/kg), or 4) M1 (2 mg/kg) for further two weeks. Behavioral tests, such as novel object recognition and Morris water maze, were performed post-treatment. Non-heme iron levels in plasma and parameters in the brain, including tight junction-related blood-brain barrier proteins, lipocalin-2, iron levels, ferroptosis, inflammation, mitochondrial function, dynamics, mitophagy, and Alzheimer-like proteins, were assessed. DFO mitigated iron overload condition and brain abnormalities, partially ameliorating cognitive decline. Mdivi-1 and M1 showed superior effects by preventing brain inflammation, LCN2 elevation, and mitochondrial dysfunction, restoring memory function (hippocampal-dependent manner) and spatial cognition (recognition manner). These findings indicate that modulating mitochondrial dynamics via fission inhibitor and fusion promoter could be promising novel pharmacological interventions for the brain in iron overload condition.}, } @article {pmid39954799, year = {2025}, author = {Chiang, MC and Nicol, CJB and Yang, YP and Chiang, T and Yen, C}, title = {The α-MG exhibits neuroprotective potential by reducing amyloid beta peptide-induced inflammation, oxidative stress, and tau aggregation in human neural stem cells.}, journal = {Brain research}, volume = {}, number = {}, pages = {149506}, doi = {10.1016/j.brainres.2025.149506}, pmid = {39954799}, issn = {1872-6240}, abstract = {Alzheimer's disease (AD) is the primary cause of dementia in older adults. Amyloid-beta (Aβ) and tau protein neurofibrillary tangles accumulate in the brain, leading to a progressive decline in memory, thinking, and behavior. Neuroinflammation and oxidative stress play a significant role in the development and progression of AD. Research has suggested that α-mangostin (α-MG), a compound found in mangosteen peels, may have anti-inflammatory, antioxidant, and neuroprotective properties, which could be beneficial in the context of AD. Further research is required to fully comprehend the therapeutic mechanisms of α-MG on AD and determine its potential as a treatment option. α-MG treatment significantly improves the viability of hNSCs exposed to Aβ and reduces caspase activity. Furthermore, this treatment is associated with a notable decrease in the expression of TNF-α and IL-1β. The treatment effectively restores alterations in the expression of IKK and NF-κB (p65) induced by Aβ, which are critical factors in the inflammatory response. Moreover, α-MG effectively reduces iNOS and COX-2 levels in Aβ-treated hNSCs, showcasing its potential therapeutic benefits. Treatment with α-MG protects hNSCs against Aβ-induced oxidative stress and effectively prevents the decrease in Nrf2 levels caused by Aβ. The treatment significantly enhances the activity and mRNA expression of Nrf2 downstream antioxidant target genes, including SOD-1, SOD-2, Gpx1, GSH, catalase, and HO-1, compared to Aβ-treated controls. α-MG significantly reduces tau and ubiquitin (Ub) aggregates, enhances proteasome activity, and increases the mRNA expression of HSF1, HSP27, HSP70, and HSP90 in Tau-GFP-expressed hNSCs. This study significantly improves our comprehension of the anti-inflammatory, antioxidative stress, and anti-aggregated effects of α-MG. These findings have potential therapeutic implications for developing treatments that could delay AD progression and promote healthy aging.}, } @article {pmid39954619, year = {2025}, author = {Qi, Y and Zhang, J and Zhang, Y and Zhu, H and Wang, J and Xu, X and Jin, S and Wang, C and Zhang, F and Zhao, M and Wu, Z and Zhu, H and Yan, P}, title = {Curcuma wenyujin extract alleviates cognitive deficits and restrains pyroptosis through PINK1/Parkin mediated autophagy in Alzheimer's disease.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {139}, number = {}, pages = {156482}, doi = {10.1016/j.phymed.2025.156482}, pmid = {39954619}, issn = {1618-095X}, abstract = {BACKGROUND: Pyroptosis and mitophagy have gained significant attention in Alzheimer's disease (AD) treatment. Curcumae Radix (CR), the dried radix of Curcuma wenyujin Y. H. Chen et C. Ling, is a traditional Chinese medicine (TCM) extensively utilized for neurological disorders. Yet, its impact and mechanistic role in AD remain unclear.

PURPOSE: This study aims to explore the active fraction of CR in AD treatment and its potential mechanisms.

METHODS: CR extracts were qualitatively analyzed using UHPLC-Triple-TOF/MS. Aβ1-42-induced mice received daily intragastric drug treatments for three weeks. Cognitive abilities of AD model mice were assessed through Y maze, novel object recognition, and eight-arm maze tests. Therapeutic targets of CR extracts were identified using quantitative proteomics. In both in vivo and in vitro settings, effects on pyroptosis and mitophagy were examined by Western blot (WB), immunofluorescence (IF) staining, and ELISA assays.

RESULTS: The ethyl acetate (EAC) fraction of CR extract exhibited optimal anti-AD effects. CR extracts enhanced memory and cognition in Aβ1-42-induced mice, improved neuronal morphology, and reduced Aβ accumulation in the brain. Proteomics analysis suggested the anti-AD properties of CR might involve inflammation reduction, cell survival enhancement, and mitophagy modulation. CR treatments in both AD mice and Aβ-induced SH-SY5Y cells resulted in reduced pyroptosis, increased LC3 and Beclin1 levels, and activation of the PINK1/Parkin pathway.

CONCLUSION: The EAC fraction of CR is effective in AD treatment by mitigating pyroptosis, reducing neuroinflammation, and promoting mitophagy, actions facilitated through the PINK1/Parkin pathway.}, } @article {pmid39954613, year = {2025}, author = {Kaur, N and Gupta, S and Pal, J and Bansal, Y and Bansal, G}, title = {Design of BBB permeable BACE-1 inhibitor as potential drug candidate for Alzheimer disease: 2D-QSAR, molecular docking, ADMET, molecular dynamics, MMGBSA.}, journal = {Computational biology and chemistry}, volume = {116}, number = {}, pages = {108371}, doi = {10.1016/j.compbiolchem.2025.108371}, pmid = {39954613}, issn = {1476-928X}, abstract = {BACE-1 is a prime therapeutic target for treatment of Alzheimer disease as it cleaves the β-site of APP leading to formation of amyloid plaques. A dataset of 229 benzo-fused heterocyclic compounds reported as BACE-1 inhibitors was utilized to develop various QSAR models (regression and classification) utilizing Monte Carlo algorithm. The dataset was randomly split into different sets for generation of models. The IIC and CCC were calculated to increase the predictive ability of generated models. Among various models, split-1 of Model-1 demonstrated the highest robustness and predictive accuracy for pIC50 values. Internal and external validation was performed which further confirmed the reliability of this model. Structural features responsible for enhancing or reducing pIC50 values were identified and were utilized to design library of 255 compounds. Compounds having pIC50> 5.0 were further screened on the basis of BBB permeability predicted via ADMET lab 3.0. Total nineteen compounds were found to be BBB permeable which were then docked into PDB: 2WJO. Finally, four compounds with high docking scores were identified and compared with existing BACE-1 inhibitor. MD simulations and MMGBSA analysis were performed and results demonstrated minimal fluctuations throughout the simulation of 100 ns with good binding affinity. This study highlights development of robust QSAR model which assists to design new compounds and predicts them for anti β-secretase activity. Design of novel four molecules were proposed which exhibits good potency, BBB permeability, excellent binding affinity and stable conformations with BACE-1 making them promising candidates for further development.}, } @article {pmid39954353, year = {2025}, author = {Li, Y and Zhang, Q and Wang, X and Liu, Z and Chen, H and Su, Z and Xu, Y and Zhang, W and Du, Y and Tan, Z and Huang, S and Liu, W and Sang, Z}, title = {Development of novel rivastigmine derivatives as selective BuChE inhibitors for the treatment of AD.}, journal = {Bioorganic chemistry}, volume = {157}, number = {}, pages = {108245}, doi = {10.1016/j.bioorg.2025.108245}, pmid = {39954353}, issn = {1090-2120}, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder among the elderly, and there are currently no effective treatment options available. Selective inhibition of butyrylcholinesterase (BuChE) has emerged as a promising strategy for AD therapeutics. In this study, we identified compound 6a as a lead candidate derived from the structural modification of rivastigmine. Our findings indicated that 6a acts as a potent selective BuChE inhibitor, demonstrating an IC50 value of 0.33 μM (SI > 151.5). Furthermore, compound 6a displayed favorable neuroprotective properties, along with excellent blood-brain barrier (BBB) permeability and drug-like characteristics. In vivo investigations utilizing an AlCl3-induced zebrafish model of AD revealed that compound 6a significantly improved cognitive function, which was further supported by its ability to mitigate memory impairment induced by scopolamine. Overall, these results highlight compound 6a as a promising selective BuChE inhibitor with potential therapeutic implications for the treatment of Alzheimer's disease.}, } @article {pmid39953968, year = {2025}, author = {Schaller, E and Hofmann, J and Maher, P and Stigloher, C and Decker, M}, title = {Visualizing Intracellular Localization of Natural-Product-Based Chemical Probes Using Click-Correlative Light and Electron Microscopy.}, journal = {ACS chemical biology}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschembio.4c00849}, pmid = {39953968}, issn = {1554-8937}, abstract = {Flavonoids such as sterubin and fisetin─and derivatives thereof─show strong neuroprotective effects in vitro as well as in vivo, combined with negligible toxicity and can therefore be considered novel treatment options for neurodegenerative diseases such as Alzheimer's disease. However, their subcellular locations responsible for neuroprotection and exact modes of action still remain unclear. Here, we present chemical probes based on both flavonoids sterubin and fisetin that were utilized in fluorescence microscopy and click-correlative light and electron microscopy to detect and visualize the localization of specific intracellular targets. We successfully adapted the workflow of correlative light and electron microscopy to a click-chemistry-based approach in a murine hippocampal cell line (HT22) on ultrathin resin sections making visualization of a small molecule for the first time possible in this setup. Utilizing this newly adapted technique, we could demonstrate that sterubin and fisetin show specific enrichment in the endoplasmic reticulum.}, } @article {pmid39953602, year = {2025}, author = {Wu, DP and Wei, YS and Hou, LX and Du, YX and Yan, QQ and Liu, LL and Zhao, YD and Yan, RY and Yu, C and Zhong, ZG and Huang, JL}, title = {Circular RNA APP contributes to Alzheimer's disease pathogenesis by modulating microglial polarization via miR-1906/CLIC1 axis.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {44}, pmid = {39953602}, issn = {1758-9193}, support = {BK20231179//Natural Science Foundation of Jiangsu Province/ ; 82003718//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; *RNA, Circular/metabolism/genetics ; *Microglia/metabolism ; *Chloride Channels/metabolism/genetics ; *MicroRNAs/metabolism/genetics ; Mice ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Mice, Transgenic ; Hippocampus/metabolism/pathology ; Male ; Humans ; Disease Models, Animal ; }, abstract = {BACKGROUND: Abnormal microglial polarization phenotypes contribute to the pathogenesis of Alzheimer's disease (AD). Circular RNAs (circRNAs) have garnered increasing attention due to their significant roles in human diseases. Although research has demonstrated differential expression of circRNAs in AD, their specific functions in AD pathogenesis remain largely unexplored.

METHODS: CircRNA microarray was performed to identify differentially expressed circRNAs in the hippocampus of APP/PS1 and WT mice. The stability of circAPP was assessed via RNase R treatment assay. CircAPP downstream targets miR-1906 and chloride intracellular channel 1 (CLIC1) were identified using bioinformatics and proteomics, respectively. RT-PCR assay was conducted to detect the expression of circAPP, miR-1906 and CLIC1. Morris water maze (MWM) test, passive avoidance test and novel object recognition task were used to detect cognitive function of APP/PS1 mice. Microglial M1/M2 polarization and AD pathology were assessed using Western blot, flow cytometry and Golgi staining assays. CLIC1 expression and channel activity were evaluated using Western blot and functional chloride channel assays, respectively. The subcellular location of circAPP was assessed via FISH and RT-PCR assays. RNA pull-down assay was performed to detect the interaction of miR-1906 with circAPP and 3' untranslated region (3'UTR) of CLIC1 mRNA.

RESULTS: In this study, we identified a novel circRNA, named circAPP, that is encoded by amyloid precursor protein (APP) and is implicated in AD. CircAPP is a stable circRNA that was upregulated in Aβ-treated microglial cells and the hippocampus of APP/PS1 mice. Downregulation of circAPP or CLIC1, or overexpression of miR-1906 in microglia modulated microglial M1/M2 polarization in Aβ-treated microglial cells and the hippocampus of APP/PS1 mice, and improved AD pathology and the cognitive function of APP/PS1 mice. Further results revealed that circAPP was mainly distributed in the cytoplasm, and circAPP could regulate CLIC1 expression and channel activity by interacting with miR-1906 and affecting miR-1906 expression, thereby regulating microglial polarization in AD.

CONCLUSIONS: Taken together, our study elucidates the regulatory role of circAPP in AD microglial polarization via miR-1906/CLIC1 axis, and suggests that circAPP may act as a critical player in AD pathogenesis and represent a promising therapeutic target for AD.}, } @article {pmid39953559, year = {2025}, author = {Liang, Y and Xie, S and Jia, J}, title = {Pathway-based network medicine identifies novel natural products for Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {43}, pmid = {39953559}, issn = {1758-9193}, support = {No.2021ZD0201802//the STI2030-Major Projects/ ; U20A20354//the Key Project of the National Natural Science Foundation of China/ ; Z201100005520016, Z201100005520017//Beijing Brain Initiative from Beijing Municipal Science & Technology Commission/ ; CX23YZ15//the grant from the Chinese Institutes for Medical Research/ ; 31627803//the National Key Scientific Instrument and Equipment Development Project/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/metabolism ; *Mice, Transgenic ; Mice ; *Biological Products/pharmacology/therapeutic use ; *Mice, Inbred C57BL ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics ; Gene Regulatory Networks/drug effects ; Male ; Maze Learning/drug effects ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia, characterized by a complex pathogenesis that complicates the development of effective treatments. Natural products are promising multitarget agents because of their ability to interact with multiple molecular targets. Network-based medicine presents a robust strategy for discovering such agents, which can address the intricate mechanisms underlying AD.

METHODS: In this study, we constructed an AD-related pathway-gene network via text mining and pathway database construction. This network facilitated the identification of natural products that target multiple pathways and genes associated with AD. We evaluated the safety profiles of two selected natural products in C57BL/6J mice through assessments of general behavior, body weight changes, vital organ weight and morphology, and hematological and biochemical parameters. APP/PS1 transgenic mice were subsequently treated with these natural products-either individually or in combination-to assess their therapeutic effects. Cognitive function was evaluated via behavioral tests, such as novel object recognition, Y-maze, and Morris water maze tests. Additionally, immunohistochemical staining and enzyme-linked immunosorbent assays were performed to examine Aβ-associated pathological changes. Transcriptomic analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to elucidate the mechanisms underlying the effects of the natural products.

RESULTS: The constructed AD-related pathway-gene network encompassed three perspectives: (i) Most Studied Pathways (21 pathways with 5325 genes), (ii) Gene-Associated Pathways (26 pathways with 2557 genes), and (iii) Popular Pathways (24 pathways with 3435 genes). Two natural products, (-)-Vestitol and Salviolone, were selected for further validation. Their safety was confirmed in C57BL/6J mice. Notably, the combination of (-)-Vestitol and Salviolone synergistically affected cognitive function in APP/PS1 transgenic mice by reducing Aβ deposition and lowering toxic soluble Aβ levels in the brain. Transcriptomic analysis and qRT-PCR experiments revealed that their combination regulated AD-related pathways and genes more comprehensively, particularly affecting the Neuroactive ligand-receptor interaction and Calcium signaling pathway.

CONCLUSIONS: Our findings demonstrate that screening potential natural products through an AD-related pathway-gene network is a promising strategy for discovering novel therapeutics for AD. The therapeutic potential of (-)-Vestitol and Salviolone as novel candidates for AD treatment is underscored by their synergistic effects, attributed to their comprehensive regulation of AD-associated pathways and genes.}, } @article {pmid39953505, year = {2025}, author = {Xie, Z and Li, L and Hou, W and Fan, Z and Zeng, L and He, L and Ji, Y and Zhang, J and Wang, F and Xing, Z and Wang, Y and Ye, Y}, title = {Critical role of Oas1g and STAT1 pathways in neuroinflammation: insights for Alzheimer's disease therapeutics.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {182}, pmid = {39953505}, issn = {1479-5876}, support = {196//Guangzhou Municipal Research Collaborative Innovation Projects/ ; 82101327//National Natural Science Foundation of China/ ; 2022A1515012362//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 202201020111//Guangzhou Municipal Science and Technology Project/ ; }, mesh = {*Alzheimer Disease/genetics/metabolism/pathology ; Animals ; *Microglia/metabolism/pathology ; *STAT1 Transcription Factor/metabolism/genetics ; *2',5'-Oligoadenylate Synthetase/metabolism/genetics ; *Neuroinflammatory Diseases/metabolism ; *Signal Transduction ; Mice ; Humans ; Gene Regulatory Networks ; Mice, Inbred C57BL ; Gene Expression Regulation ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) has a significant impact on an individual's health and places a heavy burden on society. Studies have emphasized the importance of microglia in the progression and development of AD. Interferon responses and Interferon-stimulated genes (ISGs) significantly function in neuroinflammatory and neurodegenerative diseases involving AD. Therefore, further exploration of the relationship among microglia, ISGs, and neuroinflammation in AD is warranted.

METHODS: Microglia datasets from the GEO database were retrieved, along with additional microglia RNA-seq data from laboratory mice. Weighted Correlation Network Analysis was used on the training dataset to identify gene co-expression networks. Genes from the black module were intersected with interferon-stimulated genes, and differentially expressed genes (DEGs) were identified. Machine learning algorithms were applied to DEGs, and genes selected by both methods were identified as hub genes, with ROC curves used to evaluate their diagnostic accuracy. Gene Set Enrichment Analysis was performed to reveal functional pathways closely relating to hub genes. Microglia cells were transfected with siRNAs targeting Oas1g and STAT1. Total RNA from microglia cells and mouse brain tissues was extracted, reverse-transcribed, and analyzed via qRT-PCR. Proteins were extracted from cells, quantified, separated by SDS-PAGE, transferred to PVDF membranes, and probed with antibodies. Microglia cells were fixed, permeabilized, blocked, and stained with antibodies for STAT1, then visualized and photographed.

RESULTS: Bioinformatics and machine learning algorithms revealed that Oas1g was identified as a hub gene, with an AUC of 0.812. Enrichment Analysis revealed that Oas1g is closely associated with interferon-related pathways. Expression of Oas1g was validated in AD mouse models, where it was significantly upregulated after microglial activation. Knockdown experiments suggested siOas1g attenuated the effect of siSTAT1, and the expressions of STAT1 and p-STAT1 were elevated. siOas1g could reverse the effect of siSTAT1, indicating that Oas1g potentially regulates the ISGs through the STAT1 pathway.

CONCLUSION: We demonstrated that Oas1g was identified as a hub ISG in AD and can downregulate the activation of IFN-β and STAT1, reducing the expression of ISGs in neuroinflammation. Oas1g might potentially be a beneficial candidate for both prevention and treatment of AD.}, } @article {pmid39952696, year = {2025}, author = {Supuran, CT}, title = {Multi- and polypharmacology of carbonic anhydrase inhibitors.}, journal = {Pharmacological reviews}, volume = {77}, number = {1}, pages = {100004}, doi = {10.1124/pharmrev.124.001125}, pmid = {39952696}, issn = {1521-0081}, mesh = {*Carbonic Anhydrase Inhibitors/pharmacology/therapeutic use/chemistry ; Humans ; Animals ; *Carbonic Anhydrases/metabolism/drug effects ; *Polypharmacology ; }, abstract = {Eight genetically distinct families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) have been described in organisms overall in the phylogenetic tree. They catalyze the hydration of CO2 to bicarbonate and protons and are involved in pH regulation, chemosensing, and metabolism. The 15 α-CA isoforms present in humans are pharmacological drug targets known for decades, their inhibitors being used as diuretics, antiglaucoma, antiepileptic, or antiobesity drugs, as well as for the management of acute mountain sickness, idiopathic intracranial hypertension, and recently, as antitumor theragnostic agents. Other potential applications include the use of CA inhibitors (CAIs) in inflammatory conditions, cerebral ischemia, neuropathic pain, or Alzheimer/Parkinson disease management. CAs from pathogenic bacteria, fungi, protozoans, and nematodes have started to be considered as drug targets in recent years, with notable advances being registered. CAIs have a complex multipharmacology probably unique to this enzyme, which has been exploited intensely but may lead to other relevant applications in the future due to the emergence of drug design approaches that afforded highly isoform-selective compounds for most α-CAs known to date. They belong to a multitude of chemical classes (sulfonamides and isosteres, [iso]coumarins and related compounds, mono- and dithiocarbamates, selenols, ninhydrines, boronic acids, benzoxaboroles, etc). The polypharmacology of CAIs will also be discussed because drugs originally discovered for the treatment of non-CA related conditions (topiramate, zonisamide, celecoxib, pazopanib, thiazide, and high-ceiling diuretics) show effective inhibition against many CAs, which led to their repurposing for diverse pharmacological applications. SIGNIFICANCE STATEMENT: CAIs have multiple pharmacologic applications, such as diuretics, antiglaucoma, antiepileptic, antiobesity, antiacute mountain sickness, anti-idiopathic intracranial hypertension, and antitumor drugs. Their use in inflammatory conditions, cerebral ischemia, neuropathic pain, or neurodegenerations has started to be investigated recently. Parasite carbonic anhydrases are also drug targets for anti-infectives with novel mechanisms of action that can bypass drug resistance to commonly used agents. Drugs discovered for the management of other conditions that effectively inhibit these enzymes exert interesting polypharmacologic effects.}, } @article {pmid39952328, year = {2025}, author = {Bashir, B and Gulati, M and Vishwas, S and Gupta, G and Dhanasekaran, M and Paudel, KR and Chellappan, DK and Anand, K and Negi, P and Singh, PK and Rajput, A and Dua, K and Singh, SK}, title = {Bridging gap in the treatment of Alzheimer's disease via postbiotics: Current practices and future prospects.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {102689}, doi = {10.1016/j.arr.2025.102689}, pmid = {39952328}, issn = {1872-9649}, abstract = {Aging is an extremely significant risk associated with neurodegeneration. The most prevalent neurodegenerative disorders (NDs), such as Alzheimer's disease (AD) are distinguished by the prevalence of proteinopathy, aberrant glial cell activation, oxidative stress, neuroinflammation, defective autophagy, cellular senescence, mitochondrial dysfunction, epigenetic changes, neurogenesis suppression, increased blood-brain barrier permeability, and intestinal dysbiosis that is excessive for the patient's age. Substantial body studies have documented a close relationship between gut microbiota and AD, and restoring a healthy gut microbiota may reduce or even ameliorate AD symptoms and progression. Thus, control of the microbiota in the gut has become an innovative model for clinical management of AD, and rising emphasis is focused on finding new techniques for preventing and/or managing the disease. The etiopathogenesis of gut microbiota in driving AD progression and supplementing postbiotics as a preventive and therapeutic treatment for AD is discussed. The review additionally discusses the use of postbiotics in AD prophylaxis and therapy, portraying them as substances that address senescence-triggered dysfunctions and are worthy of translating from bench to biopharmaceutical market in response to "silver consumers" needs. The current review examines and evaluates the impact of postbiotics as whole and specific metabolites, such as short-chain fatty acids (SCFAs), lactate, polyamines, polyphenols, tryptophan metabolites, exopolysaccharides, and bacterial extracellular vesicles, on the aging-associated processes that reinforce AD. Moreover, it provides an overview of the most recent data from both clinical and preclinical research involving the use of postbiotics in AD.}, } @article {pmid39952201, year = {2025}, author = {Cheng, M and Li, M and Zhang, Y and Gu, X and Gao, W and Zhang, S and Liu, J}, title = {Exploring the mechanism of PPCPs on human metabolic diseases based on network toxicology and molecular docking.}, journal = {Environment international}, volume = {196}, number = {}, pages = {109324}, doi = {10.1016/j.envint.2025.109324}, pmid = {39952201}, issn = {1873-6750}, abstract = {This research endeavor seeks to delve into the potential mechanisms by which pharmaceutical and personal care products (PPCPs), recognized as emerging pollutants, could contribute to the human metabolic disorders and then trigger metabolic diseases. Therefore, we have selected lipid and atherosclerosis, Alzheimer's disease, and type Ⅱ diabetes mellitus as representative metabolic diseases, aiming to systematically explore the critical molecular pathways that may be disrupted by PPCPs for the metabolic disease development. By employing advanced network toxicology and molecular docking techniques, we have successfully elucidated the molecular mechanisms that trigger the three diseases. We pinpointed the potential targets associated with the disease by leveraging databases including PubChem, ADEMTlab2.0, SwissADME, and GeneCards. We further employed STRING analysis and Cytoscape software to pinpoint the core targets that were most significantly associated with these metabolic diseases. In addition, enrichment analysis of these core targets was conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways within the David database. To obtain the structural aspects of the target proteins, we also employed AlphaFold 3 for protein structure prediction. Finally, we validated the binding affinity of PPCPs to these target proteins using molecular docking with AutoDock Vina. Our findings suggested that PPCPs could potentially trigger metabolic diseases by modulating the expression of microRNAs, influencing cellular apoptosis and proliferation, and affecting signal transduction pathways. Interestingly, we also found the correlations among lipid and atherosclerosis, Alzheimer's disease, and type Ⅱ diabetes mellitus. Taken together, our study provides innovative insights into both the mechanisms of how environmental pollutants trigger human diseases and revealing the correlations among different diseases, thereby laying a theoretical foundation for disease prevention and treatment.}, } @article {pmid39951718, year = {2025}, author = {Shimada, H and Doi, T and Tsutsumimoto, K and Makino, K and Harada, K and Tomida, K and Morikawa, M and Makizako, H}, title = {A New Computer-Based Cognitive Measure for Early Detection of Dementia Risk (Japan Cognitive Function Test): Validation Study.}, journal = {Journal of medical Internet research}, volume = {27}, number = {}, pages = {e59015}, doi = {10.2196/59015}, pmid = {39951718}, issn = {1438-8871}, mesh = {Humans ; *Dementia/diagnosis ; Aged ; Female ; Male ; Japan ; Early Diagnosis ; Aged, 80 and over ; Cognitive Dysfunction/diagnosis ; Cognition ; Neuropsychological Tests/standards/statistics & numerical data ; Diagnosis, Computer-Assisted/methods ; }, abstract = {BACKGROUND: The emergence of disease-modifying treatment options for Alzheimer disease is creating a paradigm shift in strategies to identify patients with mild symptoms in primary care settings. Systematic reviews on digital cognitive tests reported that most showed diagnostic performance comparable with that of paper-and-pencil tests for mild cognitive impairment and dementia. However, most studies have small sample sizes, with fewer than 100 individuals, and are based on case-control or cross-sectional designs.

OBJECTIVE: This study aimed to examine the predictive validity of the Japanese Cognitive Function Test (J-Cog), a new computerized cognitive battery test, for dementia development.

METHODS: We randomly assigned 2520 older adults (average age 72.7, SD 6.7 years) to derivation and validation groups to determine and validate cutoff points for the onset of dementia. The Mini-Mental State Examination (MMSE) was used for comparison purposes. The J-Cog consists of 12 tasks that assess orientation, designation, attention and calculation, mental rotation, verbal fluency, sentence completion, working memory, logical reasoning, attention, common knowledge, word memory recall, and episodic memory recall. The onset of dementia was monitored for 60 months. In the derivation group, receiver operating characteristic curves were plotted to determine the MMSE and J-Cog cutoff points that best discriminated between the groups with and without dementia. In the validation group, Cox proportional regression models were developed to predict the associations of the group classified using the cutoff points of the J-Cog or MMSE with dementia incidence. Harrell C-statistic was estimated to summarize how well a predicted risk score described an observed sequence of events. The Akaike information criterion was calculated for relative goodness of fit, where lower absolute values indicate a better model fit.

RESULTS: Significant hazard ratios (HRs) for dementia incidence were found using the MMSE cutoff between 23 and 24 point (HR 1.93, 95% CI 1.13-3.27) and the J-Cog cutoff between 43 and 44 points (HR 2.42, 95% CI 1.50-3.93). In the total validation group, the C-statistic was above 0.8 for all cutoff points. Akaike information criterion with MMSE cutoff between 23 and 24 points as a reference showed a poor fit for MMSE cutoff between 28 and 29 points, and a good fit for the J-Cog cutoff between 43 and 44 points.

CONCLUSIONS: The J-Cog has higher accuracy in predicting the development of dementia than the MMSE and has advantages for use in the community as a test of cognitive function, which can be administered by nonprofessionals.}, } @article {pmid39951414, year = {2025}, author = {Yan, H and Mubonanyikuzo, V and Komolafe, TE and Zhou, L and Wu, T and Wang, N}, title = {Hybrid-RViT: Hybridizing ResNet-50 and Vision Transformer for Enhanced Alzheimer's disease detection.}, journal = {PloS one}, volume = {20}, number = {2}, pages = {e0318998}, doi = {10.1371/journal.pone.0318998}, pmid = {39951414}, issn = {1932-6203}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Magnetic Resonance Imaging/methods ; *Deep Learning ; Brain/diagnostic imaging/pathology ; Neural Networks, Computer ; Male ; Female ; Aged ; }, abstract = {Alzheimer's disease (AD) is a leading cause of disability worldwide. Early detection is critical for preventing progression and formulating effective treatment plans. This study aims to develop a novel deep learning (DL) model, Hybrid-RViT, to enhance the detection of AD. The proposed Hybrid-RViT model integrates the pre-trained convolutional neural network (ResNet-50) with the Vision Transformer (ViT) to classify brain MRI images across different stages of AD. The ResNet-50 adopted for transfer learning, facilitates inductive bias and feature extraction. Concurrently, ViT processes sequences of image patches to capture long-distance relationships via a self-attention mechanism, thereby functioning as a joint local-global feature extractor. The Hybrid-RViT model achieved a training accuracy of 97% and a testing accuracy of 95%, outperforming previous models. This demonstrates its potential efficacy in accurately identifying and classifying AD stages from brain MRI data. The Hybrid-RViT model, combining ResNet-50 and ViT, shows superior performance in AD detection, highlighting its potential as a valuable tool for medical professionals in interpreting and analyzing brain MRI images. This model could significantly improve early diagnosis and intervention strategies for AD.}, } @article {pmid39951299, year = {2025}, author = {Wu, Z and Xu, L and Xie, Y and Sambangi, A and Swaminathan, S and Pei, Z and Ji, W and Li, Z and Guo, Y and Li, Z and Chen, G}, title = {Brain-Wide Neuroregenerative Gene Therapy Improves Cognition in a Mouse Model of Alzheimer's Disease.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e2410080}, doi = {10.1002/advs.202410080}, pmid = {39951299}, issn = {2198-3844}, support = {202206060002//Key Technologies Research and Development Program of Guangzhou Municipality/ ; 2021ZT09Y552//Guangdong Provincial Introduction of Innovative Research and Development Team/ ; 2022A1515012294//Natural Science Foundation of Guangdong Province/ ; }, abstract = {Alzheimer's disease (AD) is a progressive and irreversible brain disorder with extensive neuronal loss in the neocortex and hippocampus. Current therapeutic interventions focus on the early stage of AD but lack effective treatment for the late stage of AD, largely due to the inability to replenish the lost neurons and repair the broken neural circuits. In this study, by using engineered adeno-associated virus vectors that efficiently cross the blood-brain-barrier in the mouse brain, a brain-wide neuroregenerative gene therapy is developed to directly convert endogenous astrocytes into functional neurons in a mouse model of AD. It is found that ≈500 000 new neurons are regenerated and widely distributed in the cerebral cortex and hippocampus. Importantly, it is demonstrated that the converted neurons can integrate into pre-existing neural networks and improve various cognitive performances in AD mice. Chemogenetic inhibition of the converted neurons abolishes memory enhancement in AD mice, suggesting a pivotal role for the newly converted neurons in cognitive restoration. Together, brain-wide neuroregenerative gene therapy may provide a viable strategy for the treatment of AD and other brain disorders associated with massive neuronal loss.}, } @article {pmid39951190, year = {2025}, author = {Brennan, SO and Tinworth, AC}, title = {Genetically Proxied Phosphodiesterase Type 5 (PDE5) Inhibition and Risk of Dementia: A Drug Target Mendelian Randomization Study.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39951190}, issn = {1559-1182}, abstract = {Phosphodiesterase-5 (PDE5) inhibitors have gained interest as a potential treatment for dementia. However, current evidence is limited to observational and pre-clinical studies. We conducted a drug-target Mendelian randomization (MR) analysis to investigate the on-target effects of pharmacological PDE5 inhibition on dementia subtypes and related phenotypes. We selected variants from around the PDE5A locus associated with diastolic and systolic blood pressure, as well as circulating PDE5A levels, to create three instruments for genetically proxied PDE5A inhibition. Using two-sample MR, we validated the instruments against erectile dysfunction and pulmonary arterial hypertension before assessing their associations with dementia subtypes, dementia-related proteins, and neuroimaging traits. After correcting for multiple comparisons, genetically proxied PDE5 inhibition, per one SD lower in diastolic blood pressure, was associated with higher odds of Alzheimer's disease (OR 1.09, 95% CI 1.07-1.11) and Lewy body dementia (OR 1.32, 95% CI 1.23-1.41), but a trend towards lower odds of vascular dementia across all instruments. Genetically proxied PDE5 inhibition was associated with both beneficial and adverse effects on brain MRI traits. This included lower volumes of white matter hyperintensities (SD change - 0.035, 95% CI - 0.025, - 0.045), indicating potential benefits, but also reduced volumes of other structures, including the thalamus, suggesting potential adverse effects. PDE5 inhibition was associated with the concentrations of several proteins implicated in dementia pathophysiology. Our findings suggest that while PDE5 inhibition may be associated with a lower risk of vascular dementia, possibly by preventing white matter hyperintensities, it may increase risk of Alzheimer's disease and Lewy body dementia, warranting further investigation before clinical trials.}, } @article {pmid39951189, year = {2025}, author = {Ayyubova, G and Madhu, LN}, title = {Microglial NLRP3 Inflammasomes in Alzheimer's Disease Pathogenesis: From Interaction with Autophagy/Mitophagy to Therapeutics.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39951189}, issn = {1559-1182}, abstract = {The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, discovered 20 years ago, is crucial in controlling innate immune reactions in Alzheimer's disease (AD). By initiating the release of inflammatory molecules (including caspases, IL-1β, and IL-18), the excessively activated inflammasome complex in microglia leads to chronic inflammation and neuronal death, resulting in the progression of cognitive deficiencies. Even though the involvement of NLRP3 has been implicated in neuroinflammation and widely explored in several studies, there are plenty of controversies regarding its precise roles and activation mechanisms in AD. Another prominent feature of AD is impairment in microglial autophagy, which can be either the cause or the consequence of NLRP3 activation and contributes to the aggregation of misfolded proteins and aberrant chronic inflammatory state seen in the disease course. Studies also demonstrate that intracellular buildup of dysfunctional and damaged mitochondria due to defective mitophagy enhances inflammasome activation, further suggesting that restoration of impaired autophagy and mitophagy can effectively suppress it, thereby reducing inflammation and protecting microglia and neurons. This review is primarily focused on the role of NLRP3 inflammasome in the etiopathology of AD, its interactions with microglial autophagy/mitophagy, and the latest developments in NLRP3 inflammasome-targeted therapeutic interventions being implicated for AD treatment.}, } @article {pmid39950370, year = {2025}, author = {Xiong, K and Wang, X and Feng, C and Zhang, K and Chen, D and Yang, S}, title = {Vectors in CRISPR Gene Editing for Neurological Disorders: Challenges and Opportunities.}, journal = {Advanced biology}, volume = {}, number = {}, pages = {e2400374}, doi = {10.1002/adbi.202400374}, pmid = {39950370}, issn = {2701-0198}, support = {81874304//National Natural Science Foundation of China/ ; 22122409//National Natural Science Foundation of China/ ; 22A350017//Key Scientific Research Projects/ ; 21HASTIT043//Programs for Science &Technology Innovation Talents in Universities of Henan Province/ ; ZYQR201912191//Outstanding Young Talents in Henan Province/ ; }, abstract = {Diseases of the nervous system are recognized as the second leading cause of death worldwide. The global prevalence of neurological diseases, such as Huntington's disease, Alzheimer's disease, and Parkinson's disease has seen a significant rise due to the increasing proportion of the aging population. The discovery of the clustered regularly interspaced short palindromic repeats (CRISPR) genome editing technique has paved way for universal neurological diseases treatment. However, finding a safe and effective method to deliver CRISPR gene-editing tools remains a main challenge for genome editing therapies in vivo. Adeno-associated virus (AAV) is currently one of the most commonly used vector systems, but some issues remain unresolved, including capsid immunogenicity, off-target mutations, and potential genotoxicity. To address these concerns, researchers are actively encouraging the development of new delivery systems, like virus-like particles and nanoparticles. These novel systems have the potential to enhance targeting efficiency, thereby offering possible solutions to the current challenges. This article reviews CRISPR delivery vectors for neurological disorders treatment and explores potential solutions to overcome limitations in vector systems. Additionally, the delivery strategies of CRISPR systems are highlighted as valuable tools for studying neurological diseases, and the challenges and opportunities that these vectors present.}, } @article {pmid39950283, year = {2025}, author = {Kumar, B and Sahoo, A and Singhal, M and Varshney, G and Haldar, T and Bali, V}, title = {An Emerging Prospective of Antipsychotics for Treating Neurodegenerative Disorders.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128344910241211112452}, pmid = {39950283}, issn = {1873-4286}, abstract = {CNS illnesses specified by slow deprivation of especially preganglionic neurons, as opposed to the selective static neuronal loss caused by a toxic or metabolic condition, are known as Neurodegenerative disorders. Neurodegenerative disorders are differentiated clinically by behavioral or cognitive problems. The management and treatment of neurodegenerative disorders pose significant challenges, necessitating a multidimensional approach. While primarily designed for psychiatric conditions, antipsychotics have shown potential in ameliorating behavioral and psychological symptoms in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. This review explores the existing literature, highlighting the potential benefits, risks, and considerations associated with incorporating antipsychotics into the treatment paradigm for neurodegenerative disorders. Additionally, it discusses the evolving landscape of personalized treatment strategies, emphasizing the need for a multidisciplinary approach to optimize patient outcomes in the complex realm of neurodegenerative disorder management.}, } @article {pmid39950075, year = {2025}, author = {Zhang, Y and Wang, Y and Liu, Q and Xiao, J and Huang, L and Zhou, L and Liu, X}, title = {Exploring the effects of combined nostalgic activities and music therapy on Alzheimer's disease outcomes.}, journal = {Frontiers in psychology}, volume = {16}, number = {}, pages = {1526761}, pmid = {39950075}, issn = {1664-1078}, abstract = {OBJECTIVE: Exploring the effects of combination of nostalgic activity-based therapies, including music therapy on cognitive function, negative emotions, and sleep quality in patients with mild to moderate Alzheimer's disease.

METHODS: A total of 63 patients with mild to moderate Alzheimer's disease who were treated at the Sichuan Provincial Psychiatric Center of the People's Hospital of Sichuan Province from January to June 2023 were selected as the research subjects. They were randomly divided into a study group (n = 31) and a control group (n = 32) using a random number table method. The control group received routine treatment and nursing care, while the study group received nostalgic music therapy intervention on the basis of the control group. The Mini Mental State Examination (MMSE), Montreal Cognitive Assessment Scale (MOCA), Self Rating Anxiety and Depression Scale (SAS, SDS), and Pittsburgh Sleep Quality Index (PSQI) of the two groups were compared.

RESULTS: A total of 30 cases from each group completed the study. After 12 weeks of intervention, the MMSE and MOCA scores of both groups of patients increased, and the treatment group was higher than the control group (P < 0.05); SAS, SDS and PSQI scores decreased compared with those before intervention, and the treatment group was lower than the control group (P < 0.05).

CONCLUSION: Nostalgic music therapy can improve cognitive function, alleviate negative emotions, and improve sleep quality in patients with mild to moderate Alzheimer's disease.}, } @article {pmid39949872, year = {2025}, author = {Hartz, SM and Schindler, SE and Streitz, ML and Moulder, KL and Mozersky, J and Wang, G and Xiong, C and Morris, JC}, title = {Assessing the clinical meaningfulness of slowing CDR-SB progression with disease-modifying therapies for Alzheimer's disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70033}, pmid = {39949872}, issn = {2352-8737}, abstract = {INTRODUCTION: For many patients and caregivers, a major goal of disease-modifying treatments (DMTs) for Alzheimer's disease (AD) dementia is to extend independence in instrumental and basic activities of daily living (IADLs and BADLs). The goal of this study was to estimate the effect of treatments on the time remaining independent in IADLs and BADLs.

METHODS: Participants at the Knight Alzheimer Disease Research Center (Knight ADRC) who met eligibility criteria for recent DMT trials were studied: age ≥60 years at baseline, clinical diagnosis of very mild or mild AD dementia (global Clinical Dementia Rating [CDR] score 0.5 or 1), biomarker confirmation of amyloid pathology, and at least one follow-up CDR assessment within 5 years. For IADLs, a subset of the Functional Assessment Questionnaire (FAQ) was examined that rated the degree of independence in the following: paying bills, driving, remembering medications and appointments, and preparing meals. For BADLs, the Personal Care domain of the CDR was used. Mixed-effects logistic and ordinal regression models were used to examine the relationship between CDR Sum of Boxes (CDR-SB) and the individual functional outcomes and their components. The change in CDR-SB over time was estimated with linear mixed-effects models.

RESULTS: A total of 282 participants were followed for an average of 2.9 years (standard deviation [SD] 1.3 years). For 50% of individuals, loss of independence in IADLs occurred at CDR-SB >4.5 and in BADLs at CDR-SB >11.5. For individuals with a baseline CDR-SB = 2, treatment with lecanemab would extend independence in IADLs for 10 months (95% confidence interval [CI] 4-18 months) and treatment with donanemab in the low/medium tau group would extend independence in IADLs by 13 months (95% CI 6-24 months).

DISCUSSION: Independence in ADLs can be related to CDR-SB and used to demonstrate the effect of AD treatments in extending the time of independent function, a meaningful outcome for patients and their families.

HIGHLIGHTS: We estimated time to loss of independence for people with AD dementiaEstimating time to loss of independence can help with clinical decision-makingDisease-modifying treatments for AD dementia can extend independence.}, } @article {pmid39949834, year = {2025}, author = {Tie, J and Wu, H and Liu, W and Li, Y and Li, L and Zhao, S and Yuan, Z and Mahmood, K and Chen, S and Wu, H}, title = {Overexpression of SFPQ Improves Cognition and Memory in AD Mice.}, journal = {Neural plasticity}, volume = {2025}, number = {}, pages = {3934591}, pmid = {39949834}, issn = {1687-5443}, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics ; Mice ; *Cognition/physiology ; PTB-Associated Splicing Factor/metabolism ; Memory/physiology ; Hippocampus/metabolism ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Male ; Mice, Transgenic ; tau Proteins/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Peptide Fragments/metabolism ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder with multifaceted pathogenesis, which has been extensively investigated, yet effective treatments remain lacking. Splicing factor proline and glutamine rich (SFPQ) is known to play a crucial role in neurodegenerative diseases, including antioxidant-related functions and regulating gene expression within brain neurons. However, the specific role of SFPQ in AD pathology is not well understood. In this study, an AD mouse model was established through lateral ventricular injection of amyloid-beta1-42 (Aβ 1-42). Subsequently, adeno-associated virus was administered to overexpress SFPQ in the hippocampus of AD mice. The results demonstrate that SFPQ overexpression improves recognition and memory in AD mice, while reducing AD-related marker proteins such as amyloid precursor protein (APP) and Tau. Additionally, synaptic and memory-associated proteins, as well as antioxidant proteins like glutathione S-transferase (GST) and heme oxygenase-1 (HO-1), were upregulated. The ratio of antiapoptotic protein Bcl-2 to proapoptotic protein Bax also increased. Furthermore, phosphorylated phosphoinositide 3-kinase (p-PI3K)/PI3K and phosphorylated protein kinase B (p-AKT)/AKT ratios were elevated, indicating activation of the PI3K/AKT signaling pathway. These findings suggest that SFPQ may serve as a promising molecular target for the prevention and treatment of AD.}, } @article {pmid39949498, year = {2025}, author = {Tiong, SQ and Mohgan, RN and Quek, JY and Liew, JYS and Wong, GYS and Thang, ZQ and Chan, ZL and Gan, SY and Chan, EWL}, title = {Inhibition of the Transforming Growth Factor-β Signaling Pathway Confers Neuroprotective Effects on Beta-Amyloid-Induced Direct Neurotoxicity and Microglia-Mediated Neuroinflammation.}, journal = {Neurology research international}, volume = {2025}, number = {}, pages = {8948290}, pmid = {39949498}, issn = {2090-1852}, abstract = {Background: Abnormal elevation of transforming growth factor-beta (TGF-β) has been observed among Alzheimer's disease (AD) patients. This may be due to microglia-mediated release of proinflammatory cytokines, which promote neuroinflammation and neuronal apoptosis. Silencing of TGFBR1, a gene encoding TGF-β receptor type I (TGF-βR1), has resulted in neuronal survival from amyloid-beta (Aβ)-induced neurotoxicity. Therefore, the present study investigated the neuroprotective effect of TGF-βR1 inhibitors (RepSox, Galunisertib, and Vactosertib) against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. Methods: The neuroprotective effect of TGF-βR1 inhibitors against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation were investigated using the RealTime-Glo™ MT Cell Viability Assay. The inhibitory effect of TGF-βR1 inhibitors on Aβ-induced microglia-mediated production of proinflammatory cytokines (TNF-α and IL-1β) was determined using enzyme-linked immunosorbent assay (ELISA). Results: TGF-βR1 inhibitors (RepSox, Galunisertib, and Vactosertib) at the tested concentrations (6.25-150 nM) showed no significant cytotoxicity effects on SH-SY5Y and BV-2 cells. Moreover, treatments with these inhibitors exhibited neuroprotection on SH-SY5Y cells against Aβ-induced direct neurotoxicity. The trend of cell viability after 24 h treatment also supports the microscopic images of the cells' morphology. Furthermore, pretreatment with these inhibitors conferred indirect neuroprotective effect against Aβ-induced microglia-mediated neuroinflammation by attenuating the production of proinflammatory cytokines (TNF-α and IL-1β). Conclusion: The inhibition of the TGF-β signaling pathway in neuronal and microglia cells by TGF-βR1 inhibitors resulted in neuroprotection against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. Hence, targeting the TGF-β signaling pathway in both neuronal and microglia cells could provide a promising therapeutic strategy in AD.}, } @article {pmid39949308, year = {2025}, author = {Karimpourvazifehkhorani, A and Hekmati, I and Rezvanizadeh, A and Amiri, N and Kadkhoda, M and Arasteh, F}, title = {Brief Behavioral Activation Therapy is effective on apathy symptoms of the older adults with mild Alzheimer's disease but not with moderate Alzheimer's disease.}, journal = {Aging & mental health}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/13607863.2025.2464712}, pmid = {39949308}, issn = {1364-6915}, abstract = {OBJECTIVES: This study aimed to investigate the effectiveness of Brief Behavioral Activation Therapy (BBAT) on apathy symptoms in older adults with Alzheimer's disease (AD) in a medical center facility.

METHOD: In an experimental design, 90 older adults with AD were replaced into three groups including two experimental groups (mild AD group (n = 30), moderate AD group (n = 30)) and a control group (15 participants with mild AD and 15 participants with moderate AD). All participants completed the Dimensional Apathy Scale (DAS) before and after an eight-session BBAT intervention, with follow-up conducted two months post-treatment. A 3 x 3 mixed ANOVA was performed to analyze differences in apathy levels across groups over time, using SPSS version 26.

RESULTS: The mixed ANOVA revealed significant differences in all apathy dimensions (executive, emotional and initial symptoms) among the groups. Specifically, significant between-subject and within-subject differences, respectively for group main effect and time main effect, along with a significant interaction between group and time. These findings indicated that apathy symptoms in patients with mild AD significantly decreased from pretest to post- intervention, but there wasn't significant change in moderate AD and control group.

CONCLUSION: The findings suggested that BBAT is effective in reducing apathy symptoms in patients with mild AD. Early evaluation, diagnosis and treatment of apathy in the mild stages of AD are crucial for improving patient outcomes.}, } @article {pmid39948905, year = {2024}, author = {Koike, T and Karino, M and Tatsumi, H and Fujioka-Kobayashi, M and Kanno, T}, title = {[The End-of-Life Care Experienced by a Patient with Oral Cancer and Dementia Who Requested Home Palliative Care].}, journal = {Gan to kagaku ryoho. Cancer & chemotherapy}, volume = {51}, number = {13}, pages = {1504-1507}, pmid = {39948905}, issn = {0385-0684}, mesh = {Humans ; Male ; *Palliative Care ; *Home Care Services ; Aged, 80 and over ; *Terminal Care ; *Dementia/therapy ; Mouth Neoplasms/therapy/complications ; Carcinoma, Squamous Cell/therapy/complications ; Fatal Outcome ; }, abstract = {The number of patients and families who wish to spend their final moments at home is increasing, and in the future, there may be more opportunities to provide end-of-life care for oral cancer at home. We report our experience with palliative treatment for a terminal oral cancer patient with dementia who wished for home palliative care. The patient was an 87-year-old male with a history of Alzheimer's dementia and chronic heart failure. In late September 2022, he visited a nearby internal medicine clinic with complaints of loss of appetite and pain in the right maxillary gingiva and was referred to a tertiary medical institution in the prefecture for further examination and treatment. At the initial visit, a 40×30 mm easily bleeding ulcerative lesion was observed in the right maxillary molar gingiva. Based on various examinations, he was diagnosed with squamous cell carcinoma of the right maxillary gingiva(cT4bN0M0, Stage ⅣB). However, due to dementia and severe cardiac dysfunction, he was not eligible for chemoradiotherapy and a plan for palliative treatment was made. The patient strongly wished for treatment at home and at a local hospital, and palliative treatment with a view to home palliative care was initiated. He was admitted to our internal medicine department in mid-November. Our department continued local treatment for the tumor and specialized oral care by a dental hygienist, but he passed away due to cardiac arrest in early January 2023. Although the patient passed away before transitioning to home care, smooth implementation of home palliative care requires cooperation not only from hospitals but also from the entire community, and the establishment of a comprehensive home medical support system is crucial.}, } @article {pmid39948600, year = {2025}, author = {Yang, S and Zhang, X and Du, X and Yan, P and Zhang, J and Wang, W and Wang, J and Zhang, L and Sun, H and Liu, Y and Xu, X and Di, Y and Zhong, J and Wu, C and Reinhardt, JD and Zheng, Y and Wu, T}, title = {Prediction of cognitive conversion within the Alzheimer's disease continuum using deep learning.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {41}, pmid = {39948600}, issn = {1758-9193}, support = {81772454//National Natural Science Foundation of China/ ; BE2023023-2//The Key Project of Jiangsu Province's Key Research and Development Program/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/psychology/diagnosis ; *Deep Learning ; Female ; Male ; Aged ; *Cognitive Dysfunction/diagnosis/diagnostic imaging ; *Disease Progression ; *Neuropsychological Tests ; Longitudinal Studies ; Aged, 80 and over ; Neuroimaging/methods ; Prognosis ; Cohort Studies ; }, abstract = {BACKGROUND: Early diagnosis and accurate prognosis of cognitive decline in Alzheimer's disease (AD) is important to timely assignment to optimal treatment modes. We aimed to develop a deep learning model to predict cognitive conversion to guide re-assignment decisions to more intensive therapies where needed.

METHODS: Longitudinal data including five variable sets, i.e. demographics, medical history, neuropsychological outcomes, laboratory and neuroimaging results, from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort were analyzed. We first developed a deep learning model to predicted cognitive conversion using all five variable sets. We then gradually removed variable sets to obtained parsimonious models for four different years of forecasting after baseline within acceptable frames of reduction in overall model fit (AUC remaining > 0.8).

RESULTS: A total of 607 individuals were included at baseline, of whom 538 participants were followed up at 12 months, 482 at 24 months, 268 at 36 months and 280 at 48 months. Predictive performance was excellent with AUCs ranging from 0.87 to 0.92 when all variable sets were considered. Parsimonious prediction models that still had a good performance with AUC 0.80-0.84 were established, each only including two variable sets. Neuropsychological outcomes were included in all parsimonious models. In addition, biomarker was included at year 1 and year 2, imaging data at year 3 and demographics at year 4. Under our pre-set threshold, the rate of upgrade to more intensive therapies according to predicted cognitive conversion was always higher than according to actual cognitive conversion so as to decrease the false positive rate, indicating the proportion of patients who would have missed upgraded treatment based on prognostic models although they actually needed it.

CONCLUSIONS: Neurophysiological tests combined with other indicator sets that vary along the AD continuum can improve can provide aid for clinical treatment decisions leading to improved management of the disease.

ClinicalTrials.gov Identifier: NCT00106899 (Registration Date: 31 March 2005).}, } @article {pmid39948447, year = {2025}, author = {Gao, Q and Wang, J and Fang, R and Sun, H and Wang, T}, title = {A doubly robust estimator for continuous treatments in high dimensions.}, journal = {BMC medical research methodology}, volume = {25}, number = {1}, pages = {35}, pmid = {39948447}, issn = {1471-2288}, support = {82204163//National Natural Science Foundation of China/ ; 82073674//National Natural Science Foundation of China/ ; 202203021212382//Fundamental Research Program of Shanxi Province/ ; }, mesh = {Humans ; *Propensity Score ; Computer Simulation ; Models, Statistical ; Algorithms ; Observational Studies as Topic/methods/statistics & numerical data ; Alzheimer Disease/drug therapy ; }, abstract = {BACKGROUND: Generalized propensity score (GPS) methods have become popular for estimating causal relationships between a continuous treatment and an outcome in observational studies with rich covariate information. The presence of rich covariates enhances the plausibility of the unconfoundedness assumption. Nonetheless, it is also crucial to ensure the correct specification of both marginal and conditional treatment distributions, beyond the assumption of unconfoundedness.

METHOD: We address limitations in existing GPS methods by extending balance-based approaches to high dimensions and introducing the Generalized Outcome-Adaptive LASSO and Doubly Robust Estimate (GOALDeR). This novel approach integrates a balance-based method that is robust to the misspecification of distributions required for GPS methods, a doubly robust estimator that is robust to the misspecification of models, and a variable selection technique for causal inference that ensures an unbiased and statistically efficient estimation.

RESULTS: Simulation studies showed that GOALDeR was able to generate nearly unbiased estimates when either the GPS model or the outcome model was correctly specified. Notably, GOALDeR demonstrated greater precision and accuracy compared to existing methods and was slightly affected by the covariate correlation structure and ratio of sample size to covariate dimension. Real data analysis revealed no statistically significant dose-response relationship between epigenetic age acceleration and Alzheimer's disease.

CONCLUSION: In this study, we proposed GOALDeR as an advanced GPS method for causal inference in high dimensions, and empirically demonstrated that GOALDeR is doubly robust, with improved accuracy and precision compared to existing methods. The R package is available at https://github.com/QianGao-SXMU/GOALDeR .}, } @article {pmid39946000, year = {2025}, author = {Elyasi, L and Rosenholm, JM and Jahanshahi, M and Jesmi, F}, title = {The Effect of Picein on Inhibitory Avoidance Memory and Activity of Antioxidant Enzymes in Hippocampus of Male Rats with Scopolamine-Induced Injury.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39946000}, issn = {1559-1182}, support = {IR.GOUMS.REC.1400.161//Golestan University of Medical Sciences Neuroscience Research Center/ ; }, abstract = {Alzheimer disease (AD) is a common neurologic disorder, impairing memory and spatial perception. Consistent with the extensive search for its treatment, we investigated the effect of Picein on inhibitory avoidance memory, lipid peroxidation, and the activity of hippocampal antioxidant enzymes in rats. Forty adult male Wistar rats were randomized into control group (no intervention), model group (intraperitoneal injection of 3-mg/kg scopolamine), and three interventional groups (1.5-, 2.5-, and 5-mg/kg intraventricular Picein, once a day for 7 days, 24 h after scopolamine injection). After behavioral test, the rats' hippocampus was isolated for measuring oxidative stress markers, including enzymes superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GPX), catalase (CAT), and total antioxidant capacity (TAC). One-way ANOVA was used for comparing numeric variables among the groups using SPSS v.21. The results showed scopolamine decreased SOD, GPX, and CAT enzymes, and TAC level, and increased MDA level, compared with the control group (P < 0.001) that confirmed the scopolamine-induced AD model. The two doses of 2.5- and 5-mg/kg Picein increased latency for entering the dark room, compared to the scopolamine group (P < 0.05), making them similar to the control group. The number of entries into the dark room in the 2.5-mg/kg Picein reduced and approached the control group (P < 0.05). The 2.5-mg/kg Picein decreased MDA and increased SOD, GPX, and TAC, more than 5 mg/kg Picein, both different than scopolamine; only 2.5-mg/kg Picein had different CAT, compared to scopolamine group (P < 0.05). In conclusion, by lowering oxidative stress in the hippocampus, Picein was able to prevent the scopolamine-induced impaired learning and avoidance memory in rats.}, } @article {pmid39945003, year = {2024}, author = {Cai, W and Zhang, H and Wu, Y and Yao, Y and Zhang, J}, title = {Comparative the efficacy and safety of Gosuranemab, Semorinemab, Tilavonemab, and Zagotenemab in patients with Alzheimer's disease: a systematic review and network meta-analysis of randomized controlled trials.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1465871}, pmid = {39945003}, issn = {1663-4365}, abstract = {OBJECTIVE: The aim of this study was to compare the efficacy and safety of anti-tau protein monoclonal antibodies for Alzheimer's disease (AD). Tau protein aggregation, a key pathological feature of AD, is closely associated with neurodegeneration and cognitive decline. Targeting tau protein has emerged as a promising therapeutic strategy. By investigating the effects of monoclonal antibodies on cognitive function, disease progression, and overall quality of life in patients with AD, which can provide valuable insights into their potential as a therapeutic option for this devastating neurodegenerative disorder.

METHODS: The randomized controlled trials (RCTs) investigating the efficacy of Gosuranemab, Semorinemab, Tilavonemab, and Zagotenemab in Alzheimer's disease (AD) were systematically searched across PubMed, Embase, Web of Science and Cochrane Library, up to May 2024. The control group included placebo. The efficacy indicators were change in the Mini Mental State Examination (MMSE), Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL) from baseline until the time of efficacy observation. Statistical analysis was conducted using Stata 14 and RevMan 5.4. The purpose of data processing, including generating network evidence plots, surface under the cumulative ranking curve (SUCRA) ranking, league plots, and funnel plots, is to visually summarize and evaluate the relative effectiveness and safety and potential publication bias of multiple interventions. Mean differences (MD) and 95% confidence interval (95%CI) as effect sizes to analyze continuous variables.

RESULTS: This study encompassed six RCTs involving 2,193 patients. Semorinemab were more effective than placebo in MMSE and ADAS-Cog scores (MDs ranging between 0.52 and 3.21; MDs ranging between 0.17 and 3.30). Placebo showed relatively good efficacy according to SUCRA ranking on change in CDR-SB and ADCS-ADL scores (75.7 and 79.5%). Tilavonemab and Semorinemab exhibited efficacy similar to that of a placebo in the analysis of the two indicators. Tilavonemab showed a lower incidence of AE, SAE, fall, and urinary tract infections than placebo, and the differences were statistically significant. Most safety analysis results showed no statistical difference.

CONCLUSION: The results indicated that anti-tau protein monoclonal antibodies, such as Semorinemab and Tilavonemab, showed promise in terms of efficacy and safety for managing AD. Further studies are needed to confirm these findings, assess long-term effects, and refine treatment protocols.

https://www.crd.york.ac.uk/prospero/#myprospero, CRD42024583388.}, } @article {pmid39944951, year = {2025}, author = {Zhou, Z and Fan, B and Chen, Q and Li, X and Ke, X}, title = {Individual and combined effects of dietary vitamin intake on cognitive function in elderly adults: the potential mediating role of serum neurofilament light chain levels.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1485648}, pmid = {39944951}, issn = {2296-861X}, abstract = {BACKGROUND: Vitamins are essential micronutrients for the prevention and treatment of neurodegenerative diseases. The objectives of the present study were to evaluate the association between dietary vitamin intake and cognitive function in elderly adults and to explore the potential impact of serum neurofilament light chain (NfL) concentration.

METHODS: Data from 468 elderly individuals, including information on the dietary consumption of 10 vitamins, were used. Cognitive performance was assessed according to a composite Z-score of the Animal Fluency Test (AFT), Consortium to Establish a Registry for Alzheimer's Disease (CERAD), and Digit Symbol Substitution Test (DSST). Serum NfL levels were measured using a highly sensitive immunoassay. Bayesian kernel machine regression (BKMR) models were used to estimate the combined effects of vitamin mixtures on cognitive function.

RESULTS: In both single- and multiple-vitamin models, individuals with a higher intake of dietary vitamin K exhibited greater global cognitive function, compared to those with a lower vitamin intake. BKMR revealed positive associations between vitamin mixtures and global cognitive function, AFT Z-scores, and DSST Z-scores. Individuals in the third vitamin K intake tertile exhibited lower serum NfL levels than those in the first tertile (regression coefficient, β = -0.16 [95% confidence interval -0.29 to -0.02]; p = 0.023). Serum NfL levels mediated the association between higher vitamin K intake and global cognitive function (8.73%).

CONCLUSION: Vitamin mixtures were positively associated with global cognitive function in elderly participants. The association between vitamin K intake and cognitive function may be mediated by serum NfL concentration.}, } @article {pmid39944895, year = {2025}, author = {Du, H and Ma, F and Cao, Y and Bai, M and Gao, X and Yang, Z and Xu, Y and Yan, Y}, title = {Bis(7)-harmine derivatives as potential multi-target anti-Alzheimer agents.}, journal = {Frontiers in chemistry}, volume = {13}, number = {}, pages = {1545908}, pmid = {39944895}, issn = {2296-2646}, abstract = {INTRODUCTION: The multi-targeted ligands (MTDL) strategy has been recognized as a promising Approach for the development of effective treatments against Alzheimer's disease (AD), due to the presence of multiple pathological mechanisms in AD. In this study, a series of bis(7)-harmine derivatives were designed and synthesized as multifunctional drugs for the treatment of AD.

METHODS: The derivatives were synthesized by chemical methods and their structure was confirmed by nuclear magnetic resonance (NMR). The Ellman's assay was utilized to assess the inhibitory potential of derivatives against hAChE and hBuChE. The inhibitory activity of these derivatives on both hMAO-A and hMAO-B was assessed using a fluorescence-based method. The thioflavin T (Th-T) fluorescence assay was used to assess the inhibition of Aβ 1-42 self-aggregation. The cytotoxicity was evaluated using the MTT assay. The Surflex-Dock program in Sybyl-X2.0 Software was employed for molecular docking.

RESULTS: In vitro studies revealed that numerous synthesized compounds exhibited potent inhibitory activity against hAChE, and hMAO-B (IC50 < 1 μM), as well as Aβ 1-42 aggregation (IC50 < 20 μM). Importantly, the multitarget compounds 6d, 8c, and 8d exhibited remarkable efficacy in simultaneously mitigating Aβ-induced toxicity in SH-SY5Y cells while demonstrating minimal cytotoxicity. Furthermore, predicted ADMET results suggested that 6d, 8c, and 8d possessed favorable pharmacokinetic properties and demonstrated low toxicity levels. Additionally, molecular docking studies of 6d within the activesites of hAChE, hMAO-B, and Aβ 1-42 elucidated the inhibition mechanism.

DISCUSSION AND CONCLUSION: Based on these findings, it is evident that 6d, 8c, and 8d hold potential as promising multi-functional drugs for AD treatment.}, } @article {pmid39944627, year = {2025}, author = {Zhu, Y and Xu, H and Yu, C and Jiang, W and Hou, X and Ma, M and Wu, J}, title = {Polymers for the treatment of Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1512941}, pmid = {39944627}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD) is one of the most common diseases of the central nervous system in the middle-aged and elderly population. It is a neurodegenerative disorder, and its main clinical symptoms include the loss of established memories, a decline in learning capacity, and the buildup of β-amyloid peptides. The disease is often accompanied by neurodegenerative changes and the formation of neurofibrillary tangles. However, the number of drugs available for the clinical treatment of AD remains limited. Currently, existing medications are not effective in completely curing the disease or stopping its progression. Due to their excellent biocompatibility and biodegradability, polymers have been widely used as drug delivery carriers in various fields including cancer therapy and wound healing. The use of polymers enables targeted drug delivery and prolonged release profiles. In recent years, researchers have made significant progress in utilizing polymers such as polyethylene glycol, poly (lactic-co-glycolic acid) (PLGA), and chitosan (CS) to deliver drugs and blood-brain barrier receptor ligands for the treatment of AD. Moreover, many polymers with inherent therapeutic properties have been developed, including the already marketed GV-971 as well as experimental polymers such as PLGA and CS oligosaccharide. This review summarizes the applications of polymers in AD treatment over the past few years and highlights their current limitations to help researchers better understand current advancements in polymer development and identify future research directions.}, } @article {pmid39944545, year = {2025}, author = {Peng, D and Huang, W and Liu, R and Zhong, W}, title = {From pixels to prognosis: radiomics and AI in Alzheimer's disease management.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1536463}, pmid = {39944545}, issn = {1664-2295}, abstract = {Alzheimer's disease (AD), the leading cause of dementia, poses a growing global health challenge due to an aging population. Early and accurate diagnosis is essential for optimizing treatment and management, yet traditional diagnostic methods often fall short in addressing the complexity of AD pathology. Recent advancements in radiomics and artificial intelligence (AI) offer novel solutions by integrating quantitative imaging features and machine learning algorithms to enhance diagnostic and prognostic precision. This review explores the application of radiomics and AI in AD, focusing on key imaging modalities such as PET and MRI, as well as multimodal approaches combining structural and functional data. We discuss the potential of these technologies to identify disease-specific biomarkers, predict disease progression, and guide personalized interventions. Additionally, the review addresses critical challenges, including data standardization, model interpretability, and the integration of AI into clinical workflows. By highlighting current achievements and identifying future directions, this article underscores the transformative potential of AI-driven radiomics in reshaping AD diagnostics and care.}, } @article {pmid39944528, year = {2025}, author = {Byeon, G and Kang, DW and Kim, Y and Kim, GH and Kim, KW and Kim, HJ and Na, S and Park, KH and Park, YH and Suh, J and Shin, JH and Shim, Y and Yang, Y and Um, YH and Oh, SI and Wang, SM and Yoon, B and Lee, SM and Lee, J and San Lee, J and Rhee, HY and Lim, JS and Jung, YH and Chin, J and Jang, H and Hong, YJ and Choi, M and Jang, JW and , }, title = {Clinical Practice Guidelines for Dementia: Recommendations for the Pharmacological Treatment of Behavioral and Psychological Symptoms.}, journal = {Dementia and neurocognitive disorders}, volume = {24}, number = {1}, pages = {24-43}, pmid = {39944528}, issn = {2384-0757}, abstract = {BACKGROUND AND PURPOSE: Dementia often accompanies behavioral and psychological symptoms of dementia (BPSD), including agitation, aggression, depression, and psychosis, which impact patients' quality of life and caregiver burden. Effective management of BPSD is essential to support patient and caregiver well-being. This study presents evidence-based clinical practice guidelines for pharmacological treatments of BPSD in dementia, focusing on antipsychotics, antidepressants, cognitive enhancers, and other medications.

METHODS: This guideline was developed by the Korean Dementia Association's Quality Management Committee. Key questions were framed using the Population, Intervention, Comparison, Outcome methodology, followed by systematic literature searches. Randomized controlled trials were assessed for quality, and recommendations were graded based on evidence levels, employing the Grading of Recommendations, Assessment, Development and Evaluation system to establish strength and applicability.

RESULTS: Recommendations vary by medication type and symptom severity. Antipsychotics, such as risperidone, are conditionally recommended for managing aggression and psychosis in dementia, while antidepressants, specifically citalopram, are advised for agitation in Alzheimer's disease. Cognitive enhancers, including cholinesterase inhibitors and memantine, showed moderate efficacy for general BPSD improvement and rapid eye movement sleep behavior disorder in Lewy body dementia. Specific drugs, like pimavanserin, demonstrated efficacy in addressing psychosis in Alzheimer's patients.

CONCLUSIONS: These guidelines provide a structured approach to pharmacological management of BPSD in dementia, addressing efficacy and safety profiles across drug categories. The recommendations emphasize personalized treatment plans to optimize therapeutic outcomes while minimizing risks, with a conditional approach suggested in cases with limited evidence.}, } @article {pmid39944527, year = {2025}, author = {Kim, Y and Kang, DW and Kim, GH and Kim, KW and Kim, HJ and Na, S and Park, KH and Park, YH and Byeon, G and Suh, J and Shin, JH and Shim, Y and Yang, Y and Um, YH and Oh, SI and Wang, SM and Yoon, B and Lee, SM and Lee, J and San Lee, J and Lim, JS and Jung, YH and Chin, J and Jang, H and Choi, M and Hong, YJ and Rhee, HY and Jang, JW and , }, title = {Clinical Practice Guidelines for Dementia: Recommendations for Cholinesterase Inhibitors and Memantine.}, journal = {Dementia and neurocognitive disorders}, volume = {24}, number = {1}, pages = {1-23}, pmid = {39944527}, issn = {2384-0757}, abstract = {BACKGROUND AND PURPOSE: This clinical practice guideline provides evidence-based recommendations for treatment of dementia, focusing on cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists for Alzheimer's disease (AD) and other types of dementia.

METHODS: Using the Population, Intervention, Comparison, Outcomes (PICO) framework, we developed key clinical questions and conducted systematic literature reviews. A multidisciplinary panel of experts, organized by the Korean Dementia Association, evaluated randomized controlled trials and observational studies. Recommendations were graded for evidence quality and strength using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.

RESULTS: Three main recommendations are presented: (1) For AD, cholinesterase inhibitors (donepezil, rivastigmine, galantamine) are strongly recommended for improving cognition and daily function based on moderate evidence; (2) Cholinesterase inhibitors are conditionally recommended for vascular dementia and Parkinson's disease dementia, with a strong recommendation for Lewy body dementia; (3) For moderate to severe AD, NMDA receptor antagonist (memantine) is strongly recommended, demonstrating significant cognitive and functional improvements. Both drug classes showed favorable safety profiles with manageable side effects.

CONCLUSIONS: This guideline offers standardized, evidence-based pharmacologic recommendations for dementia management, with specific guidance on cholinesterase inhibitors and NMDA receptor antagonists. It aims to support clinical decision-making and improve patient outcomes in dementia care. Further updates will address emerging treatments, including amyloid-targeting therapies, to reflect advances in dementia management.}, } @article {pmid39942725, year = {2025}, author = {Zhang, X and Subbanna, S and Williams, CRO and Canals-Baker, S and Hashim, A and Wilson, DA and Weiss, LM and Shukla, S and Chokkalingam, P and Das, S and Das, BC and Saito, M}, title = {Methionine Aminopeptidase 2 (MetAP2) Inhibitor BL6 Attenuates Inflammation in Cultured Microglia and in a Mouse Model of Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {3}, pages = {}, doi = {10.3390/molecules30030620}, pmid = {39942725}, issn = {1420-3049}, support = {R01AI132614-04S1/GF/NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Microglia/drug effects/metabolism ; Mice ; *Disease Models, Animal ; *Aminopeptidases/antagonists & inhibitors/metabolism ; *Inflammation/drug therapy/chemically induced ; Male ; Lipopolysaccharides ; Anti-Inflammatory Agents/pharmacology ; Cell Line ; Methionyl Aminopeptidases/antagonists & inhibitors ; Metalloendopeptidases ; }, abstract = {Methionine aminopeptidase 2 (MetAP2) plays an important role in the regulation of protein synthesis and post-translational processing. Preclinical/clinical applications of MetAP2 inhibitors for the treatment of various diseases have been explored because of their antiangiogenic, anticancer, antiobesity, antidiabetic, and immunosuppressive properties. However, the effects of MetAP2 inhibitors on CNS diseases are rarely examined despite the abundant presence of MetAP2 in the brain. Previously, we synthesized a novel boron-containing MetAP2 inhibitor, BL6, and found that it suppressed angiogenesis and adipogenesis yet improved glucose uptake. Here, we studied the anti-inflammatory effects of BL6 in SIM-A9 microglia and in a mouse model of Alzheimer's disease generated by the intracerebroventricular (icv) injection of streptozotocin (STZ). We found that BL6 reduced proinflammatory molecules, such as nitric oxide, iNOS, IL-1β, and IL-6, together with phospho-Akt and phospho-NF-κB p65, which were elevated in lipopolysaccharide (LPS)-activated microglial SIM-A9 cells. However, the LPS-induced reduction in Arg-1 and CD206 was attenuated by BL6, suggesting that BL6 promotes microglial M1 to M2 polarization. BL6 also decreased glial activation along with a reduction in phospho-tau and an elevation in synaptophysin in the icv-STZ mouse model. Thus, our experiments demonstrate an anti-neuroinflammatory action of BL6, suggesting possible clinical applications of MetAP2 inhibitors for brain disorders in which neuroinflammation is involved.}, } @article {pmid39942548, year = {2025}, author = {Cui, S and Jin, Z and Yu, T and Guo, C and He, Y and Kan, Y and Yan, L and Wu, L}, title = {Effect of Glycosylation on the Enzymatic Degradation of D-Amino Acid-Containing Peptides.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {3}, pages = {}, doi = {10.3390/molecules30030441}, pmid = {39942548}, issn = {1420-3049}, support = {51972302//National Natural Science Foundation of China/ ; 21778054//National Natural Science Foundation of China/ ; 51772289//National Natural Science Foundation of China/ ; 2192058//Beijing Municipal Natural Science Foundation/ ; K20180202//State Key Laboratory of Natural and Biomimetic Drugs/ ; ZR2024QB225//Fundamental Research Funds for the Central Universities, Shandong Provincial Natural Science Foundation/ ; 2024BS22//Weifang University Doctor Startup Foundation/ ; }, mesh = {Glycosylation ; *Amino Acids/chemistry/metabolism ; *Molecular Docking Simulation ; *Chymotrypsin/chemistry/metabolism ; Peptides/chemistry/metabolism ; Proteolysis ; Hydrogen Bonding ; Glycopeptides/chemistry/metabolism ; }, abstract = {The accumulation of D-amino acid-containing peptides is associated with age-related diseases such as Alzheimer's disease and cataracts, while glycosylation is an important modification of proteins and plays a key role in improving the physicochemical properties of peptides and facilitating their regulation in biological systems. This study investigates the effects of glycosylation position, glycan number, and monosaccharide structure on the conformation and enzymatic degradation of D-amino acid-containing peptides, using KYNEtWRSED (5-t) as a model peptide and six monosaccharides as model glycans. The results demonstrated that glycosylation inhibited the enzymatic degradation of 5-t in the presence of most serine-like proteases. However, in the presence of chymotrypsin, glycosylation with modified monosaccharides (except for β-D-GalNAc) promoted the degradation of 5-t. Furthermore, glycosylation had no effect on the cleavage site of 5-t. Molecular docking analysis revealed that the hydrogen bonding and electrostatic interactions between the glycopeptide and chymotrypsin were markedly strengthened, likely serving as a key determinant of the enzymatic effects. Collectively, these findings highlight the potential of glycosylation to enhance the therapeutic and biomedical applications of D-amino acid-containing peptides in disease treatment and drug design.}, } @article {pmid39942106, year = {2025}, author = {Freis, AM and Vemulapalli, SPB}, title = {Analysis of the Generation of Harmful Aldehydes in Edible Oils During Sunlight Exposure and Deep-Frying Using High-Field Proton Nuclear Magnetic Resonance Spectroscopy.}, journal = {Foods (Basel, Switzerland)}, volume = {14}, number = {3}, pages = {}, doi = {10.3390/foods14030513}, pmid = {39942106}, issn = {2304-8158}, abstract = {Edible oils are essential dietary components that provide crucial micronutrients. However, their quality can deteriorate during frying-a common cooking method-and with prolonged light exposure due to chemical reactions such as hydrolysis, oxidation, and polymerization. These processes lead to the formation of harmful compounds, particularly aldehydes. This study investigates how thermal and light exposure impact the chemical composition of five widely used edible oils: olive, rapeseed, sunflower, sesame, and peanut oils. For the thermal treatment, the oils were heated to 190 ± 5 °C in a commercial fryer, with samples taken at the start and after 10 min and 60 min of heating, while intermittently frying chicken nuggets to simulate typical frying conditions. For the light exposure treatment, the oil samples were exposed to direct sunlight for 3 and 8 h, with control samples being collected beforehand. The oil composition was analyzed using an advanced 800 MHz nuclear magnetic resonance (NMR) instrument with a triple-resonance inverse cryoprobe, providing high sensitivity and resolution. The results revealed a significant increase in various aldehyde compounds in all oils under both thermal and light exposure conditions. Notably, this study identified the generation of genotoxic and cytotoxic α,β-unsaturated aldehydes, including 4-hydroperoxy-(E)-2-alkenals, 4-hydroxy-(E)-2-alkenals, and 4,5-epoxy-(E)-2-alkenals. Given the established association of aldehydes with health risks, including cancer, Alzheimer's, and Parkinson's diseases, these findings highlight the importance of monitoring oil degradation during cooking and the appropriate storage of oils to minimize light exposure to reduce potential health risks.}, } @article {pmid39941597, year = {2025}, author = {Arendash, GW}, title = {The Brain Toxin Cleansing of Sleep Achieved During Wakefulness.}, journal = {Journal of clinical medicine}, volume = {14}, number = {3}, pages = {}, doi = {10.3390/jcm14030926}, pmid = {39941597}, issn = {2077-0383}, support = {9R44AG073096-02A1//NIH/NIA/ ; }, abstract = {A primary purpose of sleep for humans is to remove toxins and metabolic wastes from the brain (e.g., Aβ, tau, lactate) that would otherwise build up and compromise brain functionality. There are currently no drugs or devices that have been clinically shown in humans to enhance brain toxin removal, either during sleep or wakefulness. This perspective article focuses on a recently (re)discovered major route of toxin drainage from the human brain through meningeal lymphatic vessels (mLVs) and the primary enhancer of their flow-the cytokine Vascular Endothelial Growth Factor (VEGF). The purpose of this perspective article is to present pre-clinical and clinical evidence relevant to a new bioengineered technology (Transcranial Radiofrequency Treatment; TRFT) that appears to enhance mLV flow to increase brain toxin cleansing in humans during wakefulness. In being both safe and non-invasive, TRFT is administered in-home, presently through a device called "MemorEM". Two months of daily TRFT during wakefulness increased the typically low plasma/brain levels of VEGF in Alzheimer's Disease (AD) subjects, which was associated with increased Aβ and tau toxin removal from their brains during wakefulness-ostensibly through VEGF-increased mLV flow. Even irrespective of baseline VEGF levels, brain toxin cleansing was increased by TRFT in AD subjects, who also experienced a notable reversal of their cognitive impairment after TRFT. Additional clinical studies are nonetheless required to firmly establish TRFT's brain cleansing abilities during wakefulness. In performing a major duty of sleep, TRFT during wakefulness is proposed as a viable intervention to counter the decline in nighttime brain toxin cleansing that occurs with aging and in multiple brain diseases, most notably Alzheimer's Disease. The implications of TRFT for insomnia and for sleep deprivation are also discussed, as is the potential for TRFT to extend healthy human longevity.}, } @article {pmid39941562, year = {2025}, author = {Agavriloaei, LM and Iliescu, BF and Pintilie, RM and Turliuc, DM}, title = {Therapeutic Potential of Experimental Stereotactic Hippocampal Cell Transplant in the Management of Alzheimer's Disease.}, journal = {Journal of clinical medicine}, volume = {14}, number = {3}, pages = {}, doi = {10.3390/jcm14030891}, pmid = {39941562}, issn = {2077-0383}, abstract = {Due to a continuous increase in life expectancy and the progress made in specialized healthcare, the incidence of Alzheimer's disease (AD) has dramatically increased to the point that it has become one of the main challenges of contemporary medicine. Despite a huge scientific and clinical effort, current treatments manage just a temporary alleviation of symptomatology but offer no cure. Modern trials involving cell transplantation in experimental animals require the involvement of neurosurgeons in the treatment protocol. CSF shunting, intraventricular infusions, or DBS for symptoms relief have been an integral part of the therapeutic arsenal from the very beginning. The development of stereotactic surgery has facilitated the experimental potential of cell transplantation in the hippocampus for Alzheimer's disease. We conducted a narrative review of the literature in the top three medical databases (PubMed, Science Direct, and Google Scholar) using the keywords "Alzheimer's disease", "hippocampus", and "transplant". After eliminating duplicates, 241 papers were selected and screened by title and abstract. Two reviewers independently analyzed the 88 papers and chose 32 experiments that involved stereotactic hippocampal transplantation of cells in experimental animals with AD. The stereotactic transplantation of cells such as mesenchymal stem cells (MSCs), neuronal stem cells (NSCs), induced pluripotent cells (iPSCs), astrocytes, and derivates from stem cells was analyzed. The experiments used either a chemically induced or transgenic AD model and observed the impact of the stereotactic transplantation with behavioral testing, MRS spectroscopy, and biochemical analysis. The stereotaxic method delivers minimal invasive treatment option by cell transplantation at the hippocampus. The results showed that amyloid deposits were lower after transplantation, showing a positive impact. Other impactful results involve proliferation of neurogenesis, downregulation of anti-inflammatory response, and increased neuronal plasticity. The increased precision with which the stereotaxic method manages to target deep structures of the brain and the results of the reviewed papers could represent an argument for future human trials. More studies are needed to confirm the viability of the transplanted cells and the long-term effects.}, } @article {pmid39941290, year = {2025}, author = {Momeni, F and Shahbazi-Gahrouei, D and Mahmoudi, T and Mehdizadeh, A}, title = {Transfer Learning and Neural Network-Based Approach on Structural MRI Data for Prediction and Classification of Alzheimer's Disease.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {3}, pages = {}, doi = {10.3390/diagnostics15030360}, pmid = {39941290}, issn = {2075-4418}, abstract = {Background: Alzheimer's disease (AD) is a neurodegenerative condition that has no definitive treatment, and its early diagnosis can help to prevent or slow down its progress. Structural magnetic resonance imaging (sMRI) and the progress of artificial intelligence (AI) have significant attention in AD detection. This study aims to differentiate AD from NC and distinguish between LMCI and EMCI from the other two classes. Another goal is the diagnostic performance (accuracy and AUC) of sMRI for predicting AD in its early stages. Methods: In this study, 398 participants were used from the ADNI and OASIS global database of sMRI including 98 individuals with AD, 102 with early mild cognitive impairment (EMCI), 98 with late mild cognitive impairment (LMCI), and 100 normal controls (NC). Results: The proposed model achieved high area under the curve (AUC) values and an accuracy of 99.7%, which is very remarkable for all four classes: NC vs. AD: AUC = [0.985], EMCI vs. NC: AUC = [0.961], LMCI vs. NC: AUC = [0.951], LMCI vs. AD: AUC = [0.989], and EMCI vs. LMCI: AUC = [1.000]. Conclusions: The results reveal that this model incorporates DenseNet169, transfer learning, and class decomposition to classify AD stages, particularly in differentiating EMCI from LMCI. The proposed model performs well with high accuracy and area under the curve for AD diagnostics at early stages. In addition, the accurate diagnosis of EMCI and LMCI can lead to early prediction of AD or prevention and slowing down of AD before its progress.}, } @article {pmid39941289, year = {2025}, author = {Huang, SY and Wu, MT and Sun, CF and Yang, FY}, title = {Volume Changes in Brain Subfields of Patients with Alzheimer's Disease After Transcranial Ultrasound Stimulation.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {3}, pages = {}, doi = {10.3390/diagnostics15030359}, pmid = {39941289}, issn = {2075-4418}, support = {NSTC 112-2218-E-A49-009- and NSTC 109-2321-B-010-004-//National Science and Technology Council of Taiwan/ ; CY11322 and CY11113//Cheng Hsin General Hospital/ ; }, abstract = {Background/Objectives: Alzheimer's disease (AD) is characterized by progressive brain atrophy marked by cognitive decline and memory loss, which significantly affect patients' quality of life. Transcranial ultrasound stimulation (TUS) is a potential physical treatment for AD patients. However, the specific brain regions stimulated by TUS and its therapeutic effects remain unclear. Methods: In this study, magnetic resonance imaging (MRI) and FreeSurfer segmentation were employed to assess alterations in the brain volume of AD patients after TUS. Results: Our findings revealed significant volume increases in the corpus callosum (CC) and lateral orbitofrontal cortex (lOFC) in the TUS group. Moreover, the volumetric changes in the CC were strongly correlated with improvements in the Mini-Mental State Examination score, which is a widely used measure of cognitive function of AD patients. Conclusions: TUS has the potential to alleviate disease progression and offers a non-invasive therapeutic approach to the improvement of cognitive function in AD patients.}, } @article {pmid39941125, year = {2025}, author = {Di Vincenzo, M and Pellegrino, P and Schiappa, G and Campanati, A and Del Vescovo, V and Piccirillo, S and Ambrogini, P and Arnaldi, G and Orciani, M}, title = {Role of 11β-Hydroxysteroid Dehydrogenase and Mineralocorticoid Receptor on Alzheimer's Disease Onset: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, doi = {10.3390/ijms26031357}, pmid = {39941125}, issn = {1422-0067}, support = {2022XF7XZF//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology/genetics ; *11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism/antagonists & inhibitors/genetics ; Animals ; *Receptors, Mineralocorticoid/metabolism/genetics ; 11-beta-Hydroxysteroid Dehydrogenases/metabolism/genetics/antagonists & inhibitors ; }, abstract = {The role of 11β-HSD1 in Alzheimer's disease (AD) has garnered significant attention due to its involvement in glucocorticoid metabolism, neuroinflammation, and cognitive decline. This review explores the current understanding of 11β-HSD1 in AD, examining genetic, preclinical, and clinical research. Genetic studies have identified 11β-HSD1 polymorphisms that may influence AD risk, although findings remain inconsistent. Mechanistically, 11β-HSD1 promotes neurodegeneration through the dysregulation of glucocorticoid activity, contributing to hippocampal atrophy, amyloid plaque formation, and tau pathology. Preclinical studies have shown that 11β-HSD1 inhibitors offer neuroprotective effects, including enhanced cognitive function, reduced inflammation, and improved mitochondrial activity. However, clinical trials, including those involving ABT-384 and Xanamem, have produced mixed results, with no substantial cognitive improvements despite effective enzyme inhibition. These inconsistencies highlight the complexity of AD and the challenges in translating preclinical findings into clinical outcomes. Moreover, while 11β-HSD1 inhibition holds therapeutic potential, other strategies targeting neuroinflammation, autophagy, and glucocorticoid signaling are also being explored. Ongoing research is focusing on optimizing 11β-HSD1 inhibitors, identifying biomarkers for patient selection, and investigating combination therapies to enhance treatment efficacy. Ultimately, 11β-HSD1's role in AD presents a promising therapeutic target, but further studies are required to fully understand its potential in managing the disease.}, } @article {pmid39941101, year = {2025}, author = {Orywal, K and Socha, K and Iwaniuk, P and Kaczyński, P and Farhan, JA and Zoń, W and Łozowicka, B and Perkowski, M and Mroczko, B}, title = {Vitamins in the Prevention and Support Therapy of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, doi = {10.3390/ijms26031333}, pmid = {39941101}, issn = {1422-0067}, support = {NdS/551580/2022/2022//Polish Ministry of Education and Science/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/prevention & control/metabolism ; *Vitamins/therapeutic use ; Dietary Supplements ; Animals ; Alzheimer Disease/prevention & control/metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), which are a consequence of the progressive loss of neuronal function and structure, cause significant cognitive impairment. The incidence of these diseases in the world's population is constantly increasing as a result of an aging population. Although genetic and environmental factors are most often mentioned as the pathogenetic factors of these diseases, increasing evidence points to the important role of proper nutrition in the prevention and support of the treatment of these disorders. A healthy, balanced diet can mitigate the risks associated with the risk factors mentioned above and slow the progression of the disease by reducing oxidative stress and inflammation. Vitamins B, D, E, C, K, and A have been shown to support cognitive functions and protect the nervous system. This review demonstrates the importance of vitamins in preventing and supporting the therapy of neurodegenerative diseases. Information regarding the health-promoting properties of these vitamins must be effectively communicated to consumers seeking to protect their health, particularly in the context of neurodegenerative diseases. Consequently, this review also examines the authorized health claims under EU food law related to these vitamins, assessing their role in promoting awareness of the vitamins' potential benefits for neuroprotection and the management of neurodegenerative diseases.}, } @article {pmid39941068, year = {2025}, author = {Martínez-Orozco, H and Bencomo-Martínez, A and Maya-Arteaga, JP and Rubio-De Anda, PF and Sanabria-Romero, F and Casas, ZGM and Rodríguez-Vargas, I and Hernández-Puga, AG and Sablón-Carrazana, M and Menéndez-Soto Del Valle, R and Rodríguez-Tanty, C and Díaz-Cintra, S}, title = {CNEURO-201, an Anti-amyloidogenic Agent and σ1-Receptor Agonist, Improves Cognition in the 3xTg Mouse Model of Alzheimer's Disease by Multiple Actions in the Pathology.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, doi = {10.3390/ijms26031301}, pmid = {39941068}, issn = {1422-0067}, support = {Pronace-Salud No. 322514//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; IN-206322//PAPIIT-DGAPA UNAM/ ; Fondo para el Desarrollo del Cono-759 cimiento UAQ-2022//Universidad Autónoma de Querétaro/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *Receptors, sigma/agonists/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; *Cognition/drug effects ; Sigma-1 Receptor ; Amyloid beta-Peptides/metabolism ; Brain/metabolism/drug effects/pathology ; Cognitive Dysfunction/drug therapy/metabolism ; Male ; Acetylcholine/metabolism ; Morpholines ; }, abstract = {The complexity of Alzheimer's disease (AD) pathophysiology represents a significant challenge in the development of effective therapeutic agents for its treatment. CNEURO-201 (CN, also Amylovis-201) is a novel pharmaceutical agent with dual activity as an anti-amyloid-β (Aβ) agent and σ1 receptor agonist. CN exhibits great efficacy at very low doses, delaying cognitive impairment and alleviating Aβ load in animal models of AD. However, CN functions on other remains related to this pathology remain to be investigated. The present study sought to evaluate the effects of CN treatment at a dosage of 0.1 mg kg[-1] (p.o) over an eight-week period in the 3xTg-AD mouse model. In silico studies, as well as biochemical and immunofluorescence assays, were conducted on brain tissue to investigate the CN effects on acetylcholine metabolism, redox system, and glial cell activation-related biomarkers in brain regions that are relevant for memory. The results demonstrated that CN effectively rescues cognitive impairment of 3xTg-AD mice by influencing glial activity to reduce existing Aβ plaques but also modulating acetylcholine metabolism and the enzymatic response of proteins involved in the redox system. Our outcomes reinforced the potential of CN in treating AD by acting on multiple pathways altered in this disease.}, } @article {pmid39940989, year = {2025}, author = {Mertaş, B and Boşgelmez, Iİ}, title = {The Role of Genetic, Environmental, and Dietary Factors in Alzheimer's Disease: A Narrative Review.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, doi = {10.3390/ijms26031222}, pmid = {39940989}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/genetics/etiology ; Diet ; Gene-Environment Interaction ; Epigenesis, Genetic ; Risk Factors ; Genetic Predisposition to Disease ; Diet, Mediterranean ; Gastrointestinal Microbiome ; Animals ; }, abstract = {Alzheimer's disease (AD) is one of the most common and severe forms of dementia and neurodegenerative disease. As life expectancy increases in line with developments in medicine, the elderly population is projected to increase in the next few decades; therefore, an increase in the prevalence of some diseases, such as AD, is also expected. As a result, until a radical treatment becomes available, AD is expected to be more frequently recorded as one of the top causes of death worldwide. Given the current lack of a cure for AD, and the only treatments available being ones that alleviate major symptoms, the identification of contributing factors that influence disease incidence is crucial. In this context, genetic and/or epigenetic factors, mainly environmental, disease-related, dietary, or combinations/interactions of these factors, are assessed. In this review, we conducted a literature search focusing on environmental factors such as air pollution, toxic elements, pesticides, and infectious agents, as well as dietary factors including various diets, vitamin D deficiency, social factors (e.g., tobacco and alcohol use), and variables that are affected by both environmental and genetic factors, such as dietary behavior and gut microbiota. We also evaluated studies on the beneficial effects of antibiotics and diets, such as the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) and Mediterranean diets.}, } @article {pmid39940973, year = {2025}, author = {Shan, X and Li, D and Yin, H and Tao, W and Zhou, L and Gao, Y and Xing, C and Zhang, C}, title = {Recent Insights on the Role of Nuclear Receptors in Alzheimer's Disease: Mechanisms and Therapeutic Application.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, doi = {10.3390/ijms26031207}, pmid = {39940973}, issn = {1422-0067}, support = {513006//Project of National Natural Science Foundation of China/ ; 202203a07020031//Anhui Province Key Research and Development Program Project/ ; KJ2021ZD0065, KJ2019A0314, KJ2018ZD031 and 1408085MH196//the Provincial Natural Science Foundation of Anhui Province/ ; 2023CXMMTCM014//Grand Health Research Institute of Hefei Comprehensive National Science Center, Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM 'Jie Bang Gua Shuai' Project/ ; }, mesh = {*Alzheimer Disease/metabolism/pathology/drug therapy ; Humans ; *Receptors, Cytoplasmic and Nuclear/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; }, abstract = {Nuclear receptors (NRs) are ligand-activated transcription factors that regulate a broad array of biological processes, including inflammation, lipid metabolism, cell proliferation, and apoptosis. Among the diverse family of NRs, peroxisome proliferator-activated receptors (PPARs), estrogen receptor (ER), liver X receptor (LXR), farnesoid X receptor (FXR), retinoid X receptor (RXR), and aryl hydrocarbon receptor (AhR) have garnered significant attention for their roles in neurodegenerative diseases, particularly Alzheimer's disease (AD). NRs influence the pathophysiology of AD through mechanisms such as modulation of amyloid-beta (Aβ) deposition, regulation of inflammatory pathways, and improvement of neuronal function. However, the dual role of NRs in AD progression, where some receptors may exacerbate the disease while others offer therapeutic potential, presents a critical challenge for their application in AD treatment. This review explores the functional diversity of NRs, highlighting their involvement in AD-related processes and discussing the therapeutic prospects of NR-targeting strategies. Furthermore, the key challenges, including the necessity for the precise identification of beneficial NRs, detailed structural analysis through molecular dynamics simulations, and further investigation of NR mechanisms in AD, such as tau pathology and autophagy, are also discussed. Collectively, continued research is essential to clarify the role of NRs in AD, ultimately facilitating their potential use in the diagnosis, prevention, and treatment of AD.}, } @article {pmid39940966, year = {2025}, author = {Jamerlan, AM and Shim, KH and Sharma, N and An, SSA}, title = {Multimer Detection System: A Universal Assay System for Differentiating Protein Oligomers from Monomers.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, doi = {10.3390/ijms26031199}, pmid = {39940966}, issn = {1422-0067}, support = {RS-2023-00251396//National Research Foundation of Korea/ ; 2021R1A6A1A03038996//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Protein Multimerization ; alpha-Synuclein/metabolism/chemistry ; Amyloid beta-Peptides/metabolism/chemistry ; Neurodegenerative Diseases/metabolism/diagnosis ; Protein Aggregates ; DNA-Binding Proteins/metabolism/chemistry ; tau Proteins/metabolism/chemistry ; Protein Aggregation, Pathological/metabolism ; }, abstract = {Depositions of protein aggregates are typical pathological hallmarks of various neurodegenerative diseases (NDs). For example, amyloid-beta (Aβ) and tau aggregates are present in the brain and plasma of patients with Alzheimer's disease (AD); α-synuclein in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); mutant huntingtin protein (Htt) in Huntington's disease (HD); and DNA-binding protein 43 kD (TDP-43) in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The same misfolded proteins can be present in multiple diseases in the form of mixed proteinopathies. Since there is no cure for all these diseases, understanding the mechanisms of protein aggregation becomes imperative in modern medicine, especially for developing diagnostics and therapeutics. A Multimer Detection System (MDS) was designed to distinguish and quantify the multimeric/oligomeric forms from the monomeric form of aggregated proteins. As the unique epitope of the monomer is already occupied by capturing or detecting antibodies, the aggregated proteins with multiple epitopes would be accessible to both capturing and detecting antibodies simultaneously, and signals will be generated from the oligomers rather than the monomers. Hence, MDS could present a simple solution for measuring various conformations of aggregated proteins with high sensitivity and specificity, which may help to explore diagnostic and treatment strategies for developing anti-aggregation therapeutics.}, } @article {pmid39940900, year = {2025}, author = {la Torre, A and Lo Vecchio, F and Angelillis, VS and Gravina, C and D'Onofrio, G and Greco, A}, title = {Reinforcing Nrf2 Signaling: Help in the Alzheimer's Disease Context.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, doi = {10.3390/ijms26031130}, pmid = {39940900}, issn = {1422-0067}, mesh = {*NF-E2-Related Factor 2/metabolism ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Humans ; *Signal Transduction ; *Oxidative Stress ; Animals ; Antioxidants/metabolism/therapeutic use ; Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Oxidative stress plays a role in various pathophysiological diseases, including neurogenerative diseases, such as Alzheimer's disease (AD), which is the most prevalent neuro-pathology in the aging population. Oxidative stress has been reported to be one of the earliest pathological alterations in AD. Additionally, it was demonstrated that in older adults, there is a loss of free radical scavenging ability. The Nrf2 transcription factor is a key regulator in antioxidant defense systems, but, with aging, both the amount and the transcriptional activity of Nrf2 decrease. With the available treatments for AD being poorly effective, reinforcing the antioxidant defense systems via the Nrf2 pathway may be a way to prevent and treat AD. To highlight the predominant role of Nrf2 signaling in defending against oxidative stress and, therefore, against neurotoxicity, we present an overview of the natural compounds that exert their own neuroprotective roles through the activation of the Nrf2 pathway. This review is an opportunity to promote a holistic approach in the treatment of AD and to highlight the need to further refine the development of new potential Nrf2-targeting drugs.}, } @article {pmid39940653, year = {2025}, author = {Silva, CFM and Guerrinha, APDMS and Carvalho, S and Pinto, DCGA and Silva, AMS}, title = {1,3,5-Triazine: A Promising Molecular Scaffold for Novel Agents for the Treatment of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, doi = {10.3390/ijms26030882}, pmid = {39940653}, issn = {1422-0067}, support = {UIDP/50006/2020//Fundação para a Ciência e Tecnologia/ ; UIDB/50006/2020//Fundação para a Ciência e Tecnologia/ ; LA/P/0008/2020//Fundação para a Ciência e Tecnologia/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Triazines/chemistry/therapeutic use/pharmacology ; Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; Animals ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors/chemistry ; Acetylcholinesterase/metabolism/chemistry ; }, abstract = {Currently, Alzheimer's disease (AD) is one of the most frequent forms of dementia. From a molecular perspective, the molecular characteristics that better define this disease consist of abnormal protein deposits between neuronal cells, namely senile plaques (SPs) and neurofibrillary tangles (NFTs), consisting of protein aggregates of amyloid-β and hyperphosphorylated tau protein, respectively. In addition to these protein aggregates, a third molecular hallmark of AD consists of depleted neurotransmitter acetylcholine levels. To date, the treatments developed for this disease are mostly focused on the use of AChE inhibitors, presenting only a symptomatic approach against the disease instead of a cure. Triazines are nitrogen-containing heterocyclic compounds that, throughout the years, have attracted a lot of curiosity from medicinal chemists for presenting numerous biological properties and being widely present in nature. In particular, this class of compounds has been associated with inhibiting several biological targets, emerging as a promising class for developing new pharmacological agents. However, there is still a scarcity of knowledge regarding the potential of this type of compound against any of the hallmarks of AD. For this reason, this paper intends to fulfill this absence by highlighting the potential of a subclass of triazines, 1,3,5-triazines (sym-triazines), as promising molecules for developing novel AD treatments. Thus, an in-depth analysis of 1,3,5-triazine derivatives is performed regarding its inhibitory activity against AChE (cholinergic hypothesis) and its capability to inhibit amyloid-β formation and aggregation (amyloid hypothesis). Through this analysis, it is possible to indicate some structural features optimal for each described activity, a compilation that we believe to be essential for the scientific community in this never-ending pursuit.}, } @article {pmid39940249, year = {2025}, author = {Reiriz, M and Beltrán-Velasco, AI and Echeverry-Alzate, V and Martínez-Miguel, E and Gómez-Senent, S and Uceda, S and Clemente-Suárez, VJ}, title = {Bifidobacterium infantis and Bifidobacterium breve Improve Symptomatology and Neuronal Damage in Neurodegenerative Disease: A Systematic Review.}, journal = {Nutrients}, volume = {17}, number = {3}, pages = {}, doi = {10.3390/nu17030391}, pmid = {39940249}, issn = {2072-6643}, mesh = {Humans ; *Bifidobacterium breve ; *Probiotics/therapeutic use ; *Neurodegenerative Diseases/therapy ; *Parkinson Disease/therapy/microbiology ; Animals ; *Alzheimer Disease/therapy/microbiology ; Bifidobacterium longum subspecies infantis ; Neurons ; }, abstract = {Background/Objectives: This systematic review focused on collecting the most significant findings on the impact of the administration of Bifidobacterium infantis (or Bifidobacterium longum subps. infantis) and Bifidobacterium breve, alone, in conjunction, or in combination with other strains, in the treatment of neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). These diseases are characterized by the progressive degeneration of neurons, resulting in a broad spectrum of clinical manifestations. AD is typified by a progressive decline in cognitive abilities, while PD is marked by motor symptoms associated with the loss of dopamine (DA). Methods: Five different databases, ScienceDirect, Scopus, Wiley, PubMed, and Web of Science (WoS), were reviewed and the studies were screened for inclusion by the following criteria: (i) studies that specifically evaluated the use of Bifidobacterium infantis, Bifidobacterium longum subsp. infantis, or Bifidobacterium breve as a therapeutic intervention, either in human or animal models, in the context of neurodegenerative diseases; (ii) the studies were required to address one or more of the pathologies examined in this article, and the pathologies included, but were not limited to, neurodegeneration, Alzheimer's disease, Parkinson's disease, and oxidative stress; (iii) the full text was accessible online; and (iv) the article was written in English. Results: The data suggest that these probiotics have neuroprotective effects that may delay disease progression. Conclusions: This study provides updated insights into the use of these Bifidobacterium strains in neurodegenerative diseases like AD and PD, with the main limitation being the limited number of clinical trials available.}, } @article {pmid39939242, year = {2025}, author = {Kuriyama, M and Wang, CF and Nagase, T and Sohma, Y and Kanai, M and Hori, Y and Tomita, T}, title = {Proteolytic therapeutic modalities for amyloidoses: Insights into immunotherapy, PROTAC, and photo-oxygenation.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {}, number = {}, pages = {e00548}, doi = {10.1016/j.neurot.2025.e00548}, pmid = {39939242}, issn = {1878-7479}, abstract = {Amyloidoses, which are characterized by abnormal accumulation of amyloid proteins leading to organ dysfunction, represent a major therapeutic challenge. They include neurodegenerative diseases, such as Alzheimer disease (AD), tauopathies and synucleinopathies. Since amyloids are causative factors in these diseases, the importance of proteolytic methods to remove amyloid, such as immunotherapy and Proteolysis Targeting Chimera (PROTAC) technology, has been recognized. Immunotherapy removes target proteins by antibody-mediated reactions and is the most studied method in practical use for the treatment of AD. PROTAC is a small molecule that uses the ubiquitin-proteasome system to degrade intracellular target proteins and has demonstrated efficacy in clinical trials for other diseases. In addition, a new modality called photo-oxygenation has been developed. Photo-oxygenation is a method of selectively adding oxygen to amyloid using a photocatalyst, which is a small molecule compound that is activated by light. Studies both in vitro and in vivo have shown promising results in inhibiting amyloid aggregation and enhancing the clearance of amyloid proteins. In this review, we introduce and discuss these proteolytic modalities, and provide insights into potential future directions for the clinical application in amyloidoses.}, } @article {pmid39939891, year = {2025}, author = {Zúñiga, CH and Acosta, BI and Menchaca, R and Amescua, CA and Hong, S and Hui, L and Gil, M and Rhee, YH and Yoon, S and Kim, M and Chang, PY and Kim, YM and Song, PY and Betito, K}, title = {Treatment of Alzheimer's Disease subjects with expanded non-genetically modified autologous natural killer cells (SNK01): a phase I study.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {40}, pmid = {39939891}, issn = {1758-9193}, abstract = {BACKGROUND: The importance of natural killer (NK) cells of the innate immune system in neurodegenerative disease has largely been overlooked despite studies demonstrating their ability to reduce neuroinflammation (thought to be mediated by the elimination of activated T cells, degradation of protein aggregates and secretion of anti-inflammatory cytokines). SNK01 is an autologous non-genetically modified NK cell product showing increased activity in vitro. We hypothesized that SNK01 can be safely infused to reduce neuroinflammation in Alzheimer's Disease (AD) patients.

METHODS: SNK01 was produced and characterized for its ability to eliminate activated T cells, degrade protein aggregates and secrete anti-inflammatory cytokines. In this phase 1 study, SNK01 was administered intravenously every three weeks for a total of 4 treatments using a 3 + 3 dose escalation design (1, 2 and 4 × 10[9] cells) in subjects with either mild, moderate, or severe AD (median CDR-SB 10.0). Cognitive assessments and cerebrospinal fluid biomarkers associated with protein aggregation, neurodegeneration and neuroinflammation including amyloid-β42 and 42/40, α-synuclein, total Tau, pTau217 and pTau181, neurofilament light, GFAP and YKL-40 analyses were performed at baseline, at 1 and 12 weeks after the last dose. The primary endpoint was safety; secondary endpoints included changes in cognitive assessments and biomarker levels.

RESULTS: In preclinical in vitro studies, SNK01 were able to uptake and degrade the protein aggregates of amyloid-β and α-synuclein, produce anti-inflammatory cytokines and eliminate activated T cells. In the phase 1 clinical study, eleven subjects were enrolled (10 evaluable). No drug-related adverse events were observed. Despite 70% of subjects being treated at relatively low doses of SNK01 (1 and 2 × 10[9] cells), 50-70% of all enrolled subjects had stable/improved CDR-SB, ADAS-Cog and/or MMSE scores and 90% had stable/improved ADCOMS at one-week after the last dose. SNK01 also appeared to have beneficial effects on protein aggregate levels and neuroinflammatory biomarkers in the cerebrospinal fluid, with decreases in pTau181 and GFAP appearing to be dose-dependent.

CONCLUSIONS: SNK01 was well tolerated and appeared to have clinical activity in AD while also having beneficial effects on cerebrospinal fluid protein and neuroinflammatory biomarker levels. A larger trial with a higher dosing/duration has been initiated in the USA in 2023.

TRIAL REGISTRATION: www.

CLINICALTRIALS: gov NCT04678453, date of registration: 2020-12-22.}, } @article {pmid39938857, year = {2025}, author = {Aqil, A and Yasmeen, I and Parveen, I and Nadaf, A and Jiba, U and Adil, M and Hasan, N and Kesharwani, P and Ahmad, FJ}, title = {In-Depth Analysis of Mangiferin and Its Formulations for Alleviating Neurodegenerative Diseases: A Comprehensive Review.}, journal = {European journal of pharmacology}, volume = {}, number = {}, pages = {177354}, doi = {10.1016/j.ejphar.2025.177354}, pmid = {39938857}, issn = {1879-0712}, abstract = {Millions of individuals worldwide are impacted by a group of conditions known as neurodegenerative disorders, characterized by the degeneration of neurons. The most prevalent neurodegenerative diseases include Alzheimer's disease and Parkinson's disease. Mangiferin, a natural polyphenol found in mangoes, is potentially beneficial for addressing neurodegenerative disorders. Its antioxidant properties help counteract oxidative stress, a common factor in most of the neurovegetative. Novel therapeutics of mangiferin have been introduced by different researchers to facilitate the treatment of various neurodegenerative disorders. In this article, we have reviewed and evaluated every relevant facet of mangiferin, which can augment comprehension regarding the therapeutic approach of the drug, pharmacodynamic and pharmacokinetic properties, adverse effects, advantages and adverse effects, various kinds of interactions, and innovative formulations.}, } @article {pmid39938752, year = {2025}, author = {Zhu, Y and Tian, M and Lu, S and Qin, Y and Zhao, T and Shi, H and Li, Z and Qin, D}, title = {The Antioxidant Role of Aromatic Plant Extracts in Managing Neurodegenerative Diseases: A Comprehensive Review.}, journal = {Brain research bulletin}, volume = {}, number = {}, pages = {111253}, doi = {10.1016/j.brainresbull.2025.111253}, pmid = {39938752}, issn = {1873-2747}, abstract = {Neurodegenerative diseases (NDDs) are a class of cognitive and motor disorders including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), and others. They are caused by lesions in cells and tissues of the central nervous system, resulting in corresponding dysfunctions and consequent decline in cognitive and motor functions. Neural tissues are extremely vulnerable to oxidative stress, which plays critical biological roles in NDDs. Aromatic compounds are found extensively in natural plants and have substantial effects of anti-oxidative stress damage, which not only have a wide range of research applications in cosmetics, foods, etc., but are also frequently utilized in the treatment of various central nervous system diseases. This review summarizes the relevant oxidative stress mechanisms in NDDs (AD, PD, HD, and ALS) and reviews aromatic compounds such as polyphenols, terpenoids, and flavonoids that can be used in the management of neurodegenerative diseases, as well as their specific mechanisms of antioxidant action. This review will serve as a reference for future experimental studies on neurodegenerative illnesses while also offering fresh insights into clinical therapy.}, } @article {pmid39938597, year = {2025}, author = {Ratne, N and Jari, S and Tadas, M and Katariya, R and Kale, M and Kotagale, N and Madia, D and Umekar, M and Taksande, B}, title = {Neurobiological Role and Therapeutic Potential of Exercise-Induced Irisin in Alzheimer's Disease Management.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {102687}, doi = {10.1016/j.arr.2025.102687}, pmid = {39938597}, issn = {1872-9649}, abstract = {Alzheimer's disease (AD) poses a significant obstacle in today's healthcare landscape, with limited effective treatments. Recent studies have revealed encouraging findings about how exercise-triggered irisin might help slow down the advancement of AD. Irisin, a myokine, released during physical activity, has garnered significant attention for its pleiotropic effects, extending beyond its traditional role in metabolic regulation. This review explores irisin's multifaceted potential in combating AD. Research indicates that irisin enhances synaptic plasticity, crucial for learning and memory, and exhibits neuroprotective properties that may slow AD progression by safeguarding neurons from degeneration. Additionally, irisin's ability to modulate inflammatory responses is significant, as neuroinflammation is a key feature of AD pathology. Irisin may also influence the metabolism and clearance of amyloid-beta plaques and tau tangles, hallmark pathological markers of AD. Furthermore, irisin boosts brain-derived neurotrophic factor (BDNF) expression, vital for neuronal health, and improves insulin glucose regulation, addressing impaired brain insulin signaling observed in AD. Exercise-induced irisin presents a non-pharmacological strategy, leveraging physical activity's brain health benefits. Future research should focus on elucidating irisin's mechanisms and conducting clinical trials to assess its therapeutic efficacy and safety in AD patients. Overall, irisin therapy offers a promising avenue for AD treatment, potentially slowing disease progression and enhancing cognitive function, paving the way for innovative therapeutic strategies in the fight against AD.}, } @article {pmid39938415, year = {2025}, author = {Roney, M and Uddin, MN and Khan, AA and Fatima, S and Mohd Aluwi, MFF and Hamim, SMI and Ahmad, A}, title = {Repurposing of dipeptidyl peptidase FDA-approved drugs in Alzheimer's disease using network pharmacology and in-silico approaches.}, journal = {Computational biology and chemistry}, volume = {116}, number = {}, pages = {108378}, doi = {10.1016/j.compbiolchem.2025.108378}, pmid = {39938415}, issn = {1476-928X}, abstract = {Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) have similar clinical characteristics in the brain and islet, as well as an increased incidence with ageing and familial susceptibility. Therefore, in recent years there has been a great desire for research that elucidates how anti-diabetic drugs affect AD. This work attempts to first elucidate the possible mechanism of action of DPP-IV inhibitors in the treatment of AD by employing techniques from network pharmacology, molecular docking, molecular dynamic simulation, principal component analysis, and MM/PBSA. A total of 463 targets were identified from the SwissTargetPrediction and 784 targets were identified from the SuperPred databases. 79 common targets were screened using the PPI network. The GO and KEGG analyses indicated that the activity of DPP-IV against AD potentially involves the hsa04080 neuroactive ligand-receptor interaction signalling pathway, which contains 17 proteins, including CHRM2, CHRM3, CHRNB1, CHRNB4, CHRM1, PTGER2, CHRM4, CHRM5, TACR2, HTR2C, TACR1, F2, GABRG2, MC4R, HTR7, CHRNG, and DRD3. Molecular docking demonstrated that sitagliptin had the greatest binding affinity of -10.7 kcal/mol and established hydrogen bonds with the Asp103, Ser107, and Asn404 residues in the active site of the CHRM2 protein. Molecular dynamic simulation, PCA, and MM/PBSA were performed for the complex of sitagliptin with the above-mentioned proteins, which revealed a stable complex throughout the simulation. The work identifies the active component and possible molecular mechanism of sitagliptin in the treatment of AD and provides a theoretical foundation for future fundamental research and practical implementation.}, } @article {pmid39937020, year = {2025}, author = {Spina, E and Ferrari, RR and Pellegrini, E and Colombo, M and Poloni, TE and Guaita, A and Davin, A}, title = {Mitochondrial Alterations, Oxidative Stress, and Therapeutic Implications in Alzheimer's Disease: A Narrative Review.}, journal = {Cells}, volume = {14}, number = {3}, pages = {}, pmid = {39937020}, issn = {2073-4409}, support = {PNRR-MAD-2022-12375822//European Union/ ; }, mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Mitochondria/metabolism ; *Oxidative Stress ; Animals ; Reactive Oxygen Species/metabolism ; }, abstract = {The relationship between aging, mitochondrial dysfunction, neurodegeneration, and the onset of Alzheimer's disease (AD) is a complex area of study. Aging is the primary risk factor for AD, and it is associated with a decline in mitochondrial function. This mitochondrial dysfunction is believed to contribute to the neurodegenerative processes observed in AD. Neurodegeneration in AD is characterized by the progressive loss of synapses and neurons, particularly in regions of the brain involved in memory and cognition. It is hypothesized that mitochondrial dysfunction plays a pivotal role by disrupting cellular energy metabolism and increasing the production of reactive oxygen species (ROS), which can damage cellular components and exacerbate neuronal loss. Despite extensive research, the precise molecular pathways linking mitochondrial dysfunction to AD pathology are not fully understood. Various hypotheses have been proposed, including the mitochondrial cascade hypothesis, which suggests that mitochondrial dysfunction is an early event in AD pathogenesis that triggers a cascade of cellular events leading to neurodegeneration. With this narrative review, we aim to summarize some specific issues in the literature on mitochondria and their involvement in AD onset, with a focus on the development of therapeutical strategies targeting the mitochondria environment and their potential application for the treatment of AD itself.}, } @article {pmid39936411, year = {2025}, author = {Si, Y and Meng, B and Qi, F}, title = {Age- and Genotype-Dependent Effects of Chronic Nicotine on Presenilin1/2 Double Knockout Mice: From Behavior to Molecular Pathways.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050363992250127072919}, pmid = {39936411}, issn = {1875-5828}, abstract = {INTRODUCTION: The potential therapeutic role of nicotine in Alzheimer's disease (AD) remains controversial, particularly regarding its age-dependent effects and underlying mechanisms.

METHOD: This study investigated the impact of chronic nicotine administration on cognitive function and molecular pathways in Presenilin 1/2 double knockout (DKO) mice, an amyloid-β-independent model of AD. Three-month-old and eight-month-old DKO and wild-type (WT) mice received oral nicotine treatment (100 μg/ml) for three months. Behavioral assessments revealed that while the 6-month-old cohort showed no significant differences between nicotine-treated and control groups regardless of genotype, nicotine improved contextual fear memory in 11-month-old DKO mice but impaired nest-building ability and cued fear memory in age-matched WT controls. Transcriptome analysis of the prefrontal cortex identified distinct molecular responses to nicotine between genotypes.

RESULT: In DKO mice, nicotine modulated neuropeptide signaling and reduced astrocyte activation, while in WT mice, it disrupted cytokine-cytokine receptor interaction and neuroactive ligand- receptor interaction pathways. Western blot analysis revealed that nicotine treatment significantly reduced tau hyperphosphorylation and GFAP expression in 11-month-old DKO mice, which was further confirmed by immunohistochemistry showing decreased astrocyte activation in multiple brain regions.

CONCLUSION: These findings demonstrate that nicotine's effects on cognition and molecular pathways are both age- and genotype-dependent, suggesting its therapeutic potential may be limited to specific stages of neurodegeneration while potentially having adverse effects in healthy aging brains.}, } @article {pmid39936324, year = {2025}, author = {Divya, and Faruq, M and Nazir, SS and Kaushik, P and Parvez, S and Vohora, D}, title = {Ganaxolone Reverses the Effect of Amyloid β-Induced Neurotoxicity by Regulating the Liver X Receptor Expression in APP Transfected SH-SY5Y Cells and Murine Model of Alzheimer's Disease.}, journal = {Journal of neurochemistry}, volume = {169}, number = {2}, pages = {e70007}, doi = {10.1111/jnc.70007}, pmid = {39936324}, issn = {1471-4159}, support = {45/05/2020-PHA/BMS//Indian Council of Medical Research/ ; IIRP/2023/1050//Indian Council of Medical Research/ ; }, mesh = {*Liver X Receptors/metabolism ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; *Amyloid beta-Peptides/toxicity ; Humans ; *Amyloid beta-Protein Precursor/genetics/metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Mice, Transgenic ; Peptide Fragments/toxicity ; Male ; Neuroprotective Agents/pharmacology ; Transfection ; Mice, Inbred C57BL ; Pregnanolone/analogs & derivatives ; }, abstract = {Inhibiting β-amyloid aggregation and enhancing its clearance are the key strategies in Alzheimer's disease (AD) treatment. Liver X receptors (LXRs) plays a crucial role in cholesterol homeostasis and inflammation, and their activation can clear Aβ aggregates in AD. Allopregnanolone, a neurosteroid, positively influences AD through LXR regulation, while ganaxolone, its synthetic analog, is known for its neuroprotective properties. This study explores the effect of ganaxolone on LXR activation and regulation of genes involved in mitigating Aβ toxicity and tauopathy in SH-SY5Y cells transfected with APP695 Swe/Ind plasmid and an Aβ1-42 induced AD mouse model. Molecular docking stimulations indicated ganaxolone's binding and interaction with LXRβ. Subsequently, transfected neuronal cells exhibited increased mRNA levels of APP, TNF-α and IL-1β, decreased cell viability, reduced MMP and altered protein expression of Aβ, LXR, BCL-2, APOE, ABCA1, along with increased levels of mROS, Bax, and caspase 3 activity. Ganaxolone treatment significantly abrogated Aβ-induced effect in transfected neuronal cells by enhancing LXRβ expression, inducing LXR:RXR colocalization, thereby increasing APOE and ABCA1 expression. It also decreased tau mRNA levels in transfected cells. Importantly, in AD mice, ganaxolone ameliorated cognitive impairment, reduced Aβ toxicity, tau levels, and neuroinflammatory markers, restored mitochondrial function, and decreased neuronal apoptosis. Taken together, these novel results highlight the central role of LXR in mediating Aβ-induced toxicity and provide preclinical evidence for ganaxolone as a potential agent to reduce toxicity in an LXR-dependent manner. This may serve as a promising treatment strategy to slow or prevent neurodegeneration in AD patients.}, } @article {pmid39936091, year = {2025}, author = {Wu, J and Sun, H and Zhao, Y and Lian, L and Bian, H and Guo, Y and Li, D and Huang, L}, title = {The spectrum-efficacy correlation of Kai-Xin-San for cognition of Aβ42 transgenic Drosophila and verification of its active ingredients.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1538837}, pmid = {39936091}, issn = {1663-9812}, abstract = {INTRODUCTION: This study aims to establish the fingerprint spectra of Kai-Xin-San (KXS) and investigate its spectrum-effect relationship in treating Alzheimer's disease (AD).

METHODS: Initially, the fingerprints of 15 batches of KXS were established and analyzed using HPLC, with the method's precision, stability, and repeatability thoroughly evaluated. Subsequently, the effects of the 15 batches of KXS were assessed in an olfactory escape memory experiment, utilizing Aβ42 transgenic drosophila as a model. Finally, the spectrum-effect relationship between the KXS fingerprint and memory improvement was analyzed, with the active ingredients subjected to validation testing.

RESULTS: The results identified seventeen common peaks in the fingerprint, and eight active components were determined: polygalaxanthone III, 3-6-disinapoylsucrose, ginsenoside Rg1, ginsenoside Rb1, β-asarone, α-asarone, dehydrotumulosic acid, and dehydropachymic acid. Treatment with KXS (1%, for 4 days) significantly enhanced the performance index of Aβ42 flies in the olfactory experiment. Both spectrum-effect analysis and validation tests indicated that polygalaxanthone III, ginsenoside Rg1, ginsenoside Rb1, β-asarone, and α-asarone were positively correlated with the performance index and improved the performance index in the olfactory experiment. The HPLC fingerprint method for KXS demonstrated excellent precision, accuracy, and reproducibility, making it suitable for quality evaluation and control of KXS. Polygalaxanthone III, ginsenoside Rg1, ginsenoside Rb1, β-asarone, and α-asarone are identified as potential active ingredients of KXS for anti-AD effects.

DISCUSSION: These findings provide an experimental basis for developing new drugs based on KXS and its active ingredient combinations.}, } @article {pmid39935618, year = {2025}, author = {Petersen, RC and Graf, A and Brady, C and De Santi, S and Florian, H and Landen, J and Pontecorvo, M and Randolph, C and Sink, K and Carrillo, M and Weber, CJ}, title = {Operationalizing selection criteria for clinical trials in Alzheimer's disease: Biomarker and clinical considerations: Proceedings from the Alzheimer's Association Research Roundtable (AARR) Fall 2021 meeting.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70038}, pmid = {39935618}, issn = {2352-8737}, abstract = {UNLABELLED: The design of clinical trials in Alzheimer's disease (AD) must consider the development of new plasma, cerebrospinal fluid (CSF), and imaging biomarkers. They must also define clinically meaningful outcomes for patients and set endpoints that measure these outcomes accurately. With the accelerated United States Food and Drug Administration (FDA) approval of the first anti-amyloid, disease-modifying treatment for AD, a monoclonal antibody called aducanumab, the landscape of clinical trial design is evolving. Enrolment in clinical trials may be impacted by the availability of this and other treatments, and trial design must take into consideration that patients may desire a disease-modifying treatment rather than potentially being randomized to the placebo arm. The Alzheimer's Association Research Roundtable (AARR) Fall 2021 meeting discussed the consideration of well-defined AD staging criteria in protocol design and how they influence more standardized inclusion/exclusion criteria for trials, as well as what constitutes meaningful differentiation between the stages. Discussion explored the current state of knowledge regarding biomarkers and how they can inform AD staging criteria, as many trials are now designed based on specific biomarker features, further underscoring the importance of coordinating AD staging criteria and biomarkers. The relationship between cognition and biomarkers has been studied and this must continue as trials move forward. Researchers, patients, clinicians, regulatory scientists, and payers discussed the state of the field as well as the future of symptomatic Alzheimer's disease clinical trials.

HIGHLIGHTS: The Alzheimer's Association Research Roundtable (AARR) convened leaders from academia and industry as well as patients, care partners, clinicians, regulators, and payers to discuss the topic of operationalizing selection criteria for clinical trials and the role of biomarkers.Well-defined Alzheimer's disease (AD) staging criteria are an important consideration in study protocol design.Staging criteria and biomarkers must be coordinated to yield high-quality clinical trial results that have meaning for patients with AD by selecting a population most likely to benefit from a specific treatment.}, } @article {pmid39935616, year = {2025}, author = {Hajós, M and Pandey, K and Singer, AC and Duong, D and Bitarafan, S and Shpokayte, M and Malchano, Z and Kern, R and Lah, JJ and Levey, AI and Seyfried, NT}, title = {CSF proteomics reveals changes in myelin and synaptic biology after Spectris treatment.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70051}, pmid = {39935616}, issn = {2352-8737}, abstract = {INTRODUCTION: Brain steady-state gamma oscillations evoked using a non-invasive medical device (Spectris) have shown potential clinical benefits in patients with mild-moderate Alzheimer's disease (AD), including reduced functional and cognitive decline, reduced brain volume and myelin loss, and increased brain functional connectivity. We analyzed changes in cerebrospinal fluid (CSF) proteins after Spectris treatment in mild cognitive impairment (MCI) and their relationship to established biological pathways implicated in AD.

METHODS: Unbiased proteomic analysis of CSF samples from participants with amyloid-positive MCI (n = 10) was conducted from the FLICKER (NCT03543878) clinical trial. Participants used the Cognito Therapeutics medical device (Spectris), confirmed to evoke steady-state gamma oscillations. Participants were instructed to use the device daily for 1 hour each day during the trial. CSF was collected prior to the start of stimulation and after 4 and 8 weeks of treatment. The proteome was analyzed using tandem mass tag mass spectrometry.

RESULTS: Differential expression analysis of proteins at baseline and after 8 weeks of treatment (N = 5) revealed that 110 out of 2951 proteins met the significance threshold (analysis of variance, P < 0.05, no false discovery rate). Sixty proteins were upregulated, and 50 proteins were downregulated after treatment. Changes in protein expression were mapped to the consensus human AD protein network, representing co-expressed and functionally linked modules linked to cell type and biochemical pathways. Treatment altered CSF proteins linked to AD-related brain proteome modules, including those involved in myelination (proteolipid protein 1, ecotropic viral integration site 2A), synaptic and neuroimmune functions, and regulation of cellular lipid transportation. Biological pathway analysis revealed that most impacted pathways were associated with lipoproteins, cholesterol, phospholipids processing, and phosphatidylcholine biosynthesis.

DISCUSSION: The CSF proteomic changes observed in this study suggest pleiotropic effects on multiple pathways involved in AD, including myelination, synaptic and neuroimmune function, and lipid transport. These findings are also consistent with observations of white matter and myelin preservation after Spectris treatment of AD.

HIGHLIGHTS: We analyzed changes in cerebrospinal fluid (CSF) proteins in response to sensory-evoked gamma oscillations in individuals with mild cognitive impairment.Sensory evoked steady-state gamma oscillations were evoked by Spectris medical device.Changes in CSF proteins were observed after 8 weeks of daily 1 hour treatment.Affected proteins were related to myelination, synaptic and neuroimmune functions, and regulation of cellular lipid transportation.Proteomic changes support clinical outcomes and myelin preservation of Spectris treatment.}, } @article {pmid39935341, year = {2025}, author = {Menon, J and Kantipudi, SJ and Vinoth, S and Kuchipudi, JD}, title = {Prevalence of subjective cognitive decline and its association with physical health problems among urban community dwelling elderly population in South India.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {e14505}, doi = {10.1002/alz.14505}, pmid = {39935341}, issn = {1552-5279}, abstract = {INTRODUCTION: No studies in India have explored subjective cognitive decline (SCD), a hallmark of stage II of preclinical Alzheimer's disease. This study aims to assess the prevalence and correlates of SCD in a South Indian, urban, elderly population.

METHODS: We screened 403 individuals 60 years of age and older using the Subjective Memory Complaints Questionnaire (SMCQ) and measured objective cognition with the Montreal Cognitive Assessment (MoCA). Physical health parameters were evaluated for all participants.

RESULTS: Among the participants, 377 (93.5%) reported subjective memory complaints. Of the 26 individuals without SCD, 15(57.7%) had objective cognitive impairment (MoCA <25). A total of 182 participants (45.2%) were identified with SCD. Higher educational attainment was significantly associated with fewer SCD reports and better cognitive performance (p < 0.001).

DISCUSSION: Subjective cognitive decline (SCD) is highly prevalent among older adults. Screening for SCD can help identify individuals at risk for Alzheimer's disease. SCD assessement combined with cost-effective biomarkers that confirms AD will help individuals to be identified for disease-modifying therapies.

HIGHLIGHTS: Nearly half of older adults population screened has reported subjective cognitive decline (SCD), highlighting the widespread occurrence of SCD in urban South India. Participants with higher educational attainment had significantly fewer memory complaints and performed better on cognitive assessments. SCD was prevalent even among individuals without major comorbid conditions such as diabetes and hypertension and those who were on regular treatment for metabolic and cardiovascular disorders. Identifying subjective cognitive decline (SCD) can facilitate early and accurate diagnosis of cognitive disorders and help delay progression to dementia. This highlights the importance of developing and implementing improved public health strategies to address these challenges. Further longitudinal studies are necessary to explore the progression of SCD to dementia, focusing on the interplay between cognitive health, biomarkers, and educational factors in the Indian population.}, } @article {pmid39934538, year = {2025}, author = {Balde, A and Benjakul, S and Nazeer, RA}, title = {A review on NLRP3 inflammasome modulation by animal venom proteins/peptides: mechanisms and therapeutic insights.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {39934538}, issn = {1568-5608}, support = {IF220025//Department of Science and Technology, Ministry of Science and Technology, India/ ; }, abstract = {The venom peptides from terrestrial as well as aquatic species have demonstrated potential in regulating the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a sophisticated assemblage present in immune cells responsible for detecting and responding to external mediators. The NLRP3 inflammasome plays a role in several pathological conditions such as type 2 diabetes, hyperglycemia, Alzheimer's disease, obesity, autoimmune disorders, and cardiovascular disorders. Venom peptides derived from animal venoms have been discovered to selectively induce certain signalling pathways, such as the NLRP3 inflammasome, mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Experimental evidence has demonstrated that venom peptides can regulate the expression and activation of the NLRP3 inflammasome, resulting in the secretion of pro-inflammatory cytokines including interleukin (IL)-1β and IL-18. Furthermore, these peptides have been discovered to impede the activation of the NLRP3 inflammasome, therefore diminishing inflammation and tissue injury. The functional properties of venom proteins and peptides obtained from snakes, bees, wasps, and scorpions have been thoroughly investigated, specifically targeting the NLRP3 inflammasome pathway, venom proteins and peptides have shown promise as therapeutic agents for the treatment of certain inflammatory disorders. This review discusses the pathophysiology of NLRP3 inflammasome in the onset of various diseases, role of venom as therapeutics. Further, various venom components and their role in the modulation of NLRP3 inflammasome are discoursed. A substantial number of venomous animals and their toxins are yet unexplored, and to comprehensively grasp the mechanisms of action of them and their potential as therapeutic agents, additional research is required which can lead to the development of novel therapeutics.}, } @article {pmid39933302, year = {2025}, author = {Li, H and Qiao, Z and Xiao, X and Cao, X and Li, Z and Liu, M and Jiao, Q and Chen, X and Du, X and Jiang, H}, title = {G protein-coupled receptors: A golden key to the treasure-trove of neurodegenerative diseases.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {46}, number = {}, pages = {155-168}, doi = {10.1016/j.clnu.2025.01.032}, pmid = {39933302}, issn = {1532-1983}, abstract = {G protein-coupled receptors (GPCRs) are a class of transmembrane proteins that distribute in various organs extensively. They can regulate physiological functions such as perception, neurotransmission and endocrinology through the synergies of signaling pathways. At present, Food and Drug Administration (FDA) have approved more than 500 drugs targeting GPCRs to treat a variety of conditions, including neurological diseases, gastrointestinal diseases and tumors. Conformational diversity and dynamic changes make GPCRs a star target for the treatment of neurodegenerative diseases. Moreover, GPCRs can also open biased signaling pathways for G protein and β-arrestin, which has unique functional selectivity and the possibility of overcoming side effects. Some studies believe that biased drugs will be the mainstream direction of drug innovation in the future. To disclose the essential role and research process of GPCRs in neurodegenerative diseases, we firstly reviewed several pivotal GPCRs and their mediated signaling pathways in Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Then we focused on the biased signaling pathway of GPCRs in these diseases. Finally, we updated the GPCR drugs under research for the treatment of neurodegenerative diseases in the clinical trials or approval. This review could provide valuable targets for precision therapy to cope with the dysfunction of neurodegenerative diseases in the future.}, } @article {pmid39932809, year = {2025}, author = {Pallares Di Nunzio, M and Martín Tenti, J and Arlego, M and Rosso, OA and Montani, F}, title = {Exploring the role of synaptic plasticity in the frequency-dependent complexity domain.}, journal = {Chaos (Woodbury, N.Y.)}, volume = {35}, number = {2}, pages = {}, doi = {10.1063/5.0239820}, pmid = {39932809}, issn = {1089-7682}, mesh = {*Neuronal Plasticity/physiology ; *Models, Neurological ; Humans ; Neurons/physiology ; Entropy ; Nonlinear Dynamics ; Action Potentials/physiology ; Nerve Net/physiology ; }, abstract = {The involvement of the neocortex in memory processes depends on neuronal plasticity, the ability to restructure inter-neuronal connections, which is essential for learning and long-term memory. Understanding these mechanisms is crucial for advancing early diagnosis and treatment of cognitive disorders such as Parkinson's, epilepsy, and Alzheimer's disease. This study explores a neuronal model with expanded populations, using information-theoretic cues to uncover dynamics underlying plasticity. By employing Bandt-Pompe's entropy-complexity (H×C) and Fisher entropy-information (H×F) planes, hidden patterns in neuronal activity are revealed. These methodologies are particularly suitable for analyzing nonlinear dynamics and causal relationships in time series. In addition, the Hénon map is applied to capture nonlinear behaviors, such as neural firing, highlighting the trade-off between stability and unpredictability in neural networks. Our approach integrates local field potential and intracranial electroencephalograms' data in multiple frequency bands, connecting computational models with experimental evidence. By addressing higher-order interactions, such as action potential triplets, this work advances the understanding of synaptic adjustments and their implications for neuronal complexity and cognitive disorders.}, } @article {pmid39932549, year = {2025}, author = {Grünblatt, E and Yde Ohki, CM and Schmitt-Böhrer, GA and Riederer, P and Walitza, S}, title = {Exploring the interplay of glucose metabolism, insulin resistance, and neurodegenerative pathologies: insights from streptozotocin and hypoglycaemic in vitro models.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {39932549}, issn = {1435-1463}, abstract = {Neurodegenerative diseases raise public health concerns. Recent evidence indicates that Alzheimer's disease (AD) sufferers will triple by 2050. The rising incidence of dementia diagnoses raises concerns about the socio-economical and emotional impact of this uncurable illness, which reduces quality of life through cognitive decline. Although genetic and environmental factors may contribute to its aetiology, neuropathological mechanisms underlying these disorders are still under investigation. One is brain insulin resistance (BIR), which has been associated with clinical cognitive dysfunction and linked to mitochondrial dysfunction, neurogenesis deficits, and cell death. Not limited to neurodegeneration, these phenotypes have been associated with other neuropsychiatric disorders. Streptozotocin (STZ), a diabetes-causing drug that targets pancreatic β-cells, may imitate BIR in suitable models. From patients' neuroimaging to in vitro approaches, scientists have been striving to understand the pathophysiology of such disorders at the behavioural, molecular, and cellular levels. Although animal models are useful for studying insulin resistance's systemic effects, in vitro phenotypic research represents an alternative to study molecular and cellular aspects. STZ and hypoglycaemia-like scenarios have been successful for studying neurodegenerative disorders in primary cell culture (e.g., neuroblastoma cells) and patient-specific neural cell lines derived from pluripotent stem cells (iPSCs). Intriguingly, STZ treatment or hypoglycaemia-like conditions in a dish were able to induce AD pathological characteristics such Aβ plaque deposition and Tau protein hyperphosphorylation. Such approaches have shown potential in understanding molecular and cellular implications of metabolic changes in neuropsychiatric disorders, according to this review. Furthermore, these models may help identify novel treatment targets.}, } @article {pmid39932239, year = {2025}, author = {Yang, L and Wang, Y and Shang, P and Ma, G}, title = {Dual-Functional Synthetic Linear and Cyclic Peptides with Anti-Amyloid and Antimicrobial Activities for Alzheimer's disease.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {}, number = {}, pages = {e202404349}, doi = {10.1002/chem.202404349}, pmid = {39932239}, issn = {1521-3765}, abstract = {Dual-functional peptides exhibiting both anti-amyloid and antimicrobial activities have attracted attention as promising candidates for Alzheimer's disease treatment. The advantage of these peptides lies in their ability to simultaneously target both the amyloid cascade hypothesis and the microbial infection hypothesis, in contrast to single-function inhibitors. However, most of the reported dual-functional peptides to date are natural peptides, and the development of synthetic peptides in this area remains limited. In this study, we propose two strategies to aid in the discovery of synthetic dual-functional peptides. We then report four distinct synthetic dual-functional peptides identified using these strategies, with the Aβ1-40/Aβ1-42 fibrillation system and common bacterial strains serving as a proof-of-concept platform. One strategy involves repurposing existing knowledge, while the other breaks from established conventions. Using the first strategy, we discovered a very short dual-functional linear peptide. With the second strategy, we identified a simple dual-functional cyclic peptide. Furthermore, by combining these two strategies, we developed a hybrid dual-functional peptide incorporating both linear and cyclic structures. We hope that our findings will contribute to the future discovery of more synthetic dual-functional peptides for treating Alzheimer's disease.}, } @article {pmid39931990, year = {2025}, author = {Khan, B and Khalid Iqbal, M and Khan, H and Kiyani, M and Bashir, S and Shao, L}, title = {Abnormality of Voltage-Gated Sodium Channels in Disease Development of the Nervous System. A Review Article.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273347470250126185122}, pmid = {39931990}, issn = {1996-3181}, abstract = {Sodium channels are necessary for electrical activity in modules of the nervous system. When such channels fail to work properly, it may cause different neurological diseases. This review will discuss how particular mutation in these channels leads to different diseases. Positive alterations can lead to such diseases as epilepsy, or any muscle disorder due to over activation of neurons. Conversely, loss-of-function mutations may cause heart diseases and problems regarding motor and mental activity since neurons are not functioning well because of lost machinery. The review would discuss over familiar channelopathies such as genetic epilepsies, the familial hemiplegic migraine, and Para myotonia congenital and relatively new interrelations with the complex ailments including Alzheimer's, Parkinson's and multiple sclerosis. Thus, knowledge of these mechanisms is important in designing specific therapeutic approaches. There is a rationale for altering the sodium channel activity in the treatment of these neurological disorders by drugs or indeed genetic methods. Thus, the review is undertaken to provide clear distinctions and discuss the issues related to sodium channel mutations for the potential development of individualized medicine. The review also gives information on the function and general distribution of voltage-gated sodium channels (VGSCs), how their activity is controlled, and what their structure is like. The purpose therefore is to draw understanding over the apparently multifaceted functions exerted by VGSCs in the nervous system relative to several diseases. This knowledge is imperative in the attempt to produce treatments for these disabling disorders.}, } @article {pmid39931983, year = {2025}, author = {Zheng, CB and Wu, LZ and Song, WY and Luo, L and Cai, JT and Huang, ZH and Tian, KQ}, title = {The Role and Molecular Mechanism of Icaritin in the Treatment of Alzheimer's Disease.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673354454250124074057}, pmid = {39931983}, issn = {1875-533X}, abstract = {Alzheimer's disease (AD), a degenerative disease of the central nervous system, affects approximately 70 million individuals worldwide. As the number of elderly in the population increases, the prevalence and incidence of AD are increasing annually. Although the drugs are currently used to alleviate certain cognitive symptoms, their overall therapeutic efficacy remains unclear. Consequently, there is significant societal demand for safe and effective therapeutic options. Icaritin (ICT), a bioactive compound derived from Epimedium brevicornu Maxim, has anti-apoptotic, antioxidant, anti-neuroinflammatory, anti-aging, and neuroprotective properties. In recent years, it has garnered significant interest because of its potential preventative and therapeutic effects in the context of AD. In this review, we analyze the therapeutic effects of ICT on AD, namely the inhibition of neuroinflammation, effects against oxidative stress and apoptosis, and promotion of cellular autophagy. The aim of this review was to provide a general reference for the research and development of new drugs, in particular ICT, for the prevention and treatment of AD.}, } @article {pmid39931956, year = {2025}, author = {Nuovo, GJ and Rice, M and Zanesi, N and Sawant, D and Crilly, C and Tili, E}, title = {The Prevention of Fatal Tauopathy in a Mouse Model of Alzheimer Disease by Blocking BCL2.}, journal = {Applied immunohistochemistry & molecular morphology : AIMM}, volume = {}, number = {}, pages = {}, doi = {10.1097/PAI.0000000000001251}, pmid = {39931956}, issn = {1533-4058}, abstract = {A major goal in Alzheimer disease (AD) research is the reduction of the abnormal tau burden. Using multispectral analyses on brain tissues from humans who died of AD it was documented that neurons with hyperphosphorylated tau protein accumulate many proteins of the BCL2 family, including those that block cell turnover (eg, BCL2, MCL1, BCLXL) and those that promote cell turnover (eg, NOXA, PUMA, BAK, BAX). A mouse model of AD with the humanized hyperphosphorylated tau protein was used to test the hypothesis that shifting this balance to a pro-cell turnover milieu would reduce the tau burden with concomitant clinical improvement. Here, we show that a mouse model of AD with death at 11 to 15 months due to CNS tauopathy had a marked reduction in the tau burden after treatment with the FDA-approved drug venetoclax, which blocks BCL2. The reduction of the number of target neurons positive for hyperphosphorylated tau protein after venetoclax treatment in the brain and spinal cord neurons was 94.5% as determined by immunohistochemistry and 98.1% as documented with the modified Bielchowsky stain. The venetoclax treatment began after documented neurofibrillary tangles (NFTs) were evident and there was a concomitant reduction in neuroinflammation. The treated mice were robust until sacrificed at 13 months as compared with the untreated mice that showed unequivocal evidence of brain and spinal cord damage both clinically and at autopsy. We conclude that otherwise inexorable abnormal tau protein deposition, even after initiation, can be prevented by a drug that blocks one anti-cell turnover protein abundant in the NFTs of human AD.}, } @article {pmid39931916, year = {2025}, author = {Jin, L and Nie, L and Deng, Y and Khana, GJ and He, N}, title = {The Application of Polymeric Nanoparticles as Drug Delivery Carriers to Cells in Neurodegenerative Diseases.}, journal = {Cell proliferation}, volume = {}, number = {}, pages = {e13804}, doi = {10.1111/cpr.13804}, pmid = {39931916}, issn = {1365-2184}, support = {62071119//National Natural Science Foundation of China/ ; 62075098//National Natural Science Foundation of China/ ; 2017YFA0205301//National Key Research and Development Program of China/ ; 2018YFC1602905//National Key Research and Development Program of China/ ; }, abstract = {In spite of great advances in modern medicine, there are a few effective strategies for the treatment of neurodegenerative diseases characterised by neuron loss or degeneration. This results from complex pathogenesis of the diseases and the limited drug uptake of the brain due to the presence of blood-brain barrier. Nanoparticle-based drug delivery systems are expected to improve the drug utilisation. Polymeric nanoparticles represent promising drug delivery carriers to the brain due to their unique advantages such as good biodegradability and biocompatibility, flexibility in surface modification and nontoxicity. In addition, the delivery of genetic drugs may stop the progression of neurodegenerative diseases at the genetic level and even avoid the irreversible damage in the central nervous system. In this review, an overview of studies on polymer-based nanoparticles for drug delivery to the central nervous system in typical neurodegenerative diseases, especially Alzheimer's diseases and Parkinson's diseases, is described. Meanwhile, their applications in gene delivery in these disorders are discussed. And the challenges and future perspectives for the development of polymeric nanoparticles as drug delivery carriers in neurodegenerative diseases are concluded.}, } @article {pmid39931856, year = {2025}, author = {Mumtaz, and Ahmed, F and Rabbani, SA and El-Tanani, M and Najmi, AK and Ali, J and Khan, MA}, title = {Tauopathy in AD: Therapeutic Potential of MARK-4.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050358397250126151707}, pmid = {39931856}, issn = {1875-5828}, abstract = {Alzheimer's disease (AD) is one of the leading causes of cognitive decline, which leads to dementia and poses significant challenges for its therapy. The reason is primarily the ineffective available treatments targeting the underlying pathology of AD. It is a neurodegenerative disease that is mainly characterised by the various molecular pathways contributing to its complex pathology, including extracellular amyloid beta (Aβ) plaques, intracellular neurofibrillary tangles (NFTs), oxidative stress, and neuroinflammation. One of the crucial features is the hyperphosphorylation of tau proteins, which is facilitated by microtubule affinity-regulating kinase-4 (MARK-4). The kinase plays a crucial role in the disease development by modifying microtubule integrity, leading to neuronal dysfunction and death. MARK-4 is thus a druggable target and has a pivotal role in AD. Amongst MARK-4 inhibitors, 16 compounds demonstrate significant capacity in molecular docking studies, showing high binding affinity to MARK-4 and promising potential for tau inhibition. Further, in-vitro investigations provide evidence of their neuroprotective properties. The present review mainly focuses on the role of MARK-4 and its potential inhibitors used in treating AD, which have been thoroughly investigated in silico and in vitro.}, } @article {pmid39931801, year = {2025}, author = {Kong, D and Meng, L and Lin, P and Wu, G}, title = {Advancements in PROTAC-based therapies for neurodegenerative diseases.}, journal = {Future medicinal chemistry}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/17568919.2025.2463310}, pmid = {39931801}, issn = {1756-8927}, abstract = {Neurodegenerative diseases are characterized by impairments in movement and cognitive functions. These disorders are frequently associated with the accumulation of misfolded protein aggregates, which present significant challenges for treatment with conventional small-molecule inhibitors. While FDA-approved amyloid-beta-directed antibodies, such as Lecanemab, have recently shown clinical success in modifying disease progression, there are currently no treatments capable of curing neurodegenerative diseases. Emerging technologies like proteolysis-targeting chimeras (PROTACs) offer additional promise by targeting disease-causing proteins for degradation, potentially opening new therapeutic avenues. Recent experiments have demonstrated that PROTACs can specifically target and degrade pathogenic proteins associated with neurodegenerative diseases, thereby offering potential therapeutic avenues. This review discusses the latest advances in employing PROTACs for treating neurodegenerative diseases and delves into the associated challenges and opportunities. Our goal is to provide researchers in drug development with new insights on creating novel PROTACs for therapeutic applications.}, } @article {pmid39931645, year = {2025}, author = {Cho, Y and Lee, J and Kim, JS and Jeon, Y and Han, S and Cho, H and Lee, Y and Kim, TK and Hong, JM and Lee, Y and Byun, Y and Chae, M and Park, S and Palomera, LF and Park, SY and Kim, H and Kim, S and Kang, S and Jee, JG and An, H and Yim, JH and Kim, SH and Jo, DG}, title = {RA-PR058, a novel ramalin derivative, reduces BACE1 expression and phosphorylation of tau in Alzheimer's disease mouse models.}, journal = {Animal cells and systems}, volume = {29}, number = {1}, pages = {122-134}, pmid = {39931645}, issn = {1976-8354}, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cognitive decline, anxiety-like behavior, β-amyloid (Aβ) accumulation, and tau hyperphosphorylation. BACE1, the enzyme critical for Aβ production, has been a major therapeutic target; however, direct BACE1 inhibition has been associated with adverse side effects. This study investigates the therapeutic potential of RA-PR058, a novel ramalin derivative, as a multi-targeted modulator of AD-related pathologies. The effects of RA-PR058 were evaluated in vitro and in vivo. In vitro studies used SH-SY5Y cells under oxidative stress conditions to assess BACE1 expression, while in vivo effects were studied in 3xTg-AD mice following one month of oral RA-PR058 treatment. Behavioral assessments, biochemical analyses, transcriptomic profiling, and pharmacokinetic evaluations were performed to determine the efficacy of RA-PR058. RA-PR058 significantly reduced oxidative stress-induced BACE1 expression in vitro and decreased cortical BACE1 expression in 3xTg-AD mice. In vivo treatment alleviated anxiety-like behavior and reduced tau phosphorylation at disease-relevant sites (Ser202/Thr205, Thr231, and Ser396). Transcriptomic analysis revealed RA-PR058-mediated gene expression changes related to central nervous system development, response to hypoxia, and neuroactive ligand-receptor interactions, suggesting broader regulatory effects on AD-related pathways. Pharmacokinetic analysis demonstrated that RA-PR058 exhibits high metabolic stability, minimal cytochrome P450 interactions, and moderate blood-brain barrier penetration. RA-PR058 demonstrates potential as a multi-target AD therapeutic by reducing BACE1 expression, tau hyperphosphorylation, and anxiety-like behavior, coupled with favorable pharmacokinetics. Additional studies are needed to assess cognitive effects and clarify molecular mechanisms, but RA-PR058 may represent a promising advancement in addressing AD's complex pathology.}, } @article {pmid39931556, year = {2025}, author = {Ding, J and Long, Z and Liu, Y and Wang, M}, title = {Study on influencing factors of age-adjusted Charlson comorbidity index in patients with Alzheimer's disease based on machine learning model.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1497662}, pmid = {39931556}, issn = {2296-858X}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a widespread neurodegenerative disease, often accompanied by multiple comorbidities, significantly increasing the risk of death for patients. The age adjusted Charlson Comorbidity Index (aCCI) is an important clinical tool for measuring the burden of comorbidities in patients, closely related to mortality and prognosis. This study aims to use the MIMIC-V database and various regression and machine learning models to screen and validate features closely related to aCCI, providing a theoretical basis for personalized management of AD patients.

METHODS: The research data is sourced from the MIMIC-V database, which contains detailed clinical information of AD patients. Multiple logistic regression, LASSO regression, random forest, Support Vector Machine (SVM), and Extreme Gradient Boosting (XGBoost) models were used to screen for feature factors significantly correlated with aCCI. By comparing model performance, evaluating the classification ability and prediction accuracy of each method, and ultimately selecting the best model to construct a regression model and a nomogram. The model performance is evaluated through classification accuracy, net benefit, and robustness. The feature selection results were validated by regression analysis.

RESULTS: Multiple models have performed well in classifying aCCI patients, among which the model constructed using LASSO regression screening feature factors has the best performance, with the highest classification accuracy and net benefit. LASSO regression identified the following 11 features closely related to aCCI: age, respiratory rate, base excess, glucose, red blood cell distribution width (RDW), alkaline phosphatase (ALP), whole blood potassium, hematocrit (HCT), phosphate, creatinine, and mean corpuscular hemoglobin (MCH). The column chart constructed based on these feature factors enables intuitive prediction of patients with high aCCI probability, providing a convenient clinical tool.

CONCLUSION: The results of this study indicate that the features screened by LASSO regression have the best predictive performance and can significantly improve the predictive ability of aCCI related comorbidities in AD patients. The column chart constructed based on this feature factor provides theoretical guidance for personalized management and precise treatment of AD patients.}, } @article {pmid39931431, year = {2024}, author = {Silva-Llanes, I and Madruga, E and Martínez, A and Lastres-Becker, I}, title = {RIPK1 expression and inhibition in tauopathies: implications for neuroinflammation and neuroprotection.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1530809}, pmid = {39931431}, issn = {1662-4548}, abstract = {Tauopathies are a group of neurodegenerative diseases characterized by the alteration/aggregation of TAU protein. One of the main challenges of these diseases is that they have neither biomarkers nor pharmacological targets to stop the neurodegenerative process. Apart from the neurodegenerative process, tauopathies are also characterized by a chronic low-grade neuroinflammation process, where the receptor-interacting protein kinase 1 (RIPK1) protein plays an essential role. Our research aimed to explore the role of RIPK1 in various tauopathies. We examined mouse models of frontotemporal dementia (FTD), as well as brain tissue samples from patients with progressive supranuclear palsy (PSP), a primary form of 4R tauopathy, and Alzheimer's disease (AD), which is considered a secondary tauopathy. Our findings show elevated levels of RIPK1 mRNA levels across various forms of tauopathies, in both mouse models and human tissue samples associated with primary and secondary TAU-related disorders. Furthermore, we investigated the potential of using a RIPK1 inhibitor, known as GSK2982772, in a mouse model as a novel treatment strategy for FTD. The data showed that GSK2982772 treatment effectively reduced the reactive astrocyte response triggered by TAU[P301L] overexpression. However, this RIPK1 inhibitor failed to protect against the neurodegeneration caused by elevated TAU[P301L] levels in the hippocampal region. These results suggest that although inhibiting RIPK1 activity may help reduce TAU-related astrogliosis in the brain, the complexity of the inflammatory pathways involved could explain the absence of neuroprotective effects against TAU-induced neurodegeneration.}, } @article {pmid39931375, year = {2024}, author = {Permana, A and Akili, AWR and Hardianto, A and Latip, JB and Sulaeman, AP and Herlina, T}, title = {Virtual Screening, Toxicity Evaluation and Pharmacokinetics of Erythrina Alkaloids as Acetylcholinesterase Inhibitor Candidates from Natural Products.}, journal = {Advances and applications in bioinformatics and chemistry : AABC}, volume = {17}, number = {}, pages = {179-201}, pmid = {39931375}, issn = {1178-6949}, abstract = {PURPOSE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options, necessitating the development of safer and more effective therapies. The potential of alkaloids derived from the genus Erythrina as acetylcholinesterase (AChE) inhibitors is being investigated to enhance acetylcholine levels in the brain, which is crucial for the treatment of AD. The objective of this study is to identify Erythrina alkaloids with strong inhibitory capacity against AChE and favorable pharmacokinetic profiles.

MATERIALS AND METHODS: A multi-step computational approach was employed, beginning with the virtual screening of 143 Erythrina alkaloid structures using molecular docking against the human AChE crystal structure. The binding affinities were compared with the known AChE inhibitor, galantamine. The top alkaloid, 8-oxoerymelanthine (128), was subjected to further analysis through molecular dynamics simulations, with the objective of evaluating its stability and interactions. In silico ADMET predictions were conducted to assess the pharmacokinetic properties. The applicability of Lipinski's Rule of Five was applied to evaluate oral drug-likeness.

RESULTS: 8-Oxoerymelanthine (128) exhibited the highest binding affinity and remarkable stability in molecular dynamics simulations. The toxicity predictions indicated a low risk of mutagenicity, hepatotoxicity, and cardiotoxicity. Pharmacokinetic assessments indicated good absorption, moderate blood-brain barrier penetration, and favorable metabolic and excretion profiles, supporting its potential as an orally active drug candidate.

CONCLUSION: 8-Oxoerythmelanthine (128) exhibits strong potential as an AChE inhibitor with a favorable balance of efficacy, safety, and pharmacokinetic properties. These results warrant further investigation in preclinical and clinical studies to validate its therapeutic potential and safety for Alzheimer's disease treatment.}, } @article {pmid39930497, year = {2025}, author = {Jang, YJ and Kang, SJ and Park, HS and Lee, DH and Kim, JH and Kim, JE and Kim, DI and Chung, CH and Yoon, JK and Bhang, SH}, title = {Drug delivery strategies with lipid-based nanoparticles for Alzheimer's disease treatment.}, journal = {Journal of nanobiotechnology}, volume = {23}, number = {1}, pages = {99}, pmid = {39930497}, issn = {1477-3155}, support = {KEIT 20018560//Ministry of Trade, Industry and Energy/ ; NTIS 2410005252//Ministry of Trade, Industry and Energy/ ; RS-2024-00448758//Ministry of Trade, Industry and Energy/ ; RS-2024-00405818//National Research Foundation of Korea/ ; RS-2023-00213691//National Research Foundation of Korea/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Nanoparticles/chemistry ; *Blood-Brain Barrier/metabolism ; Animals ; *Drug Delivery Systems/methods ; *Lipids/chemistry ; *Amyloid beta-Peptides/metabolism ; Drug Carriers/chemistry ; Liposomes/chemistry ; }, abstract = {Alzheimer's disease (AD) is a distinctive form of dementia characterized by age-related cognitive decline and memory impairment. A key hallmark of AD is the irreversible overaccumulation of beta-amyloid (Aβ) in the brain, associated with neuroinflammation and neuronal death. Although Aβ clearance and immunoregulation have been the major therapeutic strategies for AD, highly selective transport across the blood-brain barrier (BBB) negatively affects the delivery efficacy of the drugs without the ability to cross the BBB. In this review, we discuss the potential of lipid-based nanoparticles (LBNs) as promising vehicles for drug delivery in AD treatment. LBNs, composed of phospholipid mono- or bilayer, have attracted attention due to their exceptional cellular penetration capabilities and drug loading capabilities, which also facilitate cargo transcytosis across the BBB. Recent advances in the development and engineering of LBNs overcome the existing limitations of the current clinical approaches for AD treatment by addressing off-target effects and low therapeutic efficacy. Here, we review the transport pathways across the BBB, as well as various types of LBNs for AD therapy, including exosomes, liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), to elucidate their distinctive properties, preparation methodologies, and therapeutic efficacy, thereby offering innovative avenues for novel drug development for clinical translation in AD therapy.}, } @article {pmid39930283, year = {2025}, author = {Song, H and Xia, M and Zhao, P and Yang, J and Yu, W}, title = {Overexpression of TGFBR3 Aggravates Cognitive Impairment and Neuroinflammation by Promoting Microglia M1 Polarization in the APP/PS1 Mouse Model of Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39930283}, issn = {1559-1182}, support = {[2023]015//Department of Education of Guizhou Province (Guizhou Teaching and Technology)/ ; (2020)1Z060//Science and Technology Plan Project of Guizhou Province (Basic Science and Technology Cooperation)/ ; }, abstract = {Transforming growth factor beta receptor 3 (TGFBR3), also known as betaglycan, is a member of the TGF-β receptor family. In our previous study, bioinformatics analysis revealed that TGFBR3 levels are elevated in patients with Alzheimer's disease (AD) and identified TGFBR3 as a potential risk factor for the disease. However, the precise role of TGFBR3 in the pathogenesis of AD remains largely unclear. In this study, we first validated the elevated levels of TGFBR3 in postmortem brain tissues from AD patients using immunohistochemical staining. Subsequently, gain-of-function experiments and behavioral tests were conducted to explore the functional role of TGFBR3 in the APP/PS1 mouse model. Our findings confirmed that TGFBR3 levels were significantly increased in AD patients compared to normal controls. Overexpression of TGFBR3 in APP/PS1 mice impaired spatial learning and memory abilities and promoted amyloid-β (Aβ) accumulation. Additionally, TGFBR3 overexpression exacerbated neuronal apoptosis and synaptic loss. We also observed that overexpression of TGFBR3 triggered an inflammatory response by promoting microglial polarization to the M1 phenotype, although it had no effect on astrocyte activation. In conclusion, our study demonstrates that increased TGFBR3 levels worsen cognitive impairment and accelerate pathological progression in APP/PS1 mice, suggesting that TGFBR3 could serve as a potential therapeutic target for AD treatment.}, } @article {pmid39929615, year = {2025}, author = {Zhou, ZH and Xing, HY and Liang, Y and Gao, J and Liu, Y and Zhang, T and Zhu, L and Qian, JL and Zhou, C and Li, G}, title = {[Molecular mechanism of verbascoside in promoting acetylcholine release of neurotransmitter].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {2}, pages = {335-348}, doi = {10.19540/j.cnki.cjcmm.20240802.702}, pmid = {39929615}, issn = {1001-5302}, mesh = {Animals ; Rats ; *Acetylcholine/metabolism ; PC12 Cells ; *Glucosides/pharmacology ; *Phenols/pharmacology/chemistry ; Alzheimer Disease/metabolism/drug therapy ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Neurotransmitter Agents/metabolism ; Molecular Docking Simulation ; Humans ; Calcium/metabolism ; Phosphorylation/drug effects ; Polyphenols ; }, abstract = {The molecular mechanism of verbascoside(OC1) in promoting acetylcholine(ACh) release in the pathogenesis of Alzheimer's disease(AD) was studied. Adrenal pheochromocytoma cells(PC12) of rats induced by β-amyloid protein(1-42)(Aβ_(1-42)) were used as AD models in vitro and were divided into control group, model group(Aβ_(1-42) 10 μmol·L~(-1)), OC1 treatment group(2 and 10 μg·mL~(-1)). The effect of OC1 on phosphorylated proteins in AD models was analyzed by whole protein phosphorylation quantitative omics, and the selectivity of OC1 for calcium channel subtypes was virtually screened in combination with computer-aided drug design. The fluorescence probe Fluo-3/AM was used to detect Ca~(2+) concentration in cells. Western blot analysis was performed to detect the effects of OC1 on the expression of phosphorylated calmodulin-dependent protein kinase Ⅱ(p-CaMKⅡ, Thr286) and synaptic vesicle-related proteins, and UPLC/Q Exactive MS was used to detect the effects of OC1 on ACh release in AD models. The effects of OC1 on acetylcholine esterase(AChE) activity in AD models were detected. The results showed that the differentially modified proteins in the model group and the OC1 treatment group were related to calcium channel activation at three levels: GO classification, KEGG pathway, and protein domain. The results of molecular docking revealed the dominant role of L-type calcium channels. Fluo-3/AM fluorescence intensity decreased under the presence of Ca~(2+) chelating agent ethylene glycol tetraacetic acid(EGTA), L-type calcium channel blocker verapamil, and N-type calcium channel blocker conotoxin, and the effect of verapamil was stronger than that of conotoxin. This confirmed that OC1 promoted extracellular Ca~(2+) influx mainly through its interaction with L-type calcium channel protein. In addition, proteomic analysis and Western blot results showed that the expression of p-CaMKⅡ and downstream vesicle-related proteins was up-regulated after OC1 treatment, indicating that OC1 acted on vesicle-related proteins by activating CaMKⅡ and participated in synaptic remodeling and transmitter release, thus affecting learning and memory. OC1 also decreased the activity of AChE and prolonged the action time of ACh in synaptic gaps.}, } @article {pmid39929614, year = {2025}, author = {Xiang, JB and Wen, W and Xu, SJ}, title = {[Mechanism of Jiawei Xionggui Decoction in ameliorating cognitive impairment in APP/PS1 mice based on network pharmacology and metabolomics].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {2}, pages = {322-342}, doi = {10.19540/j.cnki.cjcmm.20240902.704}, pmid = {39929614}, issn = {1001-5302}, mesh = {Animals ; Mice ; *Drugs, Chinese Herbal/pharmacology ; *Cognitive Dysfunction/drug therapy/metabolism/genetics ; *Metabolomics ; *Network Pharmacology ; *Mice, Inbred C57BL ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Male ; Amyloid beta-Protein Precursor/genetics/metabolism ; Brain/metabolism/drug effects ; Presenilin-1/genetics/metabolism ; Humans ; Mice, Transgenic ; Disease Models, Animal ; }, abstract = {This study explored the action mechanism of Jiawei Xionggui Decoction in the treatment of Alzheimer's disease(AD) by integrating mouse brain tissue metabolomics and network pharmacology. Six-month-old amyloid precursor protein/presenilin 1(APP/PS1) mice were selected and divided into the APP/PS1 group and Jiawei Xionggui Decoction intervention group, with age-matched C57BL/6 mice serving as controls. Cognitive abilities and pathological damage in the mice were observed. Gas chromatography-mass spectrometry/mass spectrometry(GC-MS/MS) technology was utilized to analyze the metabolic profiles of mice brain tissue. Differential metabolites were screened, and relevant metabolic pathways were enriched. Network pharmacology was adopted to screen the active components of Jiawei Xionggui Decoction, so as to construct a protein-protein interaction network of its core targets for AD treatment and conduct Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis of potential targets for Jiawei Xionggui Decoction in treating AD. Finally, a "metabolite-reaction-enzyme-gene" network was constructed for combined analysis of metabolomics and network pharmacology. The results showed that Jiawei Xionggui Decoction significantly reversed the trends of 18 differential metabolites involved in 15 metabolic pathways such as glyoxylate and dicarboxylate metabolism, glycine, serine, and threonine metabolism, pyruvate metabolism, alanine, aspartate, and glutamate metabolism, and tricarboxylic acid cycle(TCA) in mouse brain tissue. Furthermore, 383 core targets of Jiawei Xionggui Decoction were implicated in pathways like the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway and calcium signaling pathway. Overall analysis indicated that energy metabolism, amino acid metabolism, and fatty acid metabolism were crucial metabolic pathways for Jiawei Xionggui Decoction in treating AD. The findings suggest that Jiawei Xionggui Decoction can protect neuronal cells in mouse brain tissue, thus improving cognitive impairment.}, } @article {pmid39929613, year = {2025}, author = {Xing, HW and Yang, Y and Yin, YP and Xie, L and Fang, F}, title = {[Kaixin San-medicated serum attenuates Aβ_(25-35)-induced injury in SH-SY5Y cells by regulating autophagy].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {2}, pages = {313-321}, doi = {10.19540/j.cnki.cjcmm.20241012.401}, pmid = {39929613}, issn = {1001-5302}, mesh = {*Autophagy/drug effects ; Humans ; *Amyloid beta-Peptides/toxicity ; *TOR Serine-Threonine Kinases/metabolism/genetics ; *Proto-Oncogene Proteins c-akt/metabolism/genetics ; Cell Survival/drug effects ; Cell Line, Tumor ; Drugs, Chinese Herbal/pharmacology ; Peptide Fragments ; Microtubule-Associated Proteins/genetics/metabolism ; Serum/chemistry ; }, abstract = {The aim of this study is to investigate the regulation of Kaixin San-medicated serum(KXS-MS) on autophagy induced by Aβ_(25-35) in SH-SY5Y cells. The SH-SY5Y cell model of Aβ_(25-35)(25 μmol·L~(-1))-induced injury was established, and different concentrations of KXS-MS were added into the culture media of cells, which were then incubated for 24 h. Cell viability was measured by the methyl thiazolyl tetrazolium(MTT) assay. The protein levels of microtubule-associated protein 1 light chain 3(LC3)Ⅰ, LC3Ⅱ, protein kinase B(Akt), p-Akt, mammalian target of rapamycin(mTOR), and p-mTOR were assessed by Western blot. Furthermore, the combination of rapamycin(Rapa)/3-methyladenine(3-MA) and low concentration of KXS-MS was added to the culture medium of SH-SY5Y cells injured by Aβ_(25-35), and the cell viability and the expression levels of the above proteins were determined. The results showed that Aβ_(25-35) decreased the cell viability, up-regulated the expression levels of LC3Ⅱ and LC3Ⅱ/LC3Ⅰ, and down-regulated the expression levels of p-Akt, p-mTOR, p-Akt/Akt, and p-mTOR/mTOR. Compared with the Aβ_(25-35) model group, KXS-MS treatment attenuated Aβ_(25-35)-induced injury and enhanced the survival of SH-SY5Y cells. Meanwhile, KXS-MS down-regulated the LC3Ⅱ/LC3Ⅰ level and up-regulated the p-Akt/Akt and p-mTOR/mTOR levels. Compared with the low-concentration KXS-MS group, Rapa did not affect the cell survival and the levels of p-Akt and p-Akt/Akt, while it up-regulated the levels of LC3Ⅱ and LC3Ⅱ/LC3Ⅰ and down-regulated the levels of p-mTOR and p-mTOR/mTOR. 3-MA significantly reduced the cell survival rate and p-Akt, p-Akt/Akt level in the KXS-MS group, while it had no significant effect on the levels of LC3Ⅱ, LC3Ⅱ/LC3Ⅰ, p-mTOR, and p-mTOR/mTOR. The above results indicate that KXS-MS exhibits protective effects against Aβ_(25-35)-induced damage in SH-SY5Y cells by up-regulating Akt/mTOR activity to inhibit autophagy.}, } @article {pmid39929589, year = {2025}, author = {Hirabayashi, S and Uyeda, A and Manabe, I and Yonezu, Y and Saito, T and Saido, TC and Misawa, H and Ogasawara, Y and Kinoshita, K and Muramatsu, R}, title = {CCN1 derived from vascular endothelial cells impairs cognitive function in Alzheimer's disease model mice.}, journal = {Journal of pharmacological sciences}, volume = {157}, number = {3}, pages = {146-155}, doi = {10.1016/j.jphs.2025.01.004}, pmid = {39929589}, issn = {1347-8648}, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics ; *Cysteine-Rich Protein 61/genetics/metabolism ; *Disease Models, Animal ; *Endothelial Cells/metabolism ; *Cognition ; *Hippocampus/metabolism ; Cells, Cultured ; Male ; Mice ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Mice, Inbred C57BL ; Gene Expression ; Spatial Learning ; }, abstract = {Vascular endothelial cell-expressing molecules regulate neuronal function. Although cerebrovascular dysregulation is a hallmark of Alzheimer's disease (AD), the effect of changes in molecular expression on neuronal function in vascular endothelial cells during disease progression is not clear. In this study, we demonstrated that the cellular communication network factor 1 (CCN1), which is highly expressed in vascular endothelial cells during the chronic stage of AD in mice, is involved in the impairment of cognitive function. Vascular endothelial cells isolated from the brains of App[NL-G-F] mice show differential expression of genes, including CCN1. CCN1 treatment decreased the synaptic number in cultured hippocampal cells, with changes in the expression of genes associated with morphological changes. In vivo, App[NL-G-F] mice with CCN1 silencing in vascular endothelial cells demonstrated high spine density and improved spatial learning. No significant change was observed in the number of microglia/macrophages, astrocytes, and amyloid-beta (Aβ) accumulation in the hippocampus of the mice. These results suggest that CCN1 is a key factor modulating neurological dysfunction through neurovascular interactions.}, } @article {pmid39928236, year = {2025}, author = {Kaspute, G and Ramanavicius, A and Prentice, U}, title = {Natural drug delivery systems for the treatment of neurodegenerative diseases.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {217}, pmid = {39928236}, issn = {1573-4978}, support = {S-MIP-24-111//Research Council of Lithuania (LMTLT)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Drug Delivery Systems/methods ; *Biological Products/administration & dosage ; Blood-Brain Barrier/metabolism/drug effects ; Animals ; Liposomes ; Anti-Inflammatory Agents/administration & dosage ; Nanoparticles/chemistry ; }, abstract = {Today, herbal drugs are prominent in the pharmaceutical industry due to their well-known therapeutic and side effects. Plant-based compounds often face limitations such as poor solubility, low bioavailability, and instability in physiological environments, restricting their therapeutic efficacy and delivery. Nanotechnology-based solutions, including nanoparticle formulations and advanced delivery systems like liposomes and transfersomes, address these issues by enhancing solubility, stability, bioavailability, and targeted delivery, thereby optimizing the therapeutic potential of phytoactive compounds. Neuroinflammation can be a cause of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, or amyotrophic lateral sclerosis. Consequently, there is a need for the optimal delivery of a pharmacological anti-inflammatory agents to the CNS. Thus, the non-invasive administration of a stable compound at a therapeutic concentration is needed to assure molecule crossing through the blood-brain barrier. Natural resources have more structural diversity and novelty than synthetic compounds, e.g. plant-derived drug products have higher molecular weights, incorporate more oxygen atoms, and are more complex. As a result, plant-derived products have unique features which can be used to effectively modulate neuroinflammation. Therefore, this review aims to identify herbal molecules capable of targeting neuroinflammation and present novel strategies for their efficient delivery.}, } @article {pmid39926413, year = {2025}, author = {Almehdi, AM and Aboubaker, DH and Hamdy, R and El-Keblawy, A}, title = {Nanotherapeutic smart approaches for combating Alzheimer's disease and overcoming existing obstacles: A novel eco-friendly green approach.}, journal = {Toxicology reports}, volume = {14}, number = {}, pages = {101906}, pmid = {39926413}, issn = {2214-7500}, abstract = {The scientific community has united to raise awareness of Alzheimer's disease (AD) as a critical condition for future generations because recent predictions indicate that it will become common among the elderly within a few years. Nevertheless, the intricacies of the disease's progression demand exhaustive investigations to unravel its potential mechanisms. Only then can clinicians develop more efficacious therapeutic strategies. Cognitive impairment caused by amyloid aggregation, the development of hyperphosphorylated neurofibrillary tangles, and a malfunctioning cholinergic system are the hallmarks of AD. Even after the disease has started, brain tissue integrity may degenerate. The physiological characteristics of the highly selective blood-brain barrier and the electrostatic charge of the nanoporous extracellular matrix have long placed restrictions on the treatment of brain disorders. A prospective revolution in drug delivery for the treatment of AD is the use of nanomedicine. It depends on enhancing the way that medications are distributed pharmacokinetically throughout the central nervous system. Several types of nanoparticles (Nps) are available thanks to nanotechnology, and these Nps could target the brain and have a long half-life with few systemic side effects and motor problems. With the latest technological developments, scientists are working to develop unique approaches for the treatment of AD. To evaluate the prospective uses of medicinal plants, their components, and different nanomedicine techniques, it was determined that this literature study was necessary. To provide an overview of the various challenges and approaches related to using nanoparticles (NPs) to combat Alzheimer's disease (AD), this introductory review article was developed.}, } @article {pmid39926335, year = {2025}, author = {Li, G and Chen, B and Sun, W and Liu, Z}, title = {A stacking classifier for distinguishing stages of Alzheimer's disease from a subnetwork perspective.}, journal = {Cognitive neurodynamics}, volume = {19}, number = {1}, pages = {38}, pmid = {39926335}, issn = {1871-4080}, abstract = {Accurately distinguishing stages of Alzheimer's disease (AD) is crucial for diagnosis and treatment. In this paper, we introduce a stacking classifier method that combines six single classifiers into a stacking classifier. Using brain network models and network metrics, we employ t-tests to identify abnormal brain regions, from which we construct a subnetwork and extract its features to form the training dataset. Our method is then applied to the ADNI (Alzheimer's Disease Neuroimaging Initiative) datasets, categorizing the stages into four categories: Alzheimer's disease, mild cognitive impairment (MCI), mixed Alzheimer's mild cognitive impairment (ADMCI), and healthy controls (HCs). We investigate four classification groups: AD-HCs, AD-MCI, HCs-ADMCI, and HCs-MCI. Finally, we compare the classification accuracy between a single classifier and our stacking classifier, demonstrating superior accuracy with our stacking classifier from a subnetwork-based viewpoint.}, } @article {pmid39926227, year = {2025}, author = {Liu, L and He, H and Du, B and He, Y}, title = {Nanoscale drug formulations for the treatment of Alzheimer's disease progression.}, journal = {RSC advances}, volume = {15}, number = {6}, pages = {4031-4078}, pmid = {39926227}, issn = {2046-2069}, abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no effective disease-modifying treatments. The blood-brain barrier hinders drug delivery to the brain, limiting therapeutic efficacy. Nanoparticle-based systems have emerged as promising tools to overcome these challenges. This review highlights recent advances in nanoparticle technologies for AD treatment, including liposomes, polymeric, inorganic, and biomimetic nanoparticles. These nanoparticles improve drug delivery across the blood-brain barrier, improve stability and bioavailability, and enable targeted delivery to affected brain regions. Functionalization strategies further enhance their therapeutic potential. Multifunctional nanoparticles combining therapeutic and diagnostic properties offer theranostic approaches. While progress has been made, challenges related to safety, targeting precision, and clinical translation remain. Future perspectives emphasize the need for collaborative efforts to optimize nanoparticle design, conduct rigorous studies, and accelerate the development of effective nanotherapeutics. With continued innovation, nanoparticle-based delivery systems hold great promise for revolutionizing AD treatment.}, } @article {pmid39925735, year = {2025}, author = {Bindra, S and Mostafa, EM and Abdelgawad, MA and Selim, S and Kumar, S and Mathew, B}, title = {Synthetic strategies and medicinal chemistry perspectives of dual acting carbonic anhydrase modulators with monoamine oxidase and cholinesterase inhibitors.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {39925735}, issn = {2632-8682}, abstract = {Multi-target drug design (MTDD) represents the paradigm shift in pharmaceutical research, moving beyond the conventional one-drug-one-target approach to address the complexity of multifactorial diseases. This strategy aims to develop single therapeutic candidates that can simultaneously modulate multiple biological targets, offering more comprehensive disease management and reducing the likelihood of drug resistance. In this article, we highlighted the design, synthesis, and structure-activity relationships (SARs) of various dual acting inhibitors involved in treatment of neurodegenerative diseases. Dual acting inhibitors targeting carbonic anhydrases (CAs), monoamine oxidases (MAOs), and cholinesterases (ChEs) have emerged as promising therapeutic agents due to their potential in treating complex neurodegenerative and psychiatric disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). By integrating CA inhibitors with MAO and ChE inhibition, researchers aim to address both the neuroprotective and symptomatic aspects of these disorders. The review also discusses key SAR studies that have guided the optimization of dual inhibitors, focusing on achieving selectivity and potency while minimizing off-target effects. From a medicinal chemistry perspective, the dual inhibition approach offers advantages such as improved efficacy, reduced polypharmacy, and better management of disease progression. However, challenges remain, including maintaining selectivity for target isoforms and overcoming pharmacokinetic limitations. Overall, the development of dual-acting CA-MAO-ChE inhibitors represents a compelling avenue in drug discovery, with the potential to significantly impact the treatment of neurodegenerative diseases.}, } @article {pmid39925461, year = {2024}, author = {Ouyang, Z and Wang, L and , }, title = {Imputation-Based Variable Selection Method for Block-Wise Missing Data When Integrating Multiple Longitudinal Studies.}, journal = {Mathematics (Basel, Switzerland)}, volume = {12}, number = {7}, pages = {}, pmid = {39925461}, issn = {2227-7390}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; P50 DA054039/DA/NIDA NIH HHS/United States ; R01 CE003497/CE/NCIPC CDC HHS/United States ; R01 ES033515/ES/NIEHS NIH HHS/United States ; }, abstract = {When integrating data from multiple sources, a common challenge is block-wise missing. Most existing methods address this issue only in cross-sectional studies. In this paper, we propose a method for variable selection when combining datasets from multiple sources in longitudinal studies. To account for block-wise missing in covariates, we impute the missing values multiple times based on combinations of samples from different missing pattern and predictors from different data sources. We then use these imputed data to construct estimating equations, and aggregate the information across subjects and sources with the generalized method of moments. We employ the smoothly clipped absolute deviation penalty in variable selection and use the extended Bayesian Information Criterion criteria for tuning parameter selection. We establish the asymptotic properties of the proposed estimator, and demonstrate the superior performance of the proposed method through numerical experiments. Furthermore, we apply the proposed method in the Alzheimer's Disease Neuroimaging Initiative study to identify sensitive early-stage biomarkers of Alzheimer's Disease, which is crucial for early disease detection and personalized treatment.}, } @article {pmid39924888, year = {2025}, author = {Silva, RPDS and Barbosa, BJAP}, title = {Exploring the potential of acupuncture as a complementary treatment for Alzheimer's disease: Pushing the boundaries forward.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251316572}, doi = {10.1177/13872877251316572}, pmid = {39924888}, issn = {1875-8908}, abstract = {Acupuncture has emerged as a promising adjunctive symptomatic therapy for Alzheimer's disease, demonstrating potential benefits in cognitive function and neuroprotection. Recent meta-analyses and randomized clinical trials have investigated the potential of acupuncture to improve cognitive assessments, signaling pathways, and gut regulation in Alzheimer's disease, underscoring its potential clinical application. However, the limited number of studies, small sample sizes, and lack of detailed mapping of acupuncture's core targets must be considered when interpreting these positive results.}, } @article {pmid39924842, year = {2025}, author = {Ndukwe, K and Serrano, PA and Rockwell, P and Xie, L and Figueiredo-Pereira, ME}, title = {Brain-penetrant histone deacetylase inhibitor RG2833 improves spatial memory in females of an Alzheimer's disease rat model.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251314777}, doi = {10.1177/13872877251314777}, pmid = {39924842}, issn = {1875-8908}, abstract = {BACKGROUND: Nearly two-thirds of Alzheimer's disease (AD) patients are women. Therapeutics for women are critical to lowering their elevated risk of developing this major cause of adult dementia. Moreover, targeting epigenetic processes such as histone acetylation that regulate multiple cellular pathways is advantageous given the multifactorial nature of AD. Histone acetylation takes part in memory consolidation, and its disruption is linked to AD.

OBJECTIVE: Determine whether the investigational drug RG2833 has repurposing potential for AD. RG2833 is a histone deacetylase HDAC1/3 inhibitor that is orally bioavailable and permeates the blood-brain-barrier.

METHODS: RG2833 effects were determined on cognition, transcriptome, and AD-like pathology in 11-month TgF344-AD female and male rats. Treatment started early in the course of pathology when therapeutic intervention is predicted to be most effective.

RESULTS: RG2833-treatment of 11-month TgF344-AD rats: (1) Significantly improved hippocampal-dependent spatial memory in females but not males. (2) Upregulated expression of immediate early genes, such as Arc, Egr1 and c-Fos, and other genes involved in synaptic plasticity and memory consolidation in females. Remarkably, out of 17,168 genes analyzed for each sex, no significant changes in gene expression were detected in males at p < 0.05, false discovery rate <0.05, and fold-change equal or > 1.5. (3) Failed to improve amyloid beta accumulation and microgliosis in female and male TgF344-AD rats.

CONCLUSIONS: Our study highlights the potential of histone-modifying therapeutics such as RG2833 to improve cognitive behavior and drive the expression of immediate early, synaptic plasticity and memory consolidation genes, especially in female AD patients.}, } @article {pmid39924695, year = {2025}, author = {Liu, S and Geng, D}, title = {White-Matter Structural Connectivity and Alzheimer's Disease: A Mendelian Randomization Study.}, journal = {Brain and behavior}, volume = {15}, number = {2}, pages = {e70286}, pmid = {39924695}, issn = {2162-3279}, support = {82372048//National Natural Science Foundation of China/ ; 22TS1400900//Science and Technology Commission of Shanghai Municipality/ ; 22ZR1409500//Science and Technology Commission of Shanghai Municipality/ ; 23S31904100//Science and Technology Commission of Shanghai Municipality/ ; 24SF1904200//Science and Technology Commission of Shanghai Municipality/ ; 24SF1904201//Science and Technology Commission of Shanghai Municipality/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics/pathology/diagnostic imaging ; *Mendelian Randomization Analysis ; *White Matter/diagnostic imaging/pathology ; *Genome-Wide Association Study ; Genetic Predisposition to Disease ; White ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) and white-matter structural connectivity have been linked in some observational studies, although it is unknown if this is a causal relationship. The purpose of this study was to examine the impact of various white-matter structural connectivity on AD via a two-sample multivariate Mendelian randomization (MR) approach.

METHODS: The genome-wide association study (GWAS) of Wainberg et al. provided the summary data on white-matter structural connectivity, and Bellenguez et al.'s study provided the GWAS aggregated data for AD. MR methods included inverse variance weighted, Mendelian randomization Egger, simple mode, weighted median, and weighted mode. Heterogeneity, horizontal pleiotropy, and "leave-one-out" analysis guaranteed the robustness of causation. Finally, reverse MR analysis was conducted on the white-matter structural connectivity that showed positive results in the forward MR analysis.

RESULTS: Among 206 white-matter structural connections, we identified 10 connections were strongly correlated with genetic susceptibility to AD. Right-hemisphere limbic network to thalamus white-matter structural connectivity and Right-hemisphere salience_ventral attention network to accumbens white-matter structural connectivity were positively correlated with the likelihood of AD, while the remaining 8 white-matter structural connections were negatively related with AD. None of the above 10 white-matter structural connections have a reverse causal relationship with AD.

CONCLUSION: Our MR study reveals a certain degree of association between white-matter structural connectivity and AD, which may provide support for future diagnosis and treatment of AD.}, } @article {pmid39923958, year = {2025}, author = {Zhang, H and Bi, F and Zhao, P and Cui, H and Tao, X and Zhang, J and Li, C and Cao, Y and Wang, N and Li, H}, title = {Longan Aril polysaccharides ameliorate cognitive impairment in AD mice via restoration of the immune phagocytosis of microglia.}, journal = {Journal of ethnopharmacology}, volume = {343}, number = {}, pages = {119464}, doi = {10.1016/j.jep.2025.119464}, pmid = {39923958}, issn = {1872-7573}, abstract = {Alzheimer's disease (AD) belongs to the category of "forgetfulness" or "dementia" in traditional Chinese medicine, and is often caused by deficiency of five zang-viscera. Longan Aril (the aril of Dimocarpus longan Lour., LA) possesses properties beneficial for heart and spleen health, blood nourishment, and mind tranquility, suggesting its potential as a treatment for AD. This study aimed to investigate the therapeutic effects of Longan Aril polysaccharides (LAPs), a primary active constituent of LA, on lipopolysaccharides (LPS) and amyloid β-peptide (Aβ) induced immune tolerance in AD mice. Further, BV2 cells were employed to explore the mechanism of LAPs in improving immune tolerance.

MATERIAL AND METHODS: LAPs were prepared by water extraction and alcohol precipitation. The monosaccharide composition was determined by high-performance liquid chromatography (HPLC). An AD mouse model of immune tolerance was established by intraperitoneal (i.p) injection of LPS combined with intracerebroventricular (ICV) injection of Aβ25-35. The LAPs group mice received LAPs (1.4 g/kg) daily for 40 days. The anti-AD efficacy and mechanism of LAPs in vivo was evaluated by the Y maze, Morris water maze, Degenerating Neurons Stain (FJC staining), hematoxylin-eosin (H&E) staining, Nissl staining, measurements of lactate, tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) secretion levels, immunofluorescence and western blot. Furthermore, the mechanism of LAPs in improving the function of immune-tolerant BV2 cells was explored in vitro using lactic acid kits, ELISA kits, and western blot. The phagocytic function of BV2 cells was evaluated by the fluorescent dye Alexa Fluor 488 labeled Aβ (AF448-Aβ).

RESULTS: LAPs contained five monosaccharides. LAPs improved cognitive function and increased the number of Nissl bodies, lactate secretion, the IL-10 content, the relative fluorescence intensity of the IBA1 and AXL proteins, and the protein expression levels of AXL, Mertk, Glut1, HK2, PI3K, p-Akt/Akt, p-mTOR/mTOR and HIF-1α of immune-tolerant AD mice. LAPs also reduced the TNF-α content, and the protein expression level of CD68 in immune-tolerant AD mice. In vitro, LAPs elevated the IL-10 content and protein expression levels of PI3K, Akt, p-Akt, and HIF-1α, while reducing lactate secretion and the TNF-α content in immune-tolerant BV2 cells. LAPs promoted the phagocytic activity of BV2 cells, and their effects are completely inhibited by 2-DG and partially inhibited by BAY and Rapa.

CONCLUSIONS: LAPs can enhance the cognitive abilities of immune-tolerant AD mice and diminish their pathological damage. The mechanism involves the regulation of glycolysis and the PI3K/Akt/mTOR/HIF-1α signaling pathway to promote microglial immune phagocytosis.}, } @article {pmid39923891, year = {2025}, author = {Shan, G and Zhang, Y and Tang, Z and Wang, G and Wu, SS}, title = {Disease progression trajectory curves to estimate saved time in Alzheimer's disease trials.}, journal = {Contemporary clinical trials}, volume = {}, number = {}, pages = {107814}, doi = {10.1016/j.cct.2025.107814}, pmid = {39923891}, issn = {1559-2030}, abstract = {With the recent successful disease-modifying therapies against Alzheimer's disease (AD), there have been discussions on easily interpretable measures for treatment effects. Among them, saved time for patients treated with a new drug as compared to patients randomized to the placebo group offers easier interpretation than the reduced percentage in outcome decline at last visit which were commonly used in AD trials. The existing method to calculate saved time utilized the disease progression trajectory of the placebo group and the treatment effect at the last visit. We propose to develop two new methods that use the disease progression trajectories of both groups: (1) slope adjusted method; and (2) area under the curve method. We used data from the two donanemab trials and the donepezil trial to illustrate the application of the proposed methods and conducted simulation studies to compare these methods. When a drug has a constant treatment effect over time or early and middle difference in the disease progression, the second new method often has the saved time being longer than the existing method. When the treatment effect is an increasing function of time before the last visit as observed in disease-modifying therapy trials, the slope adjusted method could have a larger saved time as compared to the existing method. In many cases, the area under the curve method often has the smallest standard deviation of saved time.}, } @article {pmid39923885, year = {2025}, author = {Li, T and Wang, W and Liu, W and Sun, M and Wang, Q and Li, Z and Hao, J and Yu, Y}, title = {Macrophage membrane coated functionalized nanoparticles for targeted drug delivery and neural function repair in cerebral ischemia-reperfusion injury.}, journal = {International journal of pharmaceutics}, volume = {}, number = {}, pages = {125329}, doi = {10.1016/j.ijpharm.2025.125329}, pmid = {39923885}, issn = {1873-3476}, abstract = {Vascular dementia (VD) is the second leading cause of cognitive impairment after Alzheimer's disease, posing a heavy burden to families and society. The majority of causes of VD are vascular diseases such as stroke, with ischemic stroke accounting for a large proportion. After ischemia-reperfusion, factors such as mitochondrial damage and increased xanthine oxidase lead to excessive production of reactive oxygen species (ROS) at the ischemic site, further exacerbating brain injury. Therefore, developing effective ROS scavengers is crucial. Polydopamine has become one of the widely used surface functionalized materials in recent years, due to its excellent biocompatibility and antioxidant properties. This paper proposed a macrophage membrane disguised polydopamine (PDA) nanoplatform for loading the neuroprotective drug puerarin (PUE). The as made PUE@PDA@CMs (PPCs) nanoplatforms can significantly and effectively clear ROS, alleviate oxidative microenvironment, and protect neurons from oxidative stress damage. The macrophage membranes modification enables PPCs to respond to lymphocyte recruitment at the site of cerebral ischemia-reperfusion injury, thereby targeting and aggregating to the injury site. In a mouse model of vascular dementia, PPCs treatment significantly reduced neuronal apoptosis and provided significant cognitive and memory function recovery, providing new strategies and prospects for the treatment of central nervous system diseases.}, } @article {pmid39923646, year = {2025}, author = {Haghi, M and Masoudi, R and Ataellahi, F and Yousefi, R and Najibi, SM}, title = {Role of Tau and Amyloid-beta in autophagy gene dysregulation through oxidative stress.}, journal = {Tissue & cell}, volume = {93}, number = {}, pages = {102765}, doi = {10.1016/j.tice.2025.102765}, pmid = {39923646}, issn = {1532-3072}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by memory impairment and cognitive decline. Our previous research has demonstrated that pathological Tau and Amyloid-beta (Aβ) disrupt autophagy gene expression, independently. Other studies have shown that these pathological aggregates create a vicious cycle with oxidative stress.

METHODS: In the current research, the effect of Tau and Amyloid-beta was compared on behavioral function, autophagy gene dysfunction, and oxidative stress in the Drosophila model for AD. Thymoquinone (TQ), an antioxidant agent, was then tested to examine if it could ameliorate the adverse effects of Tau and Amyloid-beta. In addition, the impact of TQ on Tau aggregation was investigated in vitro.

RESULTS: Our data showed that Tau and Amyloid-beta induced behavioral disability, autophagy gene dysregulation, and oxidative stress. TQ treatment significantly improved conditions in both types of transgenic flies, with a more profound alleviation in Tau transgenic flies, despite tau having a greater impact on autophagy gene dysregulation. Furthermore, TQ prevented the aggregation of Tau in vitro.

CONCLUSION: To sum up, Tau may exert its toxic effect on autophagy and behavioral dysfunctions significantly through oxidative stress while Amyloid-beta may confer its toxicity through multiple pathways, including oxidative stress. Moreover, since TQ ameliorates the adverse effect of tau and amyloid beta, it could be considered a promising approach for treating AD, probably in combination with other medications against Aβ or Tau.}, } @article {pmid39922688, year = {2025}, author = {Webeck, JA and Laing, K and Andrews, DM}, title = {Improvement in gait and functional abilities in an adult with posterior cortical atrophy after translingual neuromodulation with neurorehabilitation physical therapy: a case report.}, journal = {Physiotherapy theory and practice}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/09593985.2025.2464849}, pmid = {39922688}, issn = {1532-5040}, abstract = {BACKGROUND: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive damage to the brain's visual and association areas, resulting in impaired spatial awareness, visual processing, and functional independence.

PURPOSE: This report examines the effects of a 14-week treatment protocol consisting of translingual neuromodulation via a portable neuromodulation stimulator (PoNS®[1]) in conjunction with physical therapy on balance, gait, and functional mobility in an adult male with PCA.

CASE DESCRIPTION: Assessments included objective and subjective measures of balance and gait - the 10-Metre Walk Test, Functional Gait Assessment (FGA), Dynamic Gait Index (DGI), Community Balance and Mobility Scale (CB&M), Neuro-Quality of Life (Neuro-QoL), and Activities-specific Balance Confidence (ABC) Scale. These were performed at baseline and weeks 4, 8, and 14 to evaluate the protocol's efficacy in improving balance, stability, and gait.

OUTCOMES: Postural stability, balance, gait patterning, and gait speed improved, enhancing daily functioning abilities and self-confidence. Gait speed improved by 0.48 m/s (comfortable) and 0.46 m/s (fast), exceeding MDC thresholds. The participant's FGA score increased 21 points and DGI increased 17 points, both exceeding their respective MDC thresholds (6 points for FGA, 3.2 points for DGI), reflecting marked gait improvements. The CB&M score rose 24 points, exceeding the MDC of 9.6 points. Despite these gains, gait speed remained below age-related norms.

CONCLUSION: Given the largely positive response to the protocol, further investigation should be undertaken to continue to explore the efficacy of PoNS® and physical therapy to determine its viability as a treatment for symptoms of PCA.}, } @article {pmid39922422, year = {2025}, author = {Zheng, N and Zhang, Z and Liu, H and Zong, S and Zhang, L and Cui, X and Liu, Y and Wang, C and Chen, R and Lu, Z}, title = {MK886 Ameliorates Alzheimer's Disease by Activating the PRKCI/AKT Signaling Pathway.}, journal = {European journal of pharmacology}, volume = {}, number = {}, pages = {177359}, doi = {10.1016/j.ejphar.2025.177359}, pmid = {39922422}, issn = {1879-0712}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, associated with oxidative stress, neuronal apoptosis, and the accumulation of amyloid-β (Aβ) plaques. Despite advances in understanding AD pathology, effective treatments remain limited. This study aimed to investigate the therapeutic efficacy and underlying molecular mechanisms of MK886, a selective inhibitor of the 5-lipoxygenase pathway, in the context of AD. Network pharmacology analyses were employed to evaluate MK886's potential as a treatment for AD, revealing promising interactions with key molecular targets implicated in the disease. In vitro experiments demonstrated that MK886 effectively mitigated Aβ1-42 oligomer-induced oxidative stress, apoptosis, and ferroptosis in mouse hippocampal neuronal cells (HT22). These effects were validated using techniques such as immunofluorescence, JC-1 staining, TUNEL staining, and flow cytometry. In vivo studies involved administering MK886 to APPswe/PS1dE9 (APP/PS1) mice, which resulted in significant improvements in cognitive and emotional functions as assessed by the Y-maze and Morris water maze tests. Histological evaluations, including Nissl staining, immunofluorescence, and immunohistochemistry, revealed that MK886 preserved hippocampal neuron integrity and reduced Aβ deposition. Proteomics and molecular docking analyses identified the PRKCI/AKT signaling pathway as a key mediator of MK886's neuroprotective effects. This finding was further validated through Western blotting experiments incorporating an AKT inhibitor. Overall, these findings suggest that MK886 holds promise as a potential therapeutic agent for Alzheimer's disease by enhancing neuronal protection and cognitive function through the activation of the PRKCI/AKT pathway.}, } @article {pmid39922347, year = {2025}, author = {Zhang, Y and Zhang, X and Zhou, J and Li, Y and Kai, T and Zhang, L}, title = {Lycium ruthenicum Murray exosome-like nanovesicles alleviated Alzheimer's disease-like symptoms induced by Aβ protein in transgenic Caenorhabditis elegans through the DAF-16 pathway.}, journal = {International journal of biological macromolecules}, volume = {304}, number = {Pt 1}, pages = {140758}, doi = {10.1016/j.ijbiomac.2025.140758}, pmid = {39922347}, issn = {1879-0003}, abstract = {Alzheimer's disease (AD) is predominantly characterized by cholinergic dysfunction, mitochondrial impairment, oxidative stress, and inflammation, primarily driven by amyloid-beta (Aβ) peptides. This study investigates the protective effects of Lycium ruthenicum Murray-derived exosome-like nanoparticles (LELN) in AD models using transgenic Caenorhabditis elegans (C. elegans). Findings showed that C. elegans effectively internalized LELN, which remained stable in vivo. Compared with untreated controls, treatment with 600 μg/mL LELN significantly extended the lifespan of CL4176 [myo-3p::Aβ1-42] and CL2006 [unc-54/Aβ1-42] worms by 34.78 % and 34.85 %, respectively, and delayed Aβ-induced paralysis by 52.42 % and 42.72 %, respectively. Furthermore, LELN increased the chemotaxis index of CL2355 [snb-1::Aβ1-42] worms from 11.11 % to 55.56 %. Mechanistically, LELN reduced the levels of Aβ oligomers and monomers via the DAF-16 pathway, consequently alleviating AD-like symptoms in transgenic C. elegans. The effects of LELN include inhibiting acetylcholinesterase activity to mitigate cholinergic dysfunction, restoring mitochondrial membrane potential and adenosine triphosphate production to ameliorate mitochondrial dysfunction, and reducing oxidative stress and inflammation. Collectively, these results highlight the protective role of LELN against Aβ-induced AD pathology and underscore their potential as a therapeutic candidate for AD treatment.}, } @article {pmid39922232, year = {2025}, author = {Prabha, S and Choudhury, A and Islam, A and Thakur, SC and Hassan, MI}, title = {Understanding of Alzheimer's Disease Pathophysiology for Therapeutic Implications of Natural Products as Neuroprotective Agents.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {102680}, doi = {10.1016/j.arr.2025.102680}, pmid = {39922232}, issn = {1872-9649}, abstract = {Alzheimer's disease (AD) is a leading cause of dementia, affecting more than 24.3 million people worldwide in 2024. Sporadic AD (SAD) is more common and occurs in the geriatric population, while familial AD (FAD) is rare and appears before the age of 65 years. Due to progressive cholinergic neuronal loss and modulation in the PKC/MAPK pathway, β-secretase gets upregulated, leading to Aβ aggregation, which further activates tau kinases that form neurofibrillary tangles (NFT). Simultaneously, antioxidant enzymes are also upregulated, increasing oxidative stress and reactive species by impairing mitochondrial function, leading to DNA damage and cell death. This review discusses the classifications and components of several natural products (NPs) that target these signaling pathways for AD treatment. NPs, including alkaloids, polyphenols, flavonoids, polysaccharides, steroids, fatty acids, tannins, and polypeptides derived from plants, microbes, marine animals, venoms, insects, and mushrooms, are explored in detail. Plant metabolites, prebiotics, and probiotics are combined to increase the production of bioactive compounds. Toxins have demonstrated effectiveness in modulating signaling pathways and reducing OS. Marine metabolites have also shown neuroprotective and anti-inflammatory properties. The cholera toxin B subunit and an Aβ15 have been combined to create a possible oral AD vaccine, which enhances cognitive function in mice. Insect tea is also a reliable source of antioxidants. A functional edible mushroom snack bar showed an increment in cognitive markers. Future directions and therapeutic approaches for the treatment of AD can be improved by focusing more on NPs derived from these sources.}, } @article {pmid39921833, year = {2025}, author = {Stewart, D and Johnson, EL}, title = {The Bidirectional Relationship Between Epilepsy and Alzheimer's Disease.}, journal = {Current neurology and neuroscience reports}, volume = {25}, number = {1}, pages = {18}, pmid = {39921833}, issn = {1534-6293}, support = {K23AG063899/GF/NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/complications/physiopathology ; *Epilepsy/complications/physiopathology/diagnosis ; Anticonvulsants/therapeutic use ; Animals ; Cognitive Dysfunction/etiology/physiopathology ; }, abstract = {PURPOSE OF REVIEW: Epilepsy has long been considered a late-stage consequence of Alzheimer's Disease (AD), but recent studies highlight its role early in the disease process, even preceding cognitive symptoms. Population studies reveal a two- to fourfold increased epilepsy risk in AD, particularly in early-onset cases, with seizures clustering around diagnosis. Furthermore, individuals with late-onset unexplained epilepsy have an elevated risk of developing mild cognitive impairment and dementia, underscoring a bidirectional relationship between AD and epilepsy.

RECENT FINDINGS: Experimental models support this connection, demonstrating amyloid and tau pathology-induced hyperexcitability at pre-symptomatic stages, implicating soluble Aβ oligomers and inhibitory interneuron dysfunction in excitatory/inhibitory imbalance. Subclinical or clinical epileptiform activity, detectable in 20-50% of AD patients, is associated with cognitive decline, possibly due to sleep-related memory consolidation disruption. Emerging biomarkers, such as TIRDA and high-frequency oscillations, show promise for early detection and intervention. Anti-seizure medications (ASMs), particularly low-dose levetiracetam, show potential not only for seizure control but also for mitigating amyloid deposition, tau hyperphosphorylation, and cognitive decline. However, treatment complexities remain due to variable ASM efficacy, age-related side effects, and limited clinical trials. The bidirectional nature of AD and epilepsy emphasizes the need for integrated diagnostics, including EEG and biomarker assessments, to guide early intervention and targeted therapies. Future research should focus on the mechanistic interplay between amyloid, tau, and hyperexcitability, alongside trials of ASM regimens, to refine therapeutic strategies and improve outcomes in this population.}, } @article {pmid39921369, year = {2025}, author = {Abdulghani, MF and Barzegari, R and Almagharbeh, WT and Yazdani, Z and Amandadi Ghotbabadi, A and Seyed Bagheri, SH and Alnaiem, M and Dehghan, M}, title = {Treatments of psychosomatic symptoms in Alzheimer's disease: a scoping review of the potential therapeutic effects of essential oils.}, journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society}, volume = {25}, number = {2}, pages = {e70007}, doi = {10.1111/psyg.70007}, pmid = {39921369}, issn = {1479-8301}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Oils, Volatile/therapeutic use ; Aromatherapy/methods ; Psychophysiologic Disorders/drug therapy ; Plant Oils/therapeutic use ; Phytotherapy/methods ; }, abstract = {Alzheimer's disease, a type of dementia, poses serious challenges to patients, especially older people, and no definitive treatment is available for this disease, with drug treatments having many side effects. As essential oils of plants deserve particular attention in the treatment of diseases, this study aimed to review the potential therapeutic effects of essential oils on treatment of psychosomatic aspects of Alzheimer's disease. To collect information, we searched different databases, including MagIran, SID, IranDoc and IranMedex, Embase, Science Direct, PubMed, Google Scholar, Scopus and Web of Science using the keywords of essential oil, Alzheimer, acetylcholinesterase, memory, forgetfulness, aromatherapy, medicinal plant, herbal drugs, and their Persian equivalents from January 2010 to June 2022; the search included both single and multiple keywords. We retrieved 233 articles, reviewed the titles, abstracts, and full texts of the articles, and then included 25 related articles in this review (11 in vitro studies and 14 in vivo studies). The study results of in vitro and in vivo studies showed the effectiveness of different essential oils such as salvia family, tangerine and lemon oils, Juniperus communis, Anthriscus nemorosa, olibanum, inhaled coriander, Schisandra chinensis, lavender, rose essential oil, Nepeta cataria, Cinnamomum zeylanicum and Lippia origanoides, on memory and learning, enzymes, oxidative stress and inflammation, behavioural and cognitive symptoms in Alzheimer's disease. These findings suggest that essential oils can serve as complementary therapies for neurodegenerative diseases like Alzheimer's and for addressing memory impairments, although further research, especially human clinical trials, is needed to validate these findings, determine optimal dosages, and explore the long-term safety of essential oils in clinical settings.}, } @article {pmid39921150, year = {2025}, author = {Carrol, D and Busse, WW and Frye, CJ and Klaus, DR and Bach, JC and Floerke, H and Bendlin, BB and Zetterberg, H and Blennow, K and Heslegrave, A and Hoel, R and Rosenkranz, MA}, title = {Regional brain structural alterations in reward and salience networks in asthma.}, journal = {Brain, behavior, and immunity}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bbi.2025.01.028}, pmid = {39921150}, issn = {1090-2139}, abstract = {INTRODUCTION: Chronic systemic inflammation is highly prevalent and has deleterious effects on the brain, impacting both function and structure, and manifesting in elevations in psychological symptoms transdiagnostically. Asthma is a chronic inflammatory disease of the airway that affects more than 300 million people worldwide and is known to be highly comorbid with psychological and cognitive dysfunction. Though a growing corpus of work has identified functional brain abnormalities associated with asthma, limited research has investigated structural differences which may partially underlie functional changes. Identifying and characterizing asthma-related structural brain changes will shed light on the neurobiology through which asthma impacts mental function and has the potential to inform prophylaxis and treatment.

METHODS: We examined differences in regional brain volume, cortical thickness, and surface area, in 128 individuals with asthma compared to 134 non-asthma healthy controls. Five regions of interest were examined a priori, based on their previous implication in inflammation-related functional consequences (dorsal and ventral striatum, pallidum, and insula), or previous evidence of asthma-related structural impact (hippocampus and thalamus). We supplemented our region of interest approach with a voxel-wise whole-brain analysis. Additionally, we examined the association of brain structure with depression symptoms, asthma severity, degree of inflammation, and plasma biomarkers of neuroinflammation, neurodegeneration, and Alzheimer's disease specific pathology.

RESULTS: Compared to non-asthma control participants, those with asthma had smaller nucleus accumbens volumes, thicker orbitofrontal cortices, larger middle frontal cortex surface areas, and greater diencephalon volumes. Those with more severe asthma had smaller nucleus accumbens and dorsal striatal volumes, reduced anterior cingulate cortex surface area, and greater amygdala volume compared to those with mild asthma. In untreated asthma patients, greater depressive symptoms were associated with smaller striatal volume, suggesting a potential CNS-protective effect of medications that reduce airway inflammation in asthma. In addition, a plasma marker of astrogliosis was associated with larger diencephalon, cerebellum, brainstem, and thalamus volumes, but reduced insula thickness and surface area.

CONCLUSIONS: Patterns of structural brain changes in participants with asthma encompass key regions of reward and salience networks, which may in part give rise to the functional alterations in these networks characteristic of chronic systemic inflammation.}, } @article {pmid39920976, year = {2025}, author = {Panda, SP and Sinha, S and Kesharwani, A and Kumar, S and Singh, M and Kondepudi, GM and Samuel, A and Sanghi, AK and Thapliya, S and Chaubey, KK and Guru, A}, title = {Role of OX/OXR cascade in insomnia and sleep deprivation link Alzheimer's disease and Parkinson's disease: Therapeutic avenue of Dual OXR Antagonist (DORA).}, journal = {Biochemical pharmacology}, volume = {}, number = {}, pages = {116794}, doi = {10.1016/j.bcp.2025.116794}, pmid = {39920976}, issn = {1873-2968}, abstract = {Sleep plays a role in the elimination of neurotoxic metabolites that are accumulated in the waking brain as a result of neuronal activity. Long-term insomnia and sleep deprivation are associated with oxidative stress, neuroinflammation, amyloid beta (Aβ) deposition, and Lewy body formation, which are known to increase the risk of mild cognitive impairment (MCI) and dementia. Orexin A (OXA) and orexin B (OXB), two neuropeptides produced in the lateral hypothalamus, are known to influence the sleep-wake cycle and the stress responses through their interactions with OX receptor 1 (OX1R) and OX receptor 2 (OX2R), respectively. OX/OXR cascade demonstrates intricate neuroprotective and anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-kB) and PLC/Ca[2+] pathway activation. OX1R binds OXA more strongly than OXB by one-order ratio, whereas OX2R binds both OXA and OXB with equal strengths. Overexpression of OXs in individuals experiences sleep deprivation, circadian rhythm disturbances, insomnia-associated MCI, Parkinson's disease (PD), and Alzheimer's disease (AD). Many dual OXR antagonists (DORAs) have been effective in their clinical studies, with suvorexant and daridorexant receiving FDA clearance for insomnia therapy in 2014 and 2022 respectively. The results of clinical studies suggested that there is a new pharmaceutical option for treating insomnia and the sleep deprivation-AD/PD relationship by targeting the OXR system. DORAs treatment reduces Aβ deposition in the brain and improves synaptic plasticity and circadian expression. This review indicates the link between sleep disorders and MCI, DORAs are an appropriate medication category for treating insomnia, and sleep deprivation links AD and PD.}, } @article {pmid39919860, year = {2025}, author = {Yin, G and Sun, Y and Luo, Y and Cheng, Y and Xue, S and Wang, H and Lu, Q and Du, F and Yin, P}, title = {Fluorescence imaging of homocysteine dynamics: Complementary diagnostic applications in Alzheimer's disease.}, journal = {Analytica chimica acta}, volume = {1342}, number = {}, pages = {343688}, doi = {10.1016/j.aca.2025.343688}, pmid = {39919860}, issn = {1873-4324}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis/metabolism ; *Homocysteine/analysis/blood/metabolism ; Animals ; *Optical Imaging ; Mice ; Humans ; *Fluorescent Dyes/chemistry ; Biomarkers/analysis/blood/metabolism ; Amyloid beta-Peptides/analysis/metabolism ; Blood-Brain Barrier/metabolism ; }, abstract = {With the continue emergence of Alzheimer's disease (AD)-modifying therapies, pinpointing the treatments that offer the greatest benefits to patients is increasingly critical. Complementary diagnostics are powerful tests that can provide crucial biomarker dynamics about the drug usage that can improve treatment outcomes by individualized pharmacotherapy. Herein, we exploited a robust near-infrared fluorescent probe, by attenuating the pre-twisting tendency and the twist intramolecular charge transfer effect, for sensing of Hcy in vitro and in vivo with high quantum yield, excellent selectivity, and remarkable sensitivity. The probe is capable of monitoring endogenous Hcy dynamics in cells, tissues and in vivo with exceptional blood-brain barrier permeability. Specifically, we revealed that Hcy can contribute to the onset and development of AD by facilitating the formation of amyloid-β aggregates, elucidating the intricate relationship between brain Hcy levels and AD progression. Furthermore, we investigated the effect of four licensed drugs on endogenous marker Hcy dynamics in cells and in mice with AD model. Our study provides a valuable molecular probe platform utilizing Hcy as a biomarker for supplementary diagnosis applications.}, } @article {pmid39919551, year = {2025}, author = {Gangarde, P and Bhatt, S and Pujari, R}, title = {Assessment of neuroprotective potential of Cuscuta reflexa in aluminium chloride-induced experimental model of Alzheimer's disease: In vitro and in vivo studies.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {88}, number = {}, pages = {127612}, doi = {10.1016/j.jtemb.2025.127612}, pmid = {39919551}, issn = {1878-3252}, abstract = {BACKGROUND & AIMS: Cuscuta reflexa (family Convolvulaceae), commonly known as giant dodder or Amarbel, is a parasitic plant that has garnered attention in pharmacological research due to its diverse bioactive compounds and potential therapeutic applications. Scientific studies have validated its traditional uses in folk medicine, highlighting its pharmacological activities. Alzheimer's Disease (AD) is a neurodegenerative disorder marked by the buildup of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT) in the brain, leading to synaptic impairment and the gradual loss of neurons. Currently, no effective medication is available to treat the development and progression of the disease. Hence, there is a rising concern about using alternative therapy such as herbal medicine to limit the progression of AD and improve the quality of a patient's life with minimum side effects. The plant Cuscuta reflexa has traditionally been claimed to possess neuroprotective effects but has not yet been validated scientifically. The present study aimed to investigate the potential of the hydroalcoholic extract of Cuscuta reflexa (CRE) to ameliorate the neurodegenerative effect of aluminium chloride (AlCl3) using in vitro and in vivo studies.

METHODS: The neuroprotective activity of CRE was evaluated using in vitro and in vivo experimental models of AlCl3-induced AD.

RESULTS: The in vitro study showed that CRE markedly reduced AlCl3-induced cytotoxicity in PC12 cells. The in vivo study using the AlCl3-induced AD rat model showed that CRE treatment improved learning and memory, as evaluated using the open field test (OFT) and Morris water maze (MWM) test. CRE also showed the reduction in oxidative stress induced by AlCl3 in the brains of the rats by virtue of the significant decrease in oxidative stress biomarker malondialdehyde (MDA) and increase in the antioxidant parameters such as reduced glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD). Further, CRE exhibited its cholinergic activity by lowering the AlCl3-induced enhanced levels of acetylcholinesterase (AChE) in the brains of rats. Histopathological analysis of the brains of rats showed that CRE treatment prevented the reactive changes and the damage in the neuronal tissue caused due to the AlCl3.

CONCLUSION: Conclusively, CRE ameliorated AlCl3-induced neurobehavioural toxicity in the rat model of AD by virtue of its anti-inflammatory, antioxidant, cholinergic and neuroprotective effects which suggests its use in the treatment of progressive neural damage and cognitive deficits in AD patients.}, } @article {pmid39919463, year = {2025}, author = {Ban, SY and Nam, Y and Do, TT and Kim, BH and Shin, SJ and Thi Nguyen, MT and Kim, J and Moon, M and Park, JT}, title = {Liver-X receptor β-selective agonist CE9A215 regulates Alzheimer's disease-associated pathology in a 3xTg-AD mouse model.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {184}, number = {}, pages = {117895}, doi = {10.1016/j.biopha.2025.117895}, pmid = {39919463}, issn = {1950-6007}, abstract = {In Alzheimer's disease (AD), tau pathology is closely associated with disease progression. Therefore, therapeutics that alleviate tau pathology are essential. Liver-X receptor (LXR) has garnered interest as a potential target for the treatment of AD. We previously investigated the potent anti-allergic and anti-inflammatory effects of inotodiol, hereafter referred to as CE9A215, in various disease models. In this study, we explored the potential of CE9A215 as a treatment for AD. CE9A215 preferentially activated LXRβ (EC50 <10 nM), with no significant activation observed for LXRα at concentrations up to 1000 nM. Pharmacokinetic analysis confirmed that CE9A215 crosses the blood-brain barrier and accumulates in the brain. Moreover, CE9A215 modulated the expression of ABCA1, APOE, SREBP-1c and AQP4 in the brains of wild-type and LXR α/β knockout mice in LXRβ-dependent manner. The efficacy of CE9A215 on AD-related pathologies was evaluated using 3xTg-AD mice. CE9A215 exerted both prophylactic and therapeutic effects on AD-associated behaviors and pathologies, including reductions in amyloid-β, phosphorylated tau, and neuroinflammation in the hippocampus. Transcriptomic analysis revealed that CE9A215 induced significant changes in genes associated with tau pathology, particularly in pathways related to protein phosphorylation and PI3K/AKT signaling. Our findings suggest that CE9A215 could be a promising therapeutic candidate for AD, particularly in mitigating tau hyperphosphorylation and related AD pathologies.}, } @article {pmid39919076, year = {2025}, author = {Liu, N and Deng, Q and Peng, Z and Mao, D and Huang, Y and Meng, F and Zhang, X and Shen, J and Li, Z and Yan, W and Peng, J}, title = {Characterization of gene expression profiles in Alzheimer's disease and osteoarthritis: A bioinformatics study.}, journal = {PloS one}, volume = {20}, number = {2}, pages = {e0316708}, pmid = {39919076}, issn = {1932-6203}, mesh = {Humans ; *Osteoarthritis/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism ; *Computational Biology/methods ; *Protein Interaction Maps/genetics ; *Gene Expression Profiling ; Transcriptome ; Receptors, GABA/genetics/metabolism ; Gene Regulatory Networks ; Extracellular Matrix Proteins/genetics/metabolism ; Databases, Genetic ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) and Osteoarthritis (OA) have been shown to have a close association in previous studies, but the pathogenesis of both diseases are unclear. This study explores the potential common molecular mechanisms between AD and OA through bioinformatics analysis, providing new insights for clinical treatment strategies.

METHODS: The AD and OA-related datasets were downloaded from the gene expression database GEO. The datasets were analyzed to obtain differentially expressed gene (DEG) datasets for OA and AD, respectively. The intersection of these DEGs was analyzed to identify common DEGs (Co-DEGs). Subsequently, the Co-DEGs were enriched, and a protein-protein interaction network was constructed to identify core genes. The expression of these genes was validated in a separate dataset, and their diagnostic value for the diseases was analyzed. In addition, the core genes were analyzed using gene set enrichment analysis and single-gene genome variation analysis.

RESULTS: Analysis of DEGs on gene chips from OA and AD patients revealed significant changes in gene expression patterns. Notably, EFEMP2 and TSPO, genes associated with inflammatory responses, showed lower expression levels in both AD and OA patients, suggesting a downregulation in the pathological backgrounds of these diseases. Additionally, GABARAPL1, which is crucial for the maturation of autophagosomes, was found to be upregulated in both conditions. These findings suggest the potential of these genes as diagnostic biomarkers and potential therapeutic targets. However, to confirm the effectiveness of these genes as therapeutic targets, more in-depth mechanistic studies are needed in the future, particularly to explore the feasibility and specific mechanisms of combating disease progression by regulating the expression of these genes.

CONCLUSIONS: This study suggests that AD and OA shares common molecular mechanisms. The identification of EFEMP2, GABARAPL1, and TSPO as key target genes highlights potential common factors in both diseases. Further investigation into these findings could lead to new candidate targets and treatment directions for AD and OA, offering promising avenues for developing more effective and targeted therapeutic interventions.}, } @article {pmid39918606, year = {2025}, author = {Cantone, AF and Burgaletto, C and Di Benedetto, G and Gaudio, G and Giallongo, C and Caltabiano, R and Broggi, G and Bellanca, CM and Cantarella, G and Bernardini, R}, title = {Rebalancing Immune Interactions within the Brain-Spleen Axis Mitigates Neuroinflammation in an Aging Mouse Model of Alzheimer's Disease.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {20}, number = {1}, pages = {15}, pmid = {39918606}, issn = {1557-1904}, support = {PNRR MAD-2022-12375802//Regione Sardegna, legge regionale 7 agosto 2007 n.7- promozione della ricerca scientifica e dell'innovazione tecnologica in Sardegna/ ; }, mesh = {Animals ; *Alzheimer Disease/immunology/metabolism/pathology ; Mice ; *Brain/immunology/metabolism/pathology ; *Mice, Transgenic ; *Spleen/immunology/metabolism ; *Disease Models, Animal ; *Neuroinflammatory Diseases/immunology ; *Aging/immunology ; Mice, Inbred C57BL ; Male ; }, abstract = {Alzheimer's disease (AD) is the most common cause of dementia worldwide, characterized by accumulation of amyloid-β protein and hyperphosphorylated tau protein in the brain. Neuroinflammation, resulting from chronic activation of brain-resident innate immune cells as well as enhanced peripheral leukocyte access across the blood-brain barrier, crucially affects AD progression. In this context, TNFSF10, a cytokine substantially expressed in the AD brain, has been shown to modulate both the innate and the adaptive branches of the immune response in AD-related neuroinflammation. In this study, we explored whether a TNFSF10-neutralizing treatment could represent a tool to re-balance the overall overshooting inflammatory response in a mouse model of AD. Specifically, 3xTg-AD mice were treated sub-chronically with an anti-TNFSF10 monoclonal antibody for three months, and were then sacrificed at 15 months. TNFSF10 neutralization reduced the expression of the inflammatory marker CD86, inversely related to levels of the anti-inflammatory marker CD206 in the brain of 3xTg-AD mice, suggesting a switch of microglia towards a neuroprotective phenotype. Similar results were observed in the splenic macrophage population. Moreover, flow cytometry revealed a significant decrease of CD4[+]CD25[+]FOXP3[+] T regulatory cells as well as reduced number of CD11b[+]LY6C[high] proinflammatory monocytes in both the brain and the spleen of 3xTg-AD mice treated with anti-TNFSF10 monoclonal antibody. Finally, the treatment resulted in lower count of splenic CD4[+] and CD8[+] T cells expressing PD1. The data suggest that TNFSF10 system-targeted treatment effectively restrain overshooting central and peripheral inflammation by rebalancing the overall immune response, mitigating the progression of AD pathology.}, } @article {pmid39918090, year = {2025}, author = {Lee, H and Chater, JM and Heinitz, CC and Wang, Y}, title = {Evaluation of metabolite profiles and neuroprotective potential in four pomegranate cultivars for Alzheimer's disease prevention.}, journal = {Journal of the science of food and agriculture}, volume = {}, number = {}, pages = {}, doi = {10.1002/jsfa.14176}, pmid = {39918090}, issn = {1097-0010}, support = {//Agricultural Marketing Service/ ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss, with oxidative stress and neuroinflammation playing crucial roles in its progression. Current treatments, such as acetylcholinesterase (AChE) inhibitors, offer limited symptomatic relief and can have side effects. With growing interest in functional foods that have fewer side effects, pomegranate (Punica granatum L.) has gained attention because of its rich antioxidant content. The present study aims to evaluate the antioxidant and neuroprotective effects of four pomegranate cultivars: 'Wonderful', 'Phoenicia', 'Azadi' and 'Eversweet'. Additionally, it investigates their metabolite profiles and predicts potential bioactive compounds that could help prevent AD.

RESULTS: The 'Wonderful' cultivar demonstrated the highest levels of total phenolic content, total flavonoid content, total anthocyanin content and radical scavenging activities. The AChE and butyrylcholinesterase (BuChE) inhibition rates were highest in 'Phoenicia' and 'Wonderful' cultivars, suggesting potential neuroprotective effects. PC12 cell assays indicated that these cultivars significantly improved cell viability, reduced reactive oxygen species and malondialdehyde levels, and also enhanced catalase activity. Metabolomics analysis identified 141 metabolites, with the 'Wonderful' cultivar showing the highest metabolite abundance. Molecular docking studies indicated that some metabolites, such as taxifolin, demonstrated strong binding affinities for AChE and BuChE, suggesting potential for AD treatment.

CONCLUSION: The 'Wonderful' and 'Phoenicia' cultivars demonstrated the most promising antioxidant and neuroprotective effects among the evaluated pomegranates, likely because of their high taxifolin content. These findings suggest that these cultivars could be valuable for developing functional foods aimed at AD prevention and treatment. © 2025 Society of Chemical Industry.}, } @article {pmid39917595, year = {2025}, author = {Zhang, Y and Deng, Z and Seaman, J and Koleck, TA}, title = {Thinking About It All Together: A Descriptive Analysis to Understand Comorbidities in People Living With Dementia.}, journal = {Health science reports}, volume = {8}, number = {2}, pages = {e70449}, pmid = {39917595}, issn = {2398-8835}, support = {OT2 OD026556/OD/NIH HHS/United States ; U2C OD023196/OD/NIH HHS/United States ; OT2 OD025315/OD/NIH HHS/United States ; OT2 OD026551/OD/NIH HHS/United States ; U24 OD023121/OD/NIH HHS/United States ; OT2 OD026552/OD/NIH HHS/United States ; OT2 OD026549/OD/NIH HHS/United States ; OT2 OD025337/OD/NIH HHS/United States ; OT2 OD025277/OD/NIH HHS/United States ; OT2 OD026555/OD/NIH HHS/United States ; OT2 OD026550/OD/NIH HHS/United States ; OT2 OD026553/OD/NIH HHS/United States ; OT2 OD023205/OD/NIH HHS/United States ; OT2 OD025276/OD/NIH HHS/United States ; OT2 OD026557/OD/NIH HHS/United States ; OT2 OD026554/OD/NIH HHS/United States ; U24 OD023163/OD/NIH HHS/United States ; OT2 OD023206/OD/NIH HHS/United States ; U24 OD023176/OD/NIH HHS/United States ; OT2 OD026548/OD/NIH HHS/United States ; }, abstract = {BACKGROUND AND AIMS: The prevalence of Alzheimer's disease and related dementia (ADRD) is on the rise. There is a corresponding escalation in the number of persons living with dementia who require complex, longitudinal support in care due to the progressive declines in cognitive and clinical profiles of persons living with dementia when delivering individualized person-centered care that promotes overall health and well-being. Hence, we aim to describe the presence and patterns of co-occurring comorbidities in persons living with dementia.

METHODS: This study is a retrospective, cross-sectional descriptive analysis based on curated electronic health record data from the All of Us Research Program from October 1, 2015, to June 30, 2022. We included individuals who were 65 years of age or older with at least one dementia-related diagnosis. We categorized 14 comorbidities by the Charlson Comorbidity Index, and defined all diseases based on the International Classification of Diseases Tenth Revision Diagnosis codes. We employed descriptive statistics and visualized data with UpSet Plots. Demographic characteristics (i.e., age, sex, race, and ethnicity) between people with and without co-occurring comorbidities were compared with either chi-square or Wilcoxon signed-rank tests.

RESULTS: Persons living with dementia (N = 4003) were a mean of 73 years old, 72.5% non-Hispanic White, and 47.5% female. Approximately 87% of persons living with dementia were diagnosed with at least one additional comorbidity. The most common comorbidities included diabetes (67.82%), renal disease (40.24%), chronic pulmonary disease (39.85%), congestive heart failure (37.37%), and peripheral vascular disease (34.57%). Heterogeneous patterns of co-occurring comorbidity were noted among persons living with dementia.

CONCLUSION: Our study demonstrates the high prevalence of co-occurring comorbid illness among persons living with dementia. It is critical that the impact of these co-occurring conditions on patients' disease trajectories be better understood to promote treatment choices that are person-centered and goal-concordant.}, } @article {pmid39915859, year = {2025}, author = {Putcha, D and Katsumi, Y and Touroutoglou, A and Eloyan, A and Taurone, A and Thangarajah, M and Aisen, P and Dage, JL and Foroud, T and Jack, CR and Kramer, JH and Nudelman, KNH and Raman, R and Vemuri, P and Atri, A and Day, GS and Duara, R and Graff-Radford, NR and Grant, IM and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, JC and Mendez, MF and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, S and Turner, RS and Wingo, TS and Wolk, DA and Womack, K and Carrillo, MC and Rabinovici, GD and Dickerson, BC and Apostolova, LG and Hammers, DB and , }, title = {Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer's disease: a neuropsychological data-driven approach.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {38}, pmid = {39915859}, issn = {1758-9193}, support = {R01 AG075802/AG/NIA NIH HHS/United States ; U01AG6057195/NH/NIH HHS/United States ; K23 AG065450/NH/NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics/psychology ; Female ; Male ; *Neuropsychological Tests ; *Phenotype ; Middle Aged ; *Magnetic Resonance Imaging ; Atrophy ; Aged ; Age of Onset ; Longitudinal Studies ; Cerebral Cortex/pathology/diagnostic imaging ; Cohort Studies ; }, abstract = {BACKGROUND: The clinical presentations of early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease are distinct, with EOAD having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) described EOAD as predominantly amnestic, though this phenotypic description was based solely on clinical judgment. To better understand the phenotypic range of EOAD presentation, we applied a neuropsychological data-driven method to subtype the LEADS cohort.

METHODS: Neuropsychological test performance from 169 amyloid-positive EOAD participants were analyzed. Education-corrected normative comparisons were made using a sample of 98 cognitively normal participants. Comparing the relative levels of impairment between each cognitive domain, we applied a cut-off of 1 SD below all other domain scores to indicate a phenotype of "predominant" impairment in a given cognitive domain. Individuals were otherwise considered to have multidomain impairment. Whole-cortex general linear modeling of cortical atrophy was applied as an MRI-based validation of these distinct clinical phenotypes.

RESULTS: We identified 6 phenotypic subtypes of EOAD: Dysexecutive Predominant (22% of sample), Amnestic Predominant (11%), Language Predominant (11%), Visuospatial Predominant (15%), Mixed Amnestic/Dysexecutive Predominant (11%), and Multidomain (30%). These phenotypes did not differ by age, sex, or years of education. The APOE ɛ4 genotype was enriched in the Amnestic Predominant group, who were also rated as least impaired. Cortical thickness analysis validated these clinical phenotypes with dissociations in atrophy patterns observed between the Dysexecutive and Amnestic Predominant groups. In contrast to the heterogeneity observed from our neuropsychological data-driven approach, diagnostic classifications for this same sample based solely on clinical judgment indicated that 82% of individuals were amnestic-predominant, 9% were non-amnestic, 4% met criteria for Posterior Cortical Atrophy, and 5% met criteria for Primary Progressive Aphasia.

CONCLUSION: A neuropsychological data-driven method to phenotype EOAD individuals uncovered a more detailed understanding of the presenting heterogeneity in this atypical AD sample compared to clinical judgment alone. Clinicians and patients may over-report memory dysfunction at the expense of non-memory symptoms. These findings have important implications for diagnostic accuracy and treatment considerations.}, } @article {pmid39915222, year = {2025}, author = {Guan, T and Shang, L and Yang, P and Tan, Z and Liu, Y and Dong, C and Li, X and Hu, Z and Su, H and Zhang, Y}, title = {Joint ensemble learning-based risk prediction of Alzheimer's disease among mild cognitive impairment patients.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100083}, doi = {10.1016/j.tjpad.2025.100083}, pmid = {39915222}, issn = {2426-0266}, abstract = {OBJECTIVE: Due to the recognition for the importance of early intervention in Alzheimer's disease (AD), it is important to focus on prevention and treatment strategies for mild cognitive impairment (MCI). This study aimed to establish a risk prediction model for AD among MCI patients to provide clinical guidance for primary medical institutions.

METHODS: Data from MCI subjects were obtained from the NACC. Importance ranking and the SHapley Additive exPlanations (SHAP) method for the Random Survival Forest (RSF) and Extreme Gradient Boosting (XGBoost) algorithms in ensemble learning were adopted to select the predictors, and hierarchical clustering analysis was used to mitigate multicollinearity. The RSF, XGBoost and Cox proportional hazard regression (Cox) models were established to predict the risk of AD among MCI patients. Additionally, the effects of the three models were evaluated.

RESULTS: A total of 3674 subjects with MCI were included. Thirteen predictors were ultimately identified. In the validation set, the concordance indices were 0.781 (RSF), 0.781 (XGBoost), and 0.798 (Cox), and the Integrated Brier Score was 0.087 (Cox). The prediction effects of the XGBoost and RSF models were not better than those of the Cox model.

CONCLUSION: The ensemble learning method can effectively select predictors of AD risk among MCI subjects. The Cox proportional hazards regression model could be used in primary medical institutions to rapidly screen for the risk of AD among MCI patients once the model is fully clinically validated. The predictors were easy to explain and obtain, and the prediction of AD was accurate.}, } @article {pmid39914702, year = {2025}, author = {Geng, F and Zhao, N and Ren, Q}, title = {Circadian rhythm, microglia-mediated neuroinflammation, and Alzheimer's disease.}, journal = {Neuroscience and biobehavioral reviews}, volume = {170}, number = {}, pages = {106044}, doi = {10.1016/j.neubiorev.2025.106044}, pmid = {39914702}, issn = {1873-7528}, abstract = {Microglia, the brain's resident macrophages, are key mediators of neuroinflammation, responding to immune pathogens and toxins. They play a crucial role in clearing cellular debris, regulating synaptic plasticity, and phagocytosing amyloid-β (Aβ) plaques in Alzheimer's disease (AD). Recent studies indicate that microglia not only exhibit intrinsic circadian rhythms but are also regulated by circadian clock genes, influencing specific functions such as phagocytosis and the modulation of neuroinflammation. Disruption of the circadian rhythm is closely associated with AD pathology. In this review, we will provide an overview of how circadian rhythms regulate microglia-mediated neuroinflammation in the progression of AD, focusing on the pathway from the central nervous system (CNS) and the peripheral immune system. We also discuss potential therapeutic targets, including hormone modulation, lifestyle interventions, and anti-inflammatory therapies, aimed at maintaining brain health in AD. This will shed light on the involvement of circadian rhythm in AD and explore new avenues for AD treatment.}, } @article {pmid39914573, year = {2025}, author = {Hatakawa, Y and Tanaka, A and Furubayashi, T and Katsumi, H and Nakamura, R and Konishi, M and Akizawa, T and Sakane, T}, title = {Efficient nose-to-brain delivery of nine residues peptide (JAL-TA9) exhibiting hydrolytic activity against amyloid-β.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {}, number = {}, pages = {114661}, doi = {10.1016/j.ejpb.2025.114661}, pmid = {39914573}, issn = {1873-3441}, abstract = {JAL-TA9 (YKGSGFRMI), is a 9-residue catalytic peptide that cleaves amyloid β (Aβ) 42. Nasal administration was chosen to bypass the blood-brain barrier for efficient brain delivery of JAL-TA9 to treat Alzheimer's disease (AD). Plasma clearance of JAL-TA9 after intravenous bolus injection in rats was very rapid, with a half-life of <1 min. The stability of JAL-TA9 in cerebrospinal fluid (CSF) was much better than that in plasma and whole blood in vitro, suggesting the advantage of direct nasal delivery to avoid rapid elimination from the blood. JAL-TA9 in CSF was 0.115 μg/mL 10 min after nasal administration to rats, but below the detection limit after intravenous injection, indicating a significant direct delivery of JAL-TA9 to the brain. In mice brain, JAL-TA9 concentration was higher after nasal administration than that after intraperitoneal administration. Additionally, peak concentration in the olfactory bulb (OB) after nasal application was at 5 min, whereas in the frontal and occipital brains peaked at 30 and 60 min, respectively, suggesting sequential backward translocation of JAL-TA9 within the brain after direct transport from the nasal cavity to the OB. Therefore, nasal administration allows the efficient delivery of JAL-TA9 to the brain and may be a potential in AD treatment.}, } @article {pmid39914538, year = {2025}, author = {Cai, M and Zhang, X and Gao, X and Huo, Q and Sun, Y and Dai, X}, title = {Chitooligosaccharide ameliorates cognitive deficits and neuroinflammation in APP/PS1 mice associated with the regulation of Nrf2/NF-κB axis.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {140683}, doi = {10.1016/j.ijbiomac.2025.140683}, pmid = {39914538}, issn = {1879-0003}, abstract = {Mounting evidence suggests that neuroinflammation is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Amyloid β peptide (Aβ) could recruit and activate microglia, leading to the generation of pro-inflammatory factors, and ultimately neuroinflammation. Chitooligosaccharide (COS) is widely recognized as anti-inflammation bioactive substance, though whether it exerts beneficial effect on AD is unclear. In this study, we explored the effect of COS on AD prevention and treatment. We found that COS ameliorated cognitive deficiency, increased the expression of Nrf2 but decreased Aβ levels and the activation of NF-κB in APP/PS1 mice. In vitro, COS decreased the secretions of IL-6, IL-1β and TNF-α in Aβ25-35 + lipopolysaccharides (LPS) -exposed BV2 microglia. Meanwhile, COS down-regulated the expressions of iNOS, COX-2, NLRP3, caspase 1 and the nuclear translocation of NF-κB p65, while upregulated the expressions of Nrf2 and HO-1. Further, COS improved the viability of SK-N-SH cells that exposed to Aβ25-35 + LPS-stimulated microglial conditioned media, and the repressive effect of COS on NLRP3, iNOS, and phospho-NF-κB p65 expressions were markedly compromised upon Nrf2-siRNA transfection. Collectively, COS improved cognitive decline and suppressed neuroinflammation via the Nrf2/NF-κB signaling axis, suggesting COS might be a promising candidate in down-regulating inflammatory responses during AD progression.}, } @article {pmid39914536, year = {2025}, author = {Song, D and Gui, F and Li, G and Zhuang, S and Sun, J and Tan, X and Hong, C and Huang, J}, title = {Neuritin improves cognitive impairments in APP/PS1 Alzheimer's disease mice model by mitigating neuronal ferroptosis via PI3K/Akt activation.}, journal = {International journal of biological macromolecules}, volume = {303}, number = {}, pages = {140662}, doi = {10.1016/j.ijbiomac.2025.140662}, pmid = {39914536}, issn = {1879-0003}, abstract = {The neurotrophic factor Neuritin is known to enhance cognitive capacity and to mitigate synaptic impairments in the APP/PS1 Alzheimer's disease (AD) mouse model, suggesting therapeutic potential for clinical treatment. However, the core molecular mechanisms remain elusive. Ferroptosis, a form of programmed cell death linked to iron dysregulation and oxidative stress, contributes to neurodegeneration in AD in part by accelerating amyloid-β deposition and neurofibrillary tangle formation. Here we examined if Neuritin can mitigate cognitive decline and neural degeneration in AD model mice by suppressing ferroptosis. Age-dependent cognitive decline was associated with Neuritin downregulation and increased ferroptosis in the hippocampus. Intracerebroventricular injection of exogenous Neuritin mitigated spatial and fear learning deficits as well as neural oxidative stress, apoptosis, and ferroptosis in the hippocampus without causing deleterious side effects. Neuritin injection also upregulated the activity of NAD+ kinase (NADK), the enzyme responsible for converting NAD to anti-ferroptotic NADPH, in the hippocampus of AD mice as well as in cultured hippocampal neurons. Reduced Neuritin expression in the hippocampus AD mice was associated with reduced phosphorylation (activation) of Akt (p-Akt), and Neuritin administration enhanced p-Akt expression in both HT22 cells and AD model mice. Conversely, blocking the PI3K/Akt pathway in HT22 cells reversed the Neuritin-induced increase in NADK activity and reduction in ferroptosis, indicating that Neuritin protects neurons from AD-induced damage by enhancing NADK activity through the PI3K/Akt pathway. Collectively, our results support Neuritin upregulation as a potential therapeutic strategy for early-phase AD.}, } @article {pmid39914200, year = {2025}, author = {Madhagi, HA and Nassar, H}, title = {Harnessing network pharmacology and in silico drug discovery to uncover new targets and therapeutics for Alzheimer's disease.}, journal = {Computers in biology and medicine}, volume = {187}, number = {}, pages = {109781}, doi = {10.1016/j.compbiomed.2025.109781}, pmid = {39914200}, issn = {1879-0534}, abstract = {Alzheimer's disease (AD) is the leading cause of progressive neurodegenerative dementia, affecting approximately 50 million individuals globally. Recent studies have highlighted the differential expression of circular RNAs (circRNAs) in AD, which may disrupt the circRNA-miRNA-mRNA regulatory networks in neuronal cells. This work aims to integrate network pharmacology with in silico drug design to identify novel druggable targets for AD and propose promising drug candidates. We analyzed two circRNA datasets from the Gene Expression Omnibus, employing enrichment analysis and constructing a circRNA-miRNA-mRNA network. The RNAenrich platform facilitated the identification of hub genes and potential druggable targets. The identified target was subjected to virtual screening against a chemical drug library comprising over 6000 compounds in clinical trials while ensuring compliance with Lipinski's Rule of Five. Our findings reveal that differentially expressed circRNAs are significantly involved in gland development, apoptosis regulation, hypoxic response, and neuronal death. Notably, CDK-6 emerged as the most promising druggable target, exhibiting strong binding affinity with five selected ligands: DB06963, DB06888, DB07020, DB08683, and DB06976. These ligands demonstrated distinct binding modes and stable interactions over 500 ns of molecular dynamics simulations conducted via Desmond. In conclusion, our study identifies CDK-6 as a viable target for therapeutic intervention in Alzheimer's disease. The top five ligands present a compelling case for further investigation as innovative CDK-6 inhibitors and potential drug candidates for AD treatment.}, } @article {pmid39912605, year = {2025}, author = {Zhang, C and Ye, Y and Wang, W and Wang, C and Gao, P and Wan, P}, title = {Effects of Lingzhi or Reishi Medicinal Mushroom Ganoderma lucidum (Agaricomycetes) Triterpene on Motor and Spatial Learning Disorders in 5xFAD Mice.}, journal = {International journal of medicinal mushrooms}, volume = {27}, number = {4}, pages = {21-37}, doi = {10.1615/IntJMedMushrooms.2024057835}, pmid = {39912605}, issn = {1940-4344}, mesh = {Animals ; *Triterpenes/pharmacology ; Mice ; *Reishi/chemistry ; *Alzheimer Disease/drug therapy ; Spatial Learning/drug effects ; Disease Models, Animal ; Male ; Memory/drug effects ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that gradually destroys cognitive, memory, and thinking skills. Although increasing evidence has demonstrated that Ganoderma lucidum triterpenoids (GLT) can ameliorate the motor and spatial learning disorders of AD, the underlying mechanism remains unclear. Hence, in this study, GLT were obtained by using a traditional Chinese medicine processing method, and then the effects of GLT on motor and spatial learning disorders in 5xFAD mice were investigated by using various techniques such as behavioral analysis, micro-dialysis, and neurophysiological recording. Compared with the 5xFAD group, 0.5 g/kg GLT could decrease escape latency, the total number of limb errors, and the duration of errors. This dose could also increase the number of crossing the original platform, the total movement time, and the distance in the central region of the open-field box, as well as the maximum movement speed and continuous movement time on the rotating rod. After GLT treatment, the glutamate (Glu) content and variation coefficient of a simple spike of Purkinje cells decreased compared with the 5xFAD group, thereby improving the spatial learning and memory ability. Overall, this study shows that GLT may be a potential therapeutic method for patients with AD.}, } @article {pmid39912369, year = {2025}, author = {Wolner, SH and Gleerup, HS and Musaeus, CS and Høgh, P and Ashton, NJ and Brinkmalm, A and Nilsson, J and Grötschel, L and Zetterberg, H and Blennow, K and Hasselbalch, SG and Walls, AB and Simonsen, AH}, title = {Synaptosomal-Associated Protein 25 kDA (SNAP-25) Levels in Cerebrospinal Fluid: Implications for Alzheimer's Disease Diagnosis and Monitoring.}, journal = {Synapse (New York, N.Y.)}, volume = {79}, number = {2}, pages = {e70010}, pmid = {39912369}, issn = {1098-2396}, support = {//Kirsten and Freddy Johansen Foundation/ ; //Fondation pour la Recherche sur Alzheimer/ ; //Swedish Alzheimer Foundation/ ; //UK Dementia Research Institute/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; //European Union Joint Programme - Neurodegenerative Disease Research/ ; //European Union's Horizon 2020 research and innovation programme/ ; //Hjärnfonden/ ; //Stiftelsen för Gamla Tjänarinnor/ ; //Familjen Rönströms Stiftelse/ ; //Familjen Erling-Perssons Stiftelse/ ; //Olav Thon Stiftelsen/ ; //Cure Alzheimer's Fund/ ; //Bluefield Project/ ; //AD Strategic Fund/ ; //Alzheimer's Drug Discovery Foundation/ ; //European Union's Horizon Europe/ ; //Swedish Research Council/ ; //Absalon Foundation/ ; }, mesh = {*Synaptosomal-Associated Protein 25/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Humans ; Aged ; Female ; Male ; Middle Aged ; *Biomarkers/cerebrospinal fluid ; Retrospective Studies ; Cognitive Dysfunction/cerebrospinal fluid/diagnosis ; tau Proteins/cerebrospinal fluid ; Prospective Studies ; Aged, 80 and over ; }, abstract = {Synaptic degeneration has been linked to cognitive decline. The presynaptic protein, synaptosomal-associated protein 25 kDA (SNAP-25), is crucial for synaptic transmission and has been suggested as a biomarker in Alzheimer's disease (AD). In the current study, we investigated the ability of SNAP-25 to differentiate between heterogenous dementia etiologies and whether SNAP-25 could be a staging marker in AD. SNAP-25 in the cerebrospinal fluid (CSF) from a retrospective (n = 187) and a prospective (n = 134) cohort was investigated with immunoprecipitation mass spectrometry (IP-MS) and single-molecule array (Simoa), respectively. Both cohorts consisted of healthy controls (HC) and patients with cognitive decline of different etiologies. CSF SNAP-25 concentration was higher in AD and non-neurodegenerative diseases (i.e., vascular dementia) compared with controls but did not differ between AD and non-AD neurodegenerative diseases. We found a trend toward an association between SNAP-25 and disease burden when comparing HC, mild cognitive impairment due to AD, and AD. CSF SNAP-25 concentrations were strongly associated with CSF phosphorylated tau (p-tau) concentrations, thus strengthening the link between synaptic dysfunction and tau pathophysiology in AD. Our initial findings suggest that SNAP-25 may be a potential biomarker for differentiating AD from dementia due to other etiologies. However, due to the significant association between SNAP-25 and p-tau proteins, the clinical utility of SNAP-25 as a diagnostic biomarker for AD may be limited, while SNAP-25 may be useful for monitoring disease progression or treatment response.}, } @article {pmid39911544, year = {2025}, author = {Pakhariya, RP and Bhatnagar, A and Pemawat, G}, title = {Quinoline analogs: multifaceted heterocyclic compounds with varied synthetic strategies and potent antitubercular properties.}, journal = {RSC advances}, volume = {15}, number = {5}, pages = {3646-3663}, pmid = {39911544}, issn = {2046-2069}, abstract = {Tuberculosis cases have continuously increased by 64% over the last nine years, from 2014 to 2023. Approximately 33% of the global population is affected by TB. It is a bacterial disease, and Mycobacterium tuberculosis is the most common bacteria that affects the lungs of human beings during the infection. Other hazardous bacterial species causing tuberculosis are M. pinnipedii, M. canettii, M. caprae, M. bovis, M. africanum, and M. microti. TB symptoms in TB-infected patients include fever, chest pain, weight loss, and fatigue. Depending on the stage of infection, the treatment for TB can take approximately six months to two years. Quinoline comprises a pyridine ring fused with a benzene ring, and both these rings share two adjacent carbon atoms and can take part in electrophilic substitution reactions. Quinoline-based heterocyclic compounds are attracting substantial interest owing to their vital role as a class of synthetic and natural molecules. Quinoline and its derivatives display various biological activities, including anti-TB, anticonvulsant, antibiotic, antifungal, antimalarial, antipsychotic, antihypertensive, antileishmanial, antioxidant, tyrosine kinase inhibitory, anti-inflammatory, anticancer, anti-asthmatic, cardiotonic, anthelmintic, antiprotozoal, anti-HIV, and anti-Alzheimer effects. Some fused analogs of quinoline, such as graveolinine, ciprofloxacin, kokusaginine, bedaquiline, levofloxacin, moxifloxacin, and mefloquine, are commercially available as antitubercular drugs. There are various methods available to synthesize quinoline-containing antitubercular drugs. In this review paper, we present three types of synthetic methods in which substituted quinolines, substituted anilines, and miscellaneous starting materials are used and outline MIC values for all the synthesized compounds to signify their anti-TB activity.}, } @article {pmid39911331, year = {2025}, author = {Yi, Y and Kim, B and Kim, M and Ko, YH and Kim, JH and Lim, MH}, title = {Zn(ii)-driven impact of monomeric transthyretin on amyloid-β amyloidogenesis.}, journal = {Chemical science}, volume = {}, number = {}, pages = {}, pmid = {39911331}, issn = {2041-6520}, abstract = {Extracellular accumulation of amyloid-β (Aβ) peptides in the brain plays a significant role in the development of Alzheimer's disease (AD). While the co-localization and interaction of proteins and metal ions with Aβ in extracellular milieu are established, their precise pathological associations remain unclear. Here we report the impact of Zn(ii) on the anti-amyloidogenic properties of monomeric transthyretin (M-TTR), which coexists spatially with Aβ and Zn(ii) in extracellular fluids. Our findings demonstrate the Zn(ii)-promoted ternary complex formation involving M-TTR, Aβ, and Zn(ii) as well as M-TTR's proteolytic activity towards Aβ. These interactions decrease the inhibitory effect of M-TTR on the primary nucleation process of Aβ as well as its ability to improve cell viability upon treatment of Aβ. This study unveils the variable activities of M-TTR towards Aβ, driven by Zn(ii), providing insights into how metal ions influence the entanglement of M-TTR in the Aβ-related pathology linked to AD.}, } @article {pmid39910867, year = {2025}, author = {Guo, R and Li, D and Li, F and Ji, L and Liu, H and Qiao, H and Lv, Z and Tang, Y and Wang, D}, title = {Effects of whole-head 810 nm near-infrared therapy on cognitive and neuropsychiatric symptoms in Alzheimer's disease: A pilot study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251313819}, doi = {10.1177/13872877251313819}, pmid = {39910867}, issn = {1875-8908}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by significant cognitive and behavioral impairments. Near-infrared (NIR) light treatment has shown potential in cognitive improvement in previous studies. However, clinical trials of NIR for AD remain limited.

OBJECTIVE: This study investigated the safety and effects of whole-head 810 nm NIR therapy in AD patients, including long-term efficacy.

METHODS: An open-label pilot study on whole-head NIR treatment for AD patients was conducted. Nine AD patients completed 4-month treatment (810 nm, 100 mW/cm², 30 min/session, 6 sessions weekly). Safety and efficacy were evaluated at baseline, months 2 and 4, and 2-month post-treatment.

RESULTS: After four months of whole-head NIR treatment, mean changes from baseline on the Mini-Mental State Examination were 3.2 (p = 0.02). Mean changes from baseline on the Alzheimer's Disease Assessment Scale-Cognitive were -5.0 (p = 0.05), mean changes from baseline on the Montreal Cognitive Assessment were 1.9 (p = 0.12). Mean changes from baseline on the Neuropsychiatric Inventory were -4.2 (p = 0.47). These benefits were sustained two months at least. With no device-related adverse effects were reported.

CONCLUSIONS: Whole-head 810 nm NIR light is safe and offers promising benefits for AD patients. To fully confirm its efficacy, durability, and underlying mechanisms, further large-scale randomized controlled trials are necessary.}, } @article {pmid39910679, year = {2025}, author = {Han, G and Xuewu, G and Meng, Z and Yuejing, W and Yuchun, W and Keshuang, Z and Hongbo, Y}, title = {Therapeutic effect of dihydroartemisinin on Alzheimer's disease model mice with senile macular degeneration.}, journal = {European journal of medical research}, volume = {30}, number = {1}, pages = {81}, pmid = {39910679}, issn = {2047-783X}, support = {LH2021H122//Natural Science Foundation of Heilongjiang Province of China/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Artemisinins/pharmacology/therapeutic use ; Mice ; *Disease Models, Animal ; *Molecular Docking Simulation ; Macular Degeneration/drug therapy/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Autophagy/drug effects ; Male ; Maze Learning/drug effects ; Donepezil/pharmacology/therapeutic use ; }, abstract = {OBJECTIVES: This study focuses on the preventive and therapeutic effects of Dihydroartemisinin (DHA) on Alzheimer's disease (AD) model mice and the effects of DHA and donepezil on amyloid β-protein deposition and autophagy in nerve cells.

METHODS: Six autophagy related targets were selected for molecular docking with DHA to predict the affinity between DHA and the target. The AD mouse model was established and treated with donepezil and DHA, respectively. Morris water maze was used to detect the spatial learning and memory ability of AD mice. Hematoxylin eosin (he) staining was used to observe the structural changes of cerebral cortical neurons and retina, and transmission electron microscope was used to observe the structural changes of mitochondria and synapses. Immunohistochemistry (IHC) and immunofluorescence staining were used to detect the deposition of amyloid beta protein. Western blot was used to detect the expression of apoptosis and autophagy related proteins in the brain tissue of mice in each group.

RESULTS: The results of molecular docking showed that the selected active compounds had good binding activity with the target. The binding energy between DHA and Aβ, Bcl-2, ATG5, LC3, Caspase3, LAMP1 is -5.7, -7.0, -5.8, -7.2, -6.9 kcal/mol. The water maze test showed that compared with the wild type (WT) group, the spatial memory ability of AD model group mice (5× FAD) was significantly decreased, and the search time (27.62 ± 6.51 s vs. 282.80 ± 17.15 s) and average path (106.30 ± 29.65 cm vs. 993.20 ± 135.80 cm) were significantly prolonged. The application of donepezil and DHA significantly shortened the exploration time and average path (donepezil: 116.10 ± 10.58 s, 529.40 ± 106.00 cm; DHA: 99.71 ± 14.22 s, 373.30 ± 60.97 cm). The path to find the platform in DHA treatment group was shorter than donepezil treatment group (P < 0.05). HE staining showed that the arrangement of nerve cells in 5× FAD mice was disordered, and IHC showed that amyloid β-protein deposition was obvious. DHA and donepezil could improve the damage of cerebral cortex structure and reduce the deposition of extracellular amyloid β-protein in AD mice. Transmission electron microscopy showed that DHA and donepezil could reduce mitochondrial vacuolation and synaptic edema. The above results showed that DHA treatment effect was better than donepezil. Compared with the conventional feeding group, autophagy and apoptosis related proteins B-cell lymphoma-2 (BCL2) and anti-thymocyte globulin (ATG) were significantly down regulated in the 5× FAD group, and the expressions of BCL2 and ATG were increased after treatment with DHA and donepezil.

CONCLUSIONS: DHA combined with BCL2 and ATG protein, through promoting autophagy protein, can reduce the damage of cerebral cortex structure in AD mice, reduce the deposition of extracellular β-amyloid protein, and then improve the memory ability of AD model mice. DHA treatment is superior to donepezil monotherapy.}, } @article {pmid39910616, year = {2025}, author = {Lee, BH and Cevizci, M and Lieblich, SE and Galea, LAM}, title = {Sex-specific influences of APOEε4 genotype on hippocampal neurogenesis and progenitor cells in middle-aged rats.}, journal = {Biology of sex differences}, volume = {16}, number = {1}, pages = {10}, pmid = {39910616}, issn = {2042-6410}, support = {2018-04301//Natural Sciences and Engineering Research Council of Canada/ ; 2018-04301//Natural Sciences and Engineering Research Council of Canada/ ; }, mesh = {Animals ; *Neurogenesis ; Male ; Female ; *Sex Characteristics ; *Hippocampus/cytology ; *Apolipoprotein E4/genetics ; *Microglia/cytology ; *Neural Stem Cells/cytology ; Genotype ; Rats ; Rats, Transgenic ; Aging ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) disproportionately and uniquely affects females, and these sex differences are further exacerbated by the presence of Apolipoprotein (APOE) ε4 alleles, the top genetic risk factor for late-onset AD. To expand our understanding about how late-onset AD risk might differentially influence males and females, this study explores how APOEε4 affects hippocampal neurogenesis and microglia, key neuroplastic markers involved in AD pathogenesis, differently by sex in middle-aged rats.

METHODS: A rat model expressing the humanized (h) APOEε4 allele was characterized to examine markers of adult neurogenesis (neural progenitor cells and new-born neurons) and immune cells (microglia) in the dentate gyrus of the hippocampus in 13 month-old male and female rats.

RESULTS: We observed basal sex differences in neurogenesis at middle age, as wildtype male rats had greater densities of neural progenitor cells and new-born neurons in the dentate gyrus than wildtype female rats. Male hAPOEε4 rats exhibited fewer neural progenitor cells, fewer new-born neurons, and more microglia than male wildtype rats. On the other hand, female hAPOEε4 rats exhibited more new-born neurons than female wildtype rats. Interestingly, females had more microglia than males regardless of genotype. Correlations were conducted to further elucidate any sex differences in the relationships between these biomarkers. Notably, there was a significant positive correlation between neural progenitor cells and new-born neurons, and a significant negative correlation between new-born neurons and microglia, but only in male rats.

CONCLUSION: In contrast to the clear pattern of effects of the hAPOEε4 risk factor on hippocampal neurogenesis in males, females had unaltered levels of neural progenitor cells and increased density of new-born neurons. Furthermore, relationships between neurogenesis and microglia were significantly correlated within males, and not females. This suggests that females may be presenting a compensatory response to the hAPOEε4 genotype at middle age. Collectively, these results exemplify the importance of thoroughly examining influences of sex on AD endophenotypes, as it may reveal sex-specific pathways and protective mechanisms relevant to AD.}, } @article {pmid39910474, year = {2025}, author = {Linzhu, and Zhang, J and Fan, W and Su, C and Jin, Z}, title = {Influence of immune cells and inflammatory factors on Alzheimer's disease axis: evidence from mediation Mendelian randomization study.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {49}, pmid = {39910474}, issn = {1471-2377}, mesh = {Humans ; *Alzheimer Disease/genetics/immunology/epidemiology ; *Mendelian Randomization Analysis/methods ; Inflammation/genetics/immunology ; Sialic Acid Binding Ig-like Lectin 3/genetics ; Cytokines/metabolism ; HLA-DR Antigens/genetics ; Leukocyte Common Antigens/metabolism/genetics ; Interleukin-2/genetics ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the most common forms of dementia in the elderly, characterized by progressive neurodegeneration. While the exact etiology of AD remains unclear, immune inflammation is known to play a significant role in the disease.

METHODS: This study utilized a two-sample Mendelian randomization (MR) approach to assess the causal relationship between different types of immune cells and AD, while considering inflammatory factors as intermediate variables. Data were collected from three sources: immune cell data (731 phenotypes), inflammatory factors (48 cytokines from 8,293 individuals), and AD data (35,274 cases, 59,163 controls). Multiple MR methods were employed to minimize bias, and detailed descriptions of instrumental variable selection and statistical methods were provided.

RESULTS: The study findings suggest potential causal relationships between six different types of immune cells and AD, as well as causal relationships between 13 immune cells and inflammatory factors. Additionally, two statistically significant inflammatory factors were found to have potential causal relationships with AD. Specifically, immune cells CD33-HLA DR + and CD45 on CD33-HLA DR + may further influence AD by regulating Interleukin-2 levels.

CONCLUSION: This study provides valuable insights into the immunoinflammatory pathogenesis of AD and offers partial guidance for the development of relevant interventions, thereby contributing beneficial information for the prevention and treatment of related diseases.}, } @article {pmid39910202, year = {2025}, author = {Gao, W and Yang, G and Liu, X and Hu, K and Pan, J and Wang, X and Zhao, Y and Xu, Y}, title = {Network pharmacology and experimental verification to investigate the mechanism of isoliquiritigenin for the treatment of Alzheimer's disease.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {4379}, pmid = {39910202}, issn = {2045-2322}, support = {82174003//General Program of National Natural Science Foundation of China/ ; }, mesh = {*Chalcones/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; *Molecular Docking Simulation ; Humans ; *Network Pharmacology ; *Protein Interaction Maps/drug effects ; *Microglia/drug effects/metabolism ; Mice ; Animals ; Lipopolysaccharides ; Cell Line ; Anti-Inflammatory Agents/pharmacology/chemistry ; Gene Ontology ; }, abstract = {Isoliquiritigenin (ISL), a flavone isolated from licorice, has been demonstrated to exhibit anti-inflammatory and antioxidant properties in the treatment of Alzheimer's disease (AD). However, the molecular details of the contribution of ISL to AD remain largely elusive. The present study aimed to investigate the molecular mechanisms of ISL against AD. In this study, AD targets and ISL targets were collected via different databases. The overlapped targets between AD and ISL were generated with Venny. Then we performed Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses on these common targets. The protein-protein interaction (PPI) network was constructed and clusters were obtained using the Molecular Complex Detection (MCODE) and the Cytohubba plugins. Further, molecular docking study was performed for these core targets. Subsequently, the receiver operating characteristic (ROC) curve analysis and the assessment of hub gene expression levels between AD and healthy individuals were used to estimate a possible link between target genes in AD. Finally, experiments were conducted to verify the therapeutic mechanism of ISL in lipopolysaccharide (LPS)-induced BV2 microglial cells. GO and KEGG pathway analysis found that ISL was significantly enriched in regulation of mitogen-activated protein kinase (MAPK) signaling pathway. The PPI network manifested 7 key targets including albumin (ALB), epidermal growth factor receptor (EGFR), solute carrier family 2 member 1 (SLC2A1), insulin-like growth factor 1 (IGF1), mitogen-activated protein kinase 1 (MAPK1), peroxisome proliferator activated receptor alpha (PPARA) and peroxisome proliferator activated receptor gamma (PPAR-γ, PPARG). Molecular docking showed that ISL had high binding affinity with these key targets. The experimental results revealed that ISL decreased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and increased the expression of PPAR-γ, and suppressed the production of proinflammatory mediators. Our work revealed that ISL might be an effective treatment strategy in the treatment of AD by its anti-inflammatory effect towards microglia through the ERK/PPAR-γ pathway.}, } @article {pmid39909068, year = {2025}, author = {Richards, KC and Fry, LM and Lozano, AJ and Ji, W and Morrison, JD and Britt, KC and Bliwise, DL and Gooneratne, NS and Hanlon, AL}, title = {Treatment of Restless Legs Syndrome Improves Agitation and Sleep in Persons With Dementia: A Randomized Trial.}, journal = {Journal of the American Medical Directors Association}, volume = {}, number = {}, pages = {105485}, doi = {10.1016/j.jamda.2025.105485}, pmid = {39909068}, issn = {1538-9375}, abstract = {OBJECTIVES: Restless legs syndrome (RLS), a common, treatable, sensorimotor disorder of nighttime uncomfortable leg sensations that interfere with sleep, may prompt nighttime agitation in persons with dementia.

DESIGN: This randomized trial was double-blind and placebo-controlled. Participants received a Food and Drug Administration-approved drug for RLS, gabapentin enacarbil (GEn) (Horizant) or placebo.

SETTING AND PARTICIPANTS: Older adults (N = 147) with dementia due to Alzheimer's disease, nighttime agitation, and RLS, residing in long-term care or at home, participated.

METHODS: The primary outcome was change from baseline to 8 weeks in nighttime agitation between 5 pm and 7 am on the Cohen-Mansfield Agitation Inventory Index, Direct Observation. Multivariable linear mixed effects regression models based on multiply imputed data were estimated on nighttime agitation and sleep, with treatment group, week, the 2-way interaction of group and week as predictors, and mean arterial pressure as a covariate based on baseline group imbalances.

RESULTS: Mean age ± SD was 83.4 ± 9.1 years. Most were female (72.0%), White (92.3%), non-Hispanic (84.6%), and lived in nursing homes (76.9%). Nighttime agitation, by group over time, was significant at 8 weeks (estimate, -1.67; P = .003) and 2 weeks. Total sleep time (actigraphy) by group over time was significant at 8 weeks (estimate, 48.45; P = .026). Observed nighttime wake by group over time was significant at 2 (estimate, -12.54; P = .006) and 8 weeks (estimate, -11.12; P = .015). The number having ≥1 adverse events was 60 in the GEn group (81.1%) and 50 in the placebo group (68.5%); with 12 serious adverse events in placebo and 10 in the GEn group. The GEn group had a trend toward more falls (P = .066).

CONCLUSIONS AND IMPLICATIONS: Our findings suggest a novel approach for nighttime agitation in persons with dementia: assessing for RLS and initiating interventions. Larger and longer trials are needed.}, } @article {pmid39908690, year = {2025}, author = {Olluri, A}, title = {Clinical trials targeting tau should be halted.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {134}, number = {}, pages = {111101}, doi = {10.1016/j.jocn.2025.111101}, pmid = {39908690}, issn = {1532-2653}, abstract = {Experimental drugs lowering brain tau are heralded as improvements in the treatment of Alzheimer's disease. However, the outcomes in clinical trials testing these agents have consistently failed to improve patient outcomes, i.e. slow down disease or improving cognition. Furthermore, the scientific rationale behind such drugs is rather poor in the first place and has been questioned. Therefore, I argue that trials of anti-tau drugs should be halted.}, } @article {pmid39908485, year = {2025}, author = {Yang, P and Shuai, W and Wang, X and Hu, X and Zhao, M and Wang, A and Wu, Y and Ouyang, L and Wang, G}, title = {Mitophagy in Neurodegenerative Diseases: Mechanisms of Action and the Advances of Drug Discovery.}, journal = {Journal of medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jmedchem.4c01779}, pmid = {39908485}, issn = {1520-4804}, abstract = {Neurodegenerative diseases (NDDs), such as Parkinson's disease (PD) and Alzheimer's disease (AD), are devastating brain diseases and are incurable at the moment. Increasing evidence indicates that NDDs are associated with mitochondrial dysfunction. Mitophagy removes defective or redundant mitochondria to maintain cell homeostasis, whereas deficient mitophagy accelerates the accumulation of damaged mitochondria to mediate the pathologies of NDDs. Therefore, targeting mitophagy has become a valuable therapeutic pathway for the treatment of NDDs. Several mitophagy modulators have been shown to ameliorate neurodegeneration in PD and AD. However, it remains to be further investigated for other NDDs. Here, we describe the mechanism and key signaling pathway of mitophagy and summarize the roles of defective mitophagy on the pathogenesis of NDDs. Further, we underline the development advances of mitophagy modulators for PD and AD therapy, discuss the therapeutic challenges and limitations of the existing modulators, and provide guidelines for mitophagy mechanism exploration and drug design.}, } @article {pmid39908361, year = {2025}, author = {Wu, X and Miller, JA and Lee, BTK and Wang, Y and Ruedl, C}, title = {Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer's disease mouse model.}, journal = {Science advances}, volume = {11}, number = {6}, pages = {eadq6038}, pmid = {39908361}, issn = {2375-2548}, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Microglia/metabolism ; *Phagocytosis ; *Disease Models, Animal ; *Amyloid beta-Peptides/metabolism ; *Mice, Transgenic ; Mice ; Lipid Metabolism ; Macrophages/metabolism ; Brain/metabolism/pathology ; Lipid Droplets/metabolism ; Humans ; Plaque, Amyloid/metabolism/pathology ; CX3C Chemokine Receptor 1/metabolism/genetics ; }, abstract = {Macrophages accumulate lipid droplets (LDs) under stress and inflammatory conditions. Despite the presence of LD-loaded macrophages in many tissues, including the brain, their contribution to neurodegenerative disorders remains elusive. This study investigated the role of lipid metabolism in Alzheimer's disease (AD) by assessing the contribution of LD-loaded brain macrophages, including microglia and border-associated macrophages (BAMs), in an AD mouse model. Particularly, BAMs and activated CD11c[+] microglia localized near β amyloid (Aβ) plaques exhibited a pronounced lipid-associated gene signature and a high LD load. Having observed that elevated intracellular LD content correlated inversely with microglial phagocytic activities, we subsequently inhibited LD formation specifically in CX3CR1[+] brain macrophages using an inducible APP-KI/Fit2[i][Δ][M][φ] transgenic mouse model. We demonstrated that reducing LD content in microglia and CX3CR1[+] BAMs remarkably improved their phagocytic ability. Furthermore, lowering microglial LDs consistently enhanced their efferocytosis capacities and notably reduced Aβ deposition in the brain parenchyma. Therefore, mitigating LD accumulation in brain macrophages provides perspectives for AD treatment.}, } @article {pmid39908354, year = {2025}, author = {He, S and Li, X and Mittra, N and Bhattacharjee, A and Wang, H and Song, S and Zhao, S and Liu, F and Han, X}, title = {Microglial cGAS Deletion Preserves Intercellular Communication and Alleviates Amyloid-β-Induced Pathogenesis of Alzheimer's Disease.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e2410910}, doi = {10.1002/advs.202410910}, pmid = {39908354}, issn = {2198-3844}, support = {R01 AG061729/AG/NIA NIH HHS/United States ; R01 AG085545/AG/NIA NIH HHS/United States ; T32AG021890/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG013319/AG/NIA NIH HHS/United States ; P30 AG044271/AG/NIA NIH HHS/United States ; //Methodist Hospital Foundation/ ; //William and Ella Owens Medical Research Foundation/ ; //Cure Alzheimer's Fund/ ; //University of Texas Health Science Center at San Antonio intramural institutional research funds/ ; }, abstract = {Innate immune activation plays a crucial role in the pathogenesis of Alzheimer's disease (AD) and related dementias (ADRD). The cytosolic DNA sensing pathway, involving cGAMP synthase (cGAS) and Stimulator of Interferon Genes (STING), has emerged as a key mediator of neurodegenerative diseases. However, the precise mechanisms through which cGAS activation influences AD progression remain poorly understood. In this study, we observed significant up-regulation of cGAS-STING signaling pathway in AD. Notably, this increase is primarily attributed to microglia, rather than non-microglial cell types. Using an inducible, microglia-specific cGAS knockout mouse model in the 5xFAD background, we demonstrated that deleting microglial cGAS at the onset of amyloid-β (Aβ) pathology profoundly restricts plaque accumulation and protects mice from Aβ-induced cognitive impairment. Mechanistically, our study revealed cGAS promotes plaque-associated microglia accumulation and is essential for inflammasome activation. Moreover, we showed that restricting cGAS-mediated innate immunity is crucial for preserving inter-cellular communication in the brain and induces pleiotrophin, a neuroprotective factor. These findings offer novel insights into the specific roles of the innate immune system in AD employing a cell-type-specific approach. The conclusions provide a foundation for targeted interventions to modulate the microglial cGAS-STING signaling pathway, offering promising therapeutic strategy for AD treatment.}, } @article {pmid39907966, year = {2025}, author = {Hey, JA and Yu, JY and Abushakra, S and Schaefer, JF and Power, A and Kesslak, P and Paul, J and Tolar, M}, title = {Clinical Pharmacokinetics of Oral ALZ-801/Valiltramiprosate in a 2-Year Phase 2 Trial of APOE4 Carriers with Early Alzheimer's Disease.}, journal = {Clinical pharmacokinetics}, volume = {}, number = {}, pages = {}, pmid = {39907966}, issn = {1179-1926}, abstract = {INTRODUCTION: ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of β-amyloid (Aβ) oligomer formation in late-stage development as a potential disease-modifying therapy for Alzheimer's disease (AD). ALZ-801, a valine-conjugated prodrug, is rapidly converted to tramiprosate after oral dosing. Upon conversion to tramiprosate, it generates a single metabolite, 3-sulfopropanoic acid (3-SPA). Both tramiprosate and 3-SPA are active anti-Aβ oligomer agents that mediate ALZ-801's central mechanism of action (MOA). We summarize herein the pharmacokinetics (PK) of ALZ-801 in apolipoprotein ε4 (APOE4) carrier subjects with early AD from a phase 2 trial.

METHODS: The ALZ-801 phase 2 study was designed to evaluate longitudinal effects of ALZ-801 (265 mg BID) on plasma, cerebrospinal fluid (CSF) and volumetric magnetic resonance imaging (MRI) AD biomarkers, and clinical outcomes over 104 weeks in APOE4 carriers with early AD. Eighty-four subjects (31 APOE4/4 homozygotes and 53 APOE3/4 heterozygotes) with positive CSF biomarkers of amyloid and tau pathology were enrolled. The phase 2 study included a substudy of 24 subjects to provide 8-h steady-state PK at 65 weeks. Sparse PK samples were also analyzed. The relationships between plasma PK exposure and clinical characteristics [i.e., sex, APOE genotype, age, body mass index (BMI), estimated glomerular filtration rate (eGFR), concomitant acetylcholinesterase inhibitor (AChEI) use, and tablet lot] were evaluated.

RESULTS: The steady-state plasma PK results were closely aligned with the previous 2-week PK in the ALZ-801 phase 1b study in APOE4 carrier subjects with AD, as well as a phase 1 7-day PK study in heathy elderly volunteers. Following oral dosing, ALZ-801 was rapidly converted to the active moieties, tramiprosate and 3-SPA. The intersubject variability in plasma drug levels was low, confirming the superior performance of ALZ-801 versus oral tramiprosate tablet (150 mg BID) from the earlier tramiprosate phase 3 trials. Correlation analysis versus clinical characteristics showed that plasma exposures (Cmax and AUC8h) for ALZ-801, tramiprosate, and 3-SPA were not affected by sex, APOE genotype, age, BMI, concomitant AChEI use, or tablet lot. Plasma exposures of both tramiprosate and 3-SPA, but not ALZ-801, were inversely correlated with eGFR, in line with renal excretion as the primary route of elimination. ALZ-801 was well tolerated without new safety signals or events of amyloid-related imaging abnormalities (ARIA).

CONCLUSIONS: The steady-state PK profile of oral ALZ-801 in subjects with early AD was not affected by sex, APOE genotype, age, BMI, concomitant use of AChEI, or tablet lot. The inverse relationship of plasma exposures of tramiprosate and 3-SPA, but not ALZ-801, versus eGFR is consistent with renal clearance as the primary route of elimination for tramiprosate and 3-SPA (active moieties), and with the efficient conversion of ALZ-801 prodrug to the active moieties after dosing. These results demonstrate that ALZ-801 displays favorable PK properties without evidence of interactions with demographic characteristics and support its development as an oral disease-modifying treatment for AD.

TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04693520 .}, } @article {pmid39907903, year = {2025}, author = {Ma, K and Tian, T and Li, X and Pang, H and Ning, X and Li, M and Li, J and Luo, Z and Liu, T and Liu, M and Wang, M and Zhao, C and Song, X and Du, H and Jin, M}, title = {Silica Nanoparticles Induce SH-SY5Y Cells Death Via PARP and Caspase Signaling Pathways.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39907903}, issn = {1559-1182}, abstract = {A growing stream of research indicates that exposure to Silica nanoparticles (SiNPs) can cause nervous system damage, leading to the occurrence of neurodegenerative diseases such as Alzheimer's disease. However, the specific mechanism by which SiNPs cause neuroblast injury remains unclear and requires further research. This study established an in vitro experimental model of SH-SY5Y cells exposed to SiNPs and observed cell growth through an inverted fluorescence microscope. Cell viability was measured using an MTT assay. The intracellular ROS and Ca[2+] levels were detected by flow cytometry. Cell apoptosis was observed using both Hoechst33342 staining and TUNEL staining. The activities of SOD and ATPase and the content of ATP in the cells were tested by biochemical methods. The genes including parp-1, aif, par, ucp2, vdac and prdx3 were explored using quantitative real-time PCR. The expressions of PARP, AIF, PAR, Caspase-3, Caspase-9 and Cyt C proteins were evaluated by Western Blot. The immunofluorescence technique was used to observe the distribution of Parthanatos-related proteins induced by SiNPs. The results showed that SiNPs reduced cell survival rate, induced excessive ROS and Ca[2+] overload, decreased SOD activity, ATPase activity, intracellular and mitochondrial ATP content, increased the expression of mitochondrial function and PARP pathway related genes, as well as PARP and Caspase pathway protein expression, ultimately inducing cell apoptosis. As a further test of the roles of PARP and Caspase pathways in SiNPs induced SH-SY5Y cells death, we selected the PARP inhibitor Olaparib and Caspase inhibitor Z-VAD, and the above effects were significantly improved after treatment with the inhibitors. Conclusively, this study confirmed that SiNPs can generate excessive ROS production in SH-SY5Y cells, alter mitochondrial function, and induce cell death through Parthanatos and caspase dependent apoptotic pathways, which can coexist and interact with each other.}, } @article {pmid39907698, year = {2025}, author = {Xavier-de-Britto, I and Gomes-da-Silva, NC and Gomes Soares, MA and Follmer, C and Dabkiewicz, D and Alencar, LMR and Sant'Anna, C and Ferreira, TPT and Martins, PMRES and Ricci-Junior, E and Fechine, PBA and Santos-Oliveira, R}, title = {Therapeutic Potential of Arimoclomol Nanomicelles: In Vitro Impact on Alzheimer's and Parkinson's Pathology and Correlation with In Vivo Inflammatory Response.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.4c00734}, pmid = {39907698}, issn = {1948-7193}, abstract = {This study investigates the potential of arimoclomol-loaded nanomicelles for the treatment of neurodegenerative diseases like Alzheimer's and Parkinson's, as well as their anti-inflammatory properties. Arimoclomol, a coinducer of heat shock proteins (HSPs), has shown clinical promise in mitigating protein misfolding, a hallmark of these diseases. In this work, arimoclomol nanomicelles significantly reduced the aggregation of β-amyloid (Aβ1-42) and α-synuclein (α-syn), key pathological proteins in Alzheimer's and Parkinson's. Additionally, the nanomicelles demonstrated potent anti-inflammatory effects, reducing leukocyte and neutrophil counts in an acute inflammation model. These results suggest that arimoclomol nanomicelles could enhance clinical outcomes by targeting both neurodegenerative and inflammatory processes, offering a promising therapeutic strategy for long-term disease management.}, } @article {pmid39907502, year = {2025}, author = {Harrison, KL and Morgan, BE and Friend, J and Garrett, SB and Looi, D and Halim, M and James, JE and Boyd, ND and Gilissen, J and Geschwind, MD and Ritchie, CS and Smith, AK}, title = {"By the Time We Knew …": Poetic Analysis of End-of-Life Caregiving Experiences for Rapidly Progressive and Slower-Duration Dementia Syndromes.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.19382}, pmid = {39907502}, issn = {1532-5415}, support = {//Global Brain Health Institute (GBHI), Alzheimer's Association, and Alzheimer's Society Pilot Awards for Global Brain Health Leaders/ ; //Global Brain Health Institute/ ; 2P30AG062421/AG/NIA NIH HHS/United States ; 5T32AG049663/AG/NIA NIH HHS/United States ; K01AG059831/AG/NIA NIH HHS/United States ; K24AG068312/AG/NIA NIH HHS/United States ; P30AG044281/AG/NIA NIH HHS/United States ; R01AG031189/AG/NIA NIH HHS/United States ; R01AG062562/AG/NIA NIH HHS/United States ; R24AG065175/AG/NIA NIH HHS/United States ; R56AG055619/AG/NIA NIH HHS/United States ; T35AG026736/AG/NIA NIH HHS/United States ; T32HS022241//Agency for Healthcare Research and Quality (AHRQ)/ ; }, abstract = {BACKGROUND: One in three older adults in the United States dies with or from dementia. Little is known about whether end-of-life caregiving experiences differ by dementia diagnosis.

METHODS: We conducted a secondary analysis of two qualitative studies. Participants included caregivers of decedents with "rapid-type" sporadic Creutzfeldt-Jakob Disease (sCJD, survival prognosis of < 1 year) or "slow-type" Alzheimer's disease and related dementias (survival prognosis of 5-20 years). We used reflexive thematic analysis and a novel method, poetic analysis, to compare end-of-life caregiving experiences.

RESULTS: "Rapid-type" caregivers (n = 12) had a median age of 59 (range 45-73) years; 6 were female, and 9 were spouses. "Slow-type" caregivers (n = 15) had a median age of 69 (45-82) years; 9 were female, and 11 were spouses. We identified three main areas of differential experience that were influenced by syndrome rarity and participation in research yet hinged on time. Time enables preparation: Due to the rarity of sCJD, "rapid-type" caregivers struggled to obtain accurate diagnoses, which prevented preparation for end-of-life care. Weeks or months before death, specialists simultaneously disclosed sCJD diagnoses and recommended hospice. In contrast, for "slow-type" dementia, preparation began years before death. Time complicates conflict: Most "rapid-type" caregivers described conflicts, rarely resolved before death, about code status, treatment, or care location decisions. Fewer "slow-type" caregivers experienced such conflicts, and these were typically resolved before death; instead, they experienced conflict between needs and what the care system provides. Postmortem experience contrasts with perimortem: For "rapid-type" dementia, short perimortem periods contrasted with elongated and often intense postmortem logistics and grief. For "slow-type" caregivers, preparation and perimortem grieving typically led to shorter duration and minimally intrusive postmortem logistics and grief.

CONCLUSIONS: End-of-life care for dementia should attend to and support axes of differential experience based on diagnosis and rarity, time since symptom onset (affecting preparation and conflict resolution), and participation in research studies.}, } @article {pmid39907297, year = {2024}, author = {Čižek Sajko, M and Suklan, J and Osmanović, D and Peterlin, B}, title = {Translational Research on Polygenic Risk Scores in Common Neurodegenerative Diseases - A Scoping Review Protocol.}, journal = {Acta medica academica}, volume = {53}, number = {3}, pages = {303-308}, doi = {10.5644/ama2006-124.463}, pmid = {39907297}, issn = {1840-2879}, mesh = {Humans ; Alzheimer Disease/genetics/diagnosis ; Amyotrophic Lateral Sclerosis/genetics ; Genetic Predisposition to Disease ; Genetic Risk Score ; *Multifactorial Inheritance ; Multiple Sclerosis/genetics ; *Neurodegenerative Diseases/genetics ; Parkinson Disease/genetics/diagnosis ; Research Design ; Risk Assessment ; Risk Factors ; *Translational Research, Biomedical ; Scoping Review as Topic ; }, abstract = {OBJECTIVE: The purpose of this protocol is to clearly describe the process for the scoping review we plan to conduct on the topic of polygenic risk scores (PRS) in common neurodegenerative diseases. We will present the review's objective, the strategy for evidence search, the data extraction and analysis procedure, and how the results will be presented.

METHODS: The inclusion criteria for the planned scoping review will focus on evidence sources that involve PRS applied to neurogenerative diseases such as Multiple sclerosis, Parkinson's disease, Alzheimer's disease, and Amyotrophic lateral sclerosis in any phase of translational research, from early development to clinical implementation. This includes its use in risk prediction, early diagnosis, prognosis, and treatment decision-making. The research questions were created based on the population, context, and concept framework. We will consider both peer-reviewed papers and grey literature published in English or German for inclusion. Two independent reviewers will search for information.

CONCLUISON: The findings from the scoping review will be presented descriptively and summarized according to the research questions to illustrate the current status of translational research on PRS in common neurodegenerative diseases.}, } @article {pmid39906286, year = {2025}, author = {Darabi, S and Gorgich, EAC and Moradi, F and Rustamzadeh, A}, title = {Lipidopathy disrupts peripheral and central amyloid clearance in Alzheimer's disease: Where are our knowledge.}, journal = {IBRO neuroscience reports}, volume = {18}, number = {}, pages = {191-199}, pmid = {39906286}, issn = {2667-2421}, abstract = {Amyloid-beta (Aβ) production is a normal physiological process, essential for neuronal function. However, an imbalance in Aβ production and clearance is the central pathological feature of Alzheimer's disease (AD), leading to the accumulation of Aβ plaques in the brain. Low-density lipoprotein receptor-related protein 1 (LRP1) plays a critical role in both the central clearance of Aβ from the brain and its peripheral transport to visceral organs. Disruptions in these processes contribute to the accumulation of Aβ in the central nervous system (CNS) and the progression of AD. Recent research emphasizes the need for a broader focus on the systemic effects of organs outside the brain, particularly in the context of AD prevention and treatment. The contribution of peripheral systems, such as the liver, in Aβ clearance, is vital, given that Aβ levels in the plasma correlate closely with those in the brain. Consequently, targeting systemic processes, rather than focusing solely on the CNS, may offer promising therapeutic approaches. Furthermore, high-density lipoprotein (HDL) facilitates the formation of lipoprotein-amyloid complexes, which are important for Aβ transport and clearance, using proteins such as apolipoproteins E and J (ApoE and ApoJ) to form complexes that help manage Aβ accumulation. On the other hand, low-density lipoprotein (LDL) facilitates Aβ efflux from the brain by binding to LRP1, promoting its clearance. Given the relationship between lipid profiles and Aβ levels, along with lipid-modifying drugs, may be effective in managing Aβ accumulation and mitigating AD progression.}, } @article {pmid39905477, year = {2025}, author = {Zheng, H and Mizokami, A and Romera-Giner, S and Llera-Oyola, J and Yamawaki, Y and Sano, T and Jimi, E and García-García, F and Kanematsu, T}, title = {Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia.}, journal = {Biology of sex differences}, volume = {16}, number = {1}, pages = {9}, pmid = {39905477}, issn = {2042-6410}, support = {SPRING JPMJSP2136//Japan Science and Technology Agency/ ; 22K09904//Japan Society for the Promotion of Science/ ; PID2021-124430OA-I00//Ministerio de Ciencia e Innovación/ ; }, mesh = {*Microglia/metabolism ; Animals ; Male ; *MicroRNAs/metabolism/genetics ; Female ; *Sex Characteristics ; *Signal Transduction ; *Fatty Acids/metabolism ; *Mice, Inbred C57BL ; Cell Line ; *Testosterone ; Lipopolysaccharides/pharmacology ; Hippocampus/metabolism ; Mice ; Neuroinflammatory Diseases/metabolism ; }, abstract = {BACKGROUND: Significant sex differences exist in the prevalence and incidence of Alzheimer's disease (AD). Notably, testosterone has been reported to regulate cognitive functions in the brain, with low serum testosterone levels correlating with increased AD risk. However, the specific mechanisms underlying this relationship remain unclear. Recent studies have demonstrated that microglia, the primary innate immune cells in the brain, play a crucial role in AD development. Therefore, this study aimed to explore sex differences in microglial function, specifically focusing on the role of testosterone in miRNA-mediated regulation of microglial gene expression.

METHODS: Microglia were isolated from pooled hippocampal tissue of five 8-month-old male and female mice. Total RNA was extracted and subjected to miRNA microarray analysis. The mouse microglial cell line MG6 was used for in vitro experiments. Following testosterone treatment, miRNA, gene, and protein expression levels were investigated. An inflammatory response was induced using lipopolysaccharide (LPS) stimulation, and subsequent p65 phosphorylation was assessed.

RESULTS: Sex-dependent differences were observed in miRNA-mediated biological processes, with males exhibiting greater changes. Male-enriched miRNAs were associated with fatty acid synthesis and metabolism pathways. In MG6 cells, testosterone treatment upregulated the expression of several miRNAs enriched in male microglia, particularly those targeting genes related to fatty acid synthesis. Additionally, testosterone significantly reduced the gene expression of fatty acid synthase (FASN). This testosterone-induced inhibition of FASN expression attenuated NF-κB/p65 phosphorylation. Consequently, the suppression of FASN expression led to reduced expression and secretion of tumor necrosis factor-alpha following LPS stimulation in MG6 cells.

CONCLUSIONS: These findings suggest that testosterone modulates inflammation in male microglia by regulating fatty acid synthesis, potentially contributing to the observed sex differences in AD pathogenesis.}, } @article {pmid39905390, year = {2025}, author = {Ogunro, OB and Karigidi, ME and Gyebi, GA and Turkistani, A and Almehmadi, AH}, title = {Tangeretin offers neuroprotection against colchicine-induced memory impairment in Wistar rats by modulating the antioxidant milieu, inflammatory mediators and oxidative stress in the brain tissue.}, journal = {BMC complementary medicine and therapies}, volume = {25}, number = {1}, pages = {40}, pmid = {39905390}, issn = {2662-7671}, mesh = {Animals ; *Rats, Wistar ; *Oxidative Stress/drug effects ; Male ; Rats ; *Colchicine/pharmacology ; *Neuroprotective Agents/pharmacology ; *Antioxidants/pharmacology ; *Memory Disorders/drug therapy/chemically induced ; Brain/drug effects/metabolism ; Donepezil/pharmacology ; Disease Models, Animal ; Flavones/pharmacology ; Inflammation Mediators/metabolism ; }, abstract = {BACKGROUND: Tangeretin, a flavone compound (O-polymethoxylated) naturally present in tangerine and other citrus peels has demonstrated effectiveness as an anti-inflammatory and neuroprotective agent in several disease model. This study evaluated the impact of tangeretin in mitigating cognitive dysfunction and oxidative stress induced by colchicine in rats, comparing its efficacy with donepezil hydrochloride.

METHODS: Cognitive dysfunction was induced by administering colchicine (15 µg/rat) intracerebroventricularly (ICV) via a stereotaxic apparatus in male Wistar rats. Colchicine resulted in poor memory retention in acquiring and retaining a spatial navigation task, passive avoidance apparatus, and Morris water maze paradigms. Chronic treatment with tangeretin (at doses of 50, 100, and 200 mg/kg, p.o. once daily) and donepezil hydrochloride (at a dose of 10 mg/kg, p.o. daily) for 28 days, starting seven days before colchicine injection, significantly ameliorated colchicine-induced cognitive impairment.

RESULTS: The biochemical analysis showed that chronic administration of tangeretin effectively reversed the colchicine-induced increase in the level/activity of lipid peroxidation, hydrogen peroxide (H2O2), myeloperoxidase (MPO), nitrite, reactive oxygen species (ROS), tumour necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), serotonin, dopamine, glutamate, amyloid beta (Aβ) peptide, and caspase-3. Tangeretin also reversed the colchicine-induced reduction in the level/activity of brain-derived neurotrophic factor (BDNF), amma-aminobutyric acid (GABA), acetylcholinesterase (AChE), glutathione S-Transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), and total thiol (T-SH) in rat brains. However, donepezil hydrochloride did not prevent oxidative stress.

CONCLUSIONS: These findings suggest that chronic administration of tangeretin at 50, 100, and 200 mg/kg, p.o. once daily, was protective in mitigating colchicine-induced cognitive impairment and associated oxidative stress. At the same time, donepezil hydrochloride did not demonstrate similar effects.}, } @article {pmid39905278, year = {2025}, author = {Zhu, H and Huang, C and Luo, Z and Wu, L and Cheng, X and Wu, H}, title = {Porphyromonas gingivalis Induces Disturbance of Kynurenine Metabolism Through the Gut-Brain Axis: Implications for Alzheimer's Disease.}, journal = {Journal of dental research}, volume = {}, number = {}, pages = {220345241303141}, doi = {10.1177/00220345241303141}, pmid = {39905278}, issn = {1544-0591}, abstract = {Porphyromonas gingivalis is one of the major pathogens of chronic periodontitis. P. gingivalis can cause systemic inflammation, amyloid β protein deposition, and hyperphosphorylation of tau protein, leading to Alzheimer's disease (AD)-like lesions. P. gingivalis oral infection causes gut microbiota alteration, gut barrier dysfunction, and intestinal immune response and inflammation. The microbiota-gut-brain axis has a potential role in the pathogenesis of AD. Whether P. gingivalis affects AD-like lesions via the gut-brain axis needs more study. In this study, orally administered P. gingivalis induced alveolar resorption, intestinal barrier impairment, and AD-like lesions. Oral infection with P. gingivalis induced oral and gut microflora dysbiosis, imbalance of the tryptophan metabolism pathway of gut microbiota, and elevated levels of 3-hydroxykynurenine in the sera and hippocampi. The key metabolite, 3-hydroxykynurenine, suppressed Bcl2 gene expression, leading to neuronal apoptosis and promoting AD-like lesions in vivo and in vitro. These findings suggest that P. gingivalis can induce AD pathogenesis through the gut-brain axis, providing new ideas for the prevention and treatment of AD.}, } @article {pmid39905093, year = {2025}, author = {Zhang, HX and Hamit, D and Li, Q and Hu, X and Li, SF and Xu, F and Wang, MY and Bao, GQ and Li, HY}, title = {Integrative bioinformatic approach reveals novel melatonin-related biomarkers for Alzheimer's disease.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {4193}, pmid = {39905093}, issn = {2045-2322}, support = {null//Tianchi Talent Program/ ; }, mesh = {*Alzheimer Disease/genetics/metabolism ; Humans ; *Computational Biology/methods ; *Biomarkers/metabolism ; *Melatonin/metabolism ; Gene Regulatory Networks ; Molecular Docking Simulation ; Gene Expression Profiling ; }, abstract = {BACKGROUND: Melatonin (MLT) can improve mitophagy, thereby ameliorating cognitive deficits in Alzheimer's disease (AD) patients. Hence, our research focused on the potential value of MLT-related genes (MRGs) in AD through bioinformatic analysis.

METHODS: First, the key cells in the single-cell dataset GSE138852 were screened out based on the proportion of annotated cells and Fisher's test between the AD and control groups. The differentially expressed genes (DEGs) in the key cell and GSE5281 datasets were identified, and the MRGs in GSE5281 were selected via weighted gene coexpression network analysis. After intersecting two sets of DEGs and MRGs, we performed Mendelian randomization analysis to identify the MRGs causally related to AD. Biomarkers were further ascertained through receiver operating characteristic curve (ROC) and expression analysis in GSE5281 and GSE48350. Furthermore, gene set enrichment analysis, immune infiltration analysis and correlation analysis with metabolic pathways were conducted, as well as construction of a regulator network and molecular docking.

RESULTS: According to the Fisher test, oligodendrocytes were regarded as key cells due to their excellent abundance in the GSE138852 dataset, in which there were 281 DEGs between the AD and control groups. After overlapping with 3,490 DEGs and 550 MRGs in GSE5281, four genes were found to be causally related to AD, namely, G protein-coupled receptor, family C, group 5, member B (GPRC5B), Methyltransferase-like protein 7 A (METTL7A), NF-κB inhibitor alpha (NFKBIA) and RAS association domain family 4(RASSF4). Moreover, GPRC5B, NFKBIA and RASSF4 were deemed biomarkers, except for METTL7A, because of their indistinctive expression between the AD and control groups. Biomarkers might be involved in oxidative phosphorylation, adipogenesis and heme metabolism. Moreover, T helper type 17 cells, natural killer cells and CD56dim natural killer cells were significantly correlated with biomarkers. Transcription factors (GATA2, POU2F2, NFKB1, etc.) can regulate the expression of biomarkers. Finally, we discovered that all biomarkers could bind to MLT with a strong binding energy.

CONCLUSION: Our study identified three novel biomarkers related to MLT for AD, namely, GPRC5B, NFKBIA and RASSF4, providing a novel approach for the investigation and treatment of AD patients.}, } @article {pmid39904782, year = {2025}, author = {Mofatteh, M and Mohamed, A and Mashayekhi, MS and Skandalakis, GP and Neudorfer, C and Arfaie, S and MohanaSundaram, A and Sabahi, M and Anand, A and Aboulhosn, R and Liao, X and Horn, A and Ashkan, K}, title = {Deep brain stimulation of the hypothalamic region: a systematic review.}, journal = {Acta neurochirurgica}, volume = {167}, number = {1}, pages = {33}, pmid = {39904782}, issn = {0942-0940}, mesh = {*Deep Brain Stimulation/methods ; Humans ; *Hypothalamus/physiopathology ; Female ; Male ; Alzheimer Disease/therapy ; Prader-Willi Syndrome/therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: Deep brain stimulation (DBS) has been successfully used for the treatment of circuitopathies including movement, anxiety, and behavioral disorders. The hypothalamus is a crucial integration center for many peripheral and central pathways relating to cardiovascular, metabolic, and behavioral functions and constitutes a potential target for neuromodulation in treatment-refractory conditions. To conduct a systematic review, investigating hypothalamic targets in DBS, their indications, and the primary clinical findings.

METHODS: PubMed, Scopus, and Web of Science databases were searched in accordance with the PRISMA guideline to identify papers published in English studying DBS of the hypothalamus in humans.

RESULTS: After screening 3,148 papers, 34 studies consisting of 412 patients published over two decades were included in the final review. Hypothalamic DBS was indicated in refractory headaches (n = 238, 57.8%), aggressive behavior (n = 100, 24.3%), mild Alzheimer's disease (n = 58, 14.1%), trigeminal neuralgia in multiple sclerosis (n = 5, 1.2%), Prader-Willi syndrome (n = 4, 0.97%), and atypical facial pain (n = 3, 0.73%). The posterior hypothalamus was the most common DBS target site across 30 studies (88.2%). 262 (63.6%) participants were males, and 110 (26.7%) were females. 303 (73.5%) patients were adults whereas 33 (8.0%) were pediatrics. The lowest mean age of participants was 15.25 ± 4.6 years for chronic refractory aggressiveness, and the highest was 68.5 ± 7.9 years in Alzheimer's disease patients. The mean duration of the disease ranged from 2.2 ± 1.7 (mild Alzheimer's disease) to 19.8 ± 10.1 years (refractory headaches). 213 (51.7%) patients across 29 studies (85.3%) reported symptom improvements which ranged from 23.1% to 100%. 25 (73.5%) studies reported complications, most of which were associated with higher voltage stimulations.

CONCLUSIONS: DBS of the hypothalamus is feasible in selected patients with various refractory conditions ranging from headaches to aggression in both pediatric and adult populations. Future large-scale studies with long-term follow-up are required to validate the safety and efficacy data and extend these findings.}, } @article {pmid39903975, year = {2025}, author = {Giannakis, A and Konitsiotis, S}, title = {A new paradigm for neurodegenerative diseases classification: A clinical perspective.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {134}, number = {}, pages = {111099}, doi = {10.1016/j.jocn.2025.111099}, pmid = {39903975}, issn = {1532-2653}, abstract = {A vast progress has been made in the understanding of neurodegenerative diseases during the past few years. However, clinical diagnostic accuracy continues to be very low, despite the introduction of various diagnostic tools and repeated revisions of diagnostic criteria. For instance, patients with Alzheimer's disease (AD) may present with symptoms that overlap with other neurodegenerative conditions like dementia with Lewy bodies (DLB), making accurate diagnosis challenging. This diagnostic uncertainty can lead to delayed or incorrect treatment, significantly impacting patients' quality of life and prognosis. Thus, the definite diagnosis still relies on post-mortem pathological findings, placing a significant burden on both clinicians and researchers. As a growing body of evidence indicates, co-pathology seems to be the rule among neurodegenerative diseases. Additionally, a single pathological diagnosis, such as AD, can manifest in various clinical presentations, ranging from predominantly cognitive impairment to significant motor symptoms. Each of these presentations currently requires its own set of complicated diagnostic criteria. Perhaps, the time has come for a much-needed radical revision of existing clinical diagnostic criteria. Inclusion of patients do not neatly fit into existing diagnostic categories for neurodegenerative diseases, in future large-scale, longitudinal studies and/or clinical trials, and systematic assessment of their clinical features and disease progression using machine learning could generate valuable data on patients with mixed pathologies and improve our understanding of how to effectively treat these complex cases.}, } @article {pmid39903369, year = {2025}, author = {Tang, C and Border, JJ and Zhang, H and Gregory, A and Bai, S and Fang, X and Liu, Y and Wang, S and Hwang, SH and Gao, W and Morgan, GC and Smith, J and Bunn, D and Cantwell, C and Wagner, KM and Morisseau, C and Yang, J and Shin, SM and O'Herron, P and Bagi, Z and Filosa, JA and Dong, Y and Yu, H and Hammock, BD and Roman, RJ and Fan, F}, title = {Inhibition of soluble epoxide hydrolase ameliorates cerebral blood flow autoregulation and cognition in alzheimer's disease and diabetes-related dementia rat models.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {39903369}, issn = {2509-2723}, support = {U54NS127758//Foundation for the National Institutes of Health/ ; R35ES030443//Foundation for the National Institutes of Health/ ; R35 ES030443/ES/NIEHS NIH HHS/United States ; P42 ES004699/ES/NIEHS NIH HHS/United States ; AG057842//Foundation for the National Institutes of Health/ ; 5P42ES004699//Foundation for the National Institutes of Health/ ; A25-1690//Harrington Discovery Institute, University Hospitals/ ; 25PRE1365157//American Heart Association/ ; AG079336//Foundation for the National Institutes of Health/ ; P20GM104357//Foundation for the National Institutes of Health/ ; TRIBA Faculty Startup Fund//Augusta University/ ; }, abstract = {Alzheimer's Disease and Alzheimer's Disease-related dementias (AD/ADRD) pose major global healthcare challenges, with diabetes mellitus (DM) being a key risk factor. Both AD and DM-related ADRD are characterized by reduced cerebral blood flow, although the exact mechanisms remain unclear. We previously identified compromised cerebral hemodynamics as early signs in TgF344-AD and type 2 DM-ADRD (T2DN) rat models. Genome-wide studies have linked AD/ADRD to SNPs in soluble epoxide hydrolase (sEH). This study explored the effects of sEH inhibition with TPPU on cerebral vascular function and cognition in AD and DM-ADRD models. Chronic TPPU treatment improved cognition in both AD and DM-ADRD rats without affecting body weight. In DM-ADRD rats, TPPU reduced plasma glucose and HbA1c levels. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with TPPU revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation. Both AD and DM-ADRD rats exhibited impaired myogenic responses and autoregulation in the cerebral circulation, which were normalized with chronic sEH inhibition. Additionally, TPPU improved acetylcholine-induced vasodilation in the middle cerebral arteries (MCA) of DM-ADRD rats. Acute TPPU administration unexpectedly caused vasoconstriction in the MCA of DM-ADRD rats at lower doses. In contrast, higher doses or longer durations were required to induce effective vasodilation at physiological perfusion pressure in both control and ADRD rats. Additionally, TPPU decreased reactive oxygen species production in cerebral vessels of AD and DM-ADRD rats. These findings provide novel evidence that chronic sEH inhibition can reverse cerebrovascular dysfunction and cognitive impairments in AD/ADRD, offering a promising avenue for therapeutic development.}, } @article {pmid39903342, year = {2025}, author = {Wang, J and Meng, X and Yang, J and Tang, Y and Zeng, F and Wang, Y and Chen, Z and Chen, D and Zou, R and Liu, W}, title = {Improvements in Exercise for Alzheimer's Disease: Highlighting FGF21-Induced Cerebrovascular Protection.}, journal = {Neurochemical research}, volume = {50}, number = {2}, pages = {95}, pmid = {39903342}, issn = {1573-6903}, support = {No. 2023JJ30429//the Hunan Provincial Natural Science Foundation/ ; No. kq2202251//Changsha City Natural Science Foundation/ ; }, mesh = {Humans ; *Fibroblast Growth Factors/metabolism ; *Alzheimer Disease/prevention & control/metabolism ; Animals ; Exercise/physiology ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Exercise Therapy ; }, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease. Currently, it has shown a trend of earlier onset, with most patients experiencing a progressive decline in cognitive function following the disease's onset, which places a heavy burden on society and family. Since no drug cure for AD exists, exploring new ways for its treatment and prevention has become critical. Early vascular damage is an initial trigger for neuronal injury in AD, underscoring the importance of vascular health in the early stages of the disease. Patients with early AD experience abnormal blood-brain barrier transport of amyloid-β (Aβ) peptides, with excess Aβ being deposited in the cerebral vasculature. The toxic effects of Aβ lead to abnormalities in cerebrovascular structure and function. Fibroblast growth factor21 (FGF21) is an endocrine factor that positively regulates energy homeostasis and glucose-lipid metabolism. Notably, it is one of the effective targets for metabolic disease prevention and treatment. Recent studies have found that FGF21 has anti-aging and vasoprotective effects, with receptors for FGF21 present in the brain. Exercise stimulates the liver to produce large amounts of FGF21, which enters the blood-brain barrier with the blood to exert neurovascular protection. Therefore, we review the biological properties of FGF21, its role in the cerebrovascular structure and function in AD, and the mechanism of exercise-regulated FGF21 action on AD-related cerebrovascular changes, aiming to provide a new theoretical basis for using exercise to ameliorate degenerative neurological diseases.}, } @article {pmid39903213, year = {2025}, author = {Nester, CO and De Vito, AN and Prieto, S and Kunicki, ZJ and Strenger, J and Harrington, KD and Roque, N and Sliwinski, MJ and Rabin, LA and Thompson, LI}, title = {Association of Subjective Cognitive Concerns With Performance on Mobile App-Based Cognitive Assessment in Cognitively Normal Older Adults: Observational Study.}, journal = {JMIR aging}, volume = {8}, number = {}, pages = {e64033}, pmid = {39903213}, issn = {2561-7605}, mesh = {Humans ; Female ; *Mobile Applications ; Male ; Aged ; *Cognition/physiology ; Middle Aged ; Neuropsychological Tests ; Cognitive Dysfunction/diagnosis/psychology ; }, abstract = {BACKGROUND: Subjective cognitive concerns (SCCs) may be among the earliest clinical symptoms of dementia. There is growing interest in applying a mobile app-based cognitive assessment to remotely screen for cognitive status in preclinical dementia, but the relationship between SCC and relevant mobile assessment metrics is uncertain.

OBJECTIVE: This study aimed to characterize the relationship between SCC and adherence, satisfaction, and performance on mobile app assessments in cognitively unimpaired older adults.

METHODS: Participants (N=122; Meanage=68.85 [SD 4.93] years; Meaneducation=16.85 [SD 2.39] years; female: n=82, 66.7%; White:n=106, 86.2%) completed 8 assessment days using Mobile Monitoring of Cognitive Change (M2C2), an app-based testing platform, with brief daily sessions within morning, afternoon, and evening time windows (24 total testing sessions). M2C2 includes digital working memory, processing speed, and episodic memory tasks. Participants provided feedback about their satisfaction and motivation related to M2C2 upon study completion. SCC was assessed using the Cognitive Function Instrument. Regression analyses evaluated the association between SCC and adherence, satisfaction, and performance on M2C2, controlling for age, sex, depression, and loneliness. Linear-mixed effects models evaluated whether SCC predicted M2C2 subtest performance over the 8-day testing period, controlling for covariates.

RESULTS: SCC was not associated with app satisfaction or protocol motivation, but it was significantly associated with lower rates of protocol adherence (ß=-.20, P=.37, 95% CI -.65 to -.02). Higher SCC endorsement significantly predicted worse overall episodic memory performance (ß=-.20, P=.02, 95% CI -.02 to -.01), but not working memory or processing speed. There was a main effect of SCC on working memory performance at day 1 (estimate=-1.05, SE=0.47, P=.03) and a significant interaction between SCC and working memory over the 8-day period (estimate=0.05, SE=0.02, P=.03), such that SCC was associated with initially worse, then progressively better working memory performance.

CONCLUSIONS: SCCs are associated with worse overall memory performance on mobile app assessments, patterns of cognitive inefficiency (variable working memory), and mildly diminished adherence across an 8-day assessment period. Findings suggest that mobile app assessments may be sensitive to subtle cognitive changes, with important implications for early detection and treatment for individuals at risk for dementia.}, } @article {pmid39902055, year = {2025}, author = {Pillarisetti, L and Agrawal, DK}, title = {Semaglutide: Double-edged Sword with Risks and Benefits.}, journal = {Archives of internal medicine research}, volume = {8}, number = {1}, pages = {1-13}, pmid = {39902055}, issn = {2688-5654}, support = {R01 HL144125/HL/NHLBI NIH HHS/United States ; R01 HL147662/HL/NHLBI NIH HHS/United States ; R25 AI179582/AI/NIAID NIH HHS/United States ; }, abstract = {Type 2 Diabetes Mellitus therapy has evolved over the years to now include a new class of therapeutics, semaglutide. This article reviews the mechanism of action and formulation of semaglutide therapy, potential benefits, contraindications, adverse effects, and drug interactions. Oral and subcutaneous semaglutide therapies have shown effectiveness in improving glycemic control, weight loss, and reducing cardiovascular risks associated with diabetes mellitus. Semaglutide has also shown potential in being used as a therapeutic strategy in Alzheimer's disease due to its anti-neuroinflammatory effects and being used to treat polycystic ovary syndrome. However, semaglutide therapy is also associated with concerning adverse effects like acute pancreatitis, anesthetic risks like pulmonary aspiration or residual gastric content, acute kidney injury, acute gallbladder injury, nonarteritic anterior ischemic optic neuropathy and diabetic retinopathy. Contraindications of semaglutide include history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, and pregnancy. Drug interactions to consider with semaglutide therapy include those also used in diabetes treatment, like metformin, as well as anti-psychotics, due to anti-psychotics associated weight gain. The findings of this article emphasize the need for a cross-disciplinary approach to understand the molecular mechanisms and clinical implications of semaglutide on patients with complex medical histories and treatment regimens. The potential anesthetic risks of semaglutide therapy warrant careful consideratiion with ethical concerns. Further studies can assess if there is a need to modify pre-operative guidelines to account for patient using semaglutide and how delayed gastric emptying and constitpation will affect surgical outcomes and complications. While semaglutide therapy for diabetes mellitus has been established, there is a need for extensive research on repurposing semaglutide in neurodegenerative disease treatment.}, } @article {pmid39901180, year = {2025}, author = {Wang, S and Li, B and Li, J and Cai, Z and Hugo, C and Sun, Y and Qian, L and Tcw, J and Chui, HC and Dikeman, D and Asante, I and Louie, SG and Bennett, DA and Arvanitakis, Z and Remaley, AT and Kerman, BE and Yassine, HN}, title = {Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {15}, pmid = {39901180}, issn = {1750-1326}, support = {R01 AG067063/AG/NIA NIH HHS/United States ; R01 AG055770/AG/NIA NIH HHS/United States ; RF1 AG076124/AG/NIA NIH HHS/United States ; RF1AG076124, R01AG055770, R01AG067063, R01AG054434, R21AG056518, and P30AG066530/AG/NIA NIH HHS/United States ; R21 AG056518/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; R01 AG054434/AG/NIA NIH HHS/United States ; }, mesh = {*ATP Binding Cassette Transporter 1/metabolism ; Animals ; Humans ; *Cellular Senescence/physiology ; Mice ; *Alzheimer Disease/metabolism ; *Cholesterol/metabolism ; *Lysosomes/metabolism ; *Apolipoprotein E4/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Brain/metabolism ; Male ; Mice, Knockout ; }, abstract = {BACKGROUND: Cellular senescence, a hallmark of aging, has been implicated in Alzheimer's disease (AD) pathogenesis. Cholesterol accumulation is known to drive cellular senescence; however, its underlying mechanisms are not fully understood. ATP-binding cassette transporter A1 (ABCA1) plays an important role in cholesterol homeostasis, and its expression and trafficking are altered in APOE4 and AD models. However, the role of ABCA1 trafficking in cellular senescence associated with APOE4 and AD remains unclear.

METHODS: We examined the association between cellular senescence and ABCA1 expression in human postmortem brain samples using transcriptomic, histological, and biochemical analyses. Unbiased proteomic screening was performed to identify the proteins that mediate cellular ABCA1 trafficking. We created ABCA1 knock out cell lines and mouse models to validate the role of ABCA1 in cholesterol-induced mTORC1 activation and senescence. Additionally, we used APOE4-TR mice and induced pluripotent stem cell (iPSC) models to explore cholesterol-ABCA1-senescence pathways.

RESULTS: Transcriptomic profiling of the human dorsolateral prefrontal cortex from the Religious Order Study/Memory Aging Project (ROSMAP) cohort revealed the upregulation of cellular senescence transcriptome signatures in AD, which correlated with ABCA1 expression and oxysterol levels. Immunofluorescence and immunoblotting analyses confirmed increased lipofuscin-stained lipids and ABCA1 expression in AD brains and an association with mTOR phosphorylation. Discovery proteomics identified caveolin-1, a sensor of cellular cholesterol accumulation, as a key promoter of ABCA1 endolysosomal trafficking. Greater caveolin-1 expression was observed in APOE4-TR mouse models and AD human brains. Oxysterol induced mTORC1 activation and senescence were regulated by ABCA1 lysosomal trapping. Treatment of APOE4-TR mice with cyclodextrin reduced brain oxysterol levels, ABCA1 lysosome trapping, mTORC1 activation, and attenuated senescence and neuroinflammation markers. In human iPSC-derived astrocytes, the reduction of cholesterol by cyclodextrin attenuated inflammatory responses.

CONCLUSIONS: Oxysterol accumulation in APOE4 and AD induced ABCA1 and caveolin-1 expression, contributing to lysosomal dysfunction and increased cellular senescence markers. This study provides novel insights into how cholesterol metabolism accelerates features of brain cellular senescence pathway and identifies therapeutic targets to mitigate these processes.}, } @article {pmid39900729, year = {2025}, author = {Sohn, E and Kim, BY and Kim, YJ and Kim, JH and Jeong, SJ}, title = {Bauhinia coccinea extract prevents memory loss induced by scopolamine through activation of antiapoptotic and antioxidant pathways in mice.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {4037}, pmid = {39900729}, issn = {2045-2322}, support = {KSN1515293//Korea Institute of Oriental Medicine,South Korea/ ; NRF-2020R1A2C2012917//National Research Foundation of Korea/ ; }, mesh = {Animals ; *Scopolamine ; *Memory Disorders/drug therapy/chemically induced/metabolism ; *Plant Extracts/pharmacology/chemistry ; *Apoptosis/drug effects ; Mice ; *Antioxidants/pharmacology ; Male ; *Mice, Inbred ICR ; *Bauhinia/chemistry ; Oxidative Stress/drug effects ; Acetylcholinesterase/metabolism ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; Brain/metabolism/drug effects/pathology ; Acetylcholine/metabolism ; }, abstract = {Alzheimer's disease (AD) is characterized by oxidative stress-mediated memory dysfunction and neuronal cell death. This study investigated the effects of an ethanol extract from Bauhinia coccinea (EEBC) on memory impairment and neuronal damage in a memory deficit mouse model. EEBC was administered to ICR mice at doses of 50, 100, or 200 mg/kg daily for 3 weeks. Cognitive impairment was induced via scopolamine (SCO) injection. Brain tissues were analyzed for acetylcholine (ACh) levels, acetylcholinesterase (AChE) activity, neuronal apoptosis, and antioxidant markers. Behavioral tests showed that SCO injection induced memory loss, whereas EEBC significantly ameliorated SCO-mediated memory impairment. EEBC regulated the cholinergic system by decreasing ACh levels and enhancing AChE activity. Nissl staining and immunohistochemistry for NeuN showed that EEBC exerted neuroprotective effects in SCO-injected mice brains. Moreover, EEBC significantly reduced the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptotic cells increased by SCO treatment. EEBC also reversed the SCO-induced changes in apoptosis-related protein expression in brain tissues. Furthermore, EEBC significantly reduced malondialdehyde levels and activated catalase in SCO-administered brains. Quantitative RNA sequencing showed involvement of lipid metabolism in EEBC memory function regulation. Thus, EEBC is a promising candidate for attenuating AD progression as it targets the cholinergic system and neuronal apoptosis.}, } @article {pmid39898049, year = {2025}, author = {Fuller, OK and McLennan, ED and Egan, CL and Perera, N and Terry, LV and Pyun, J and de Mendonca, M and Telles, GD and Smeuninx, B and Burrows, EL and Siddiqui, G and Creek, DJ and Scott, JW and Pearen, MA and Fonseka, P and Nicolazzo, JA and Mathivanan, S and Hannan, AJ and Ramm, GA and Whitham, M and Febbraio, MA}, title = {Extracellular vesicles contribute to the beneficial effects of exercise training in APP/PS1 mice.}, journal = {iScience}, volume = {28}, number = {2}, pages = {111752}, pmid = {39898049}, issn = {2589-0042}, abstract = {Exercise improves cognitive function in Alzheimer's disease (AD) via mechanism that are not fully clear. Here, we first examined the effect of voluntary exercise training (VET) on energy metabolism and cognitive function in the APP/PS1 transgenic mouse (Tg) model of familial AD. Next, we profiled extracellular vesicles (EVs) and examined whether they may play a role in the protective effects of VET via intranasal administration of EVs, purified from the blood of sedentary (sEV) and/or acutely exercised (eEV) donor wild-type mice into APP/PS1Tg mice. We show that VET reduced resting energy expenditure (REE) and improved cognition in APP/PS1 Tg mice. Administration of eEV, but not sEV, also reduced REE, but had no effect on cognition. Taken together, these data show that exercise is effective intervention to improve symptoms of AD in APP/PS1Tg mice. In addition, eEVs mediate some of these effects, implicating EVs in the treatment of age-related neurodegenerative diseases.}, } @article {pmid39897852, year = {2025}, author = {Artime-Naveda, F and Hevia, D and Alonso-Arias, R and Martínez, C and Quirós-González, I and Cernuda-Cernuda, R and Alvarez-Artime, A and Menéndez-Valle, I and Sainz, RM and Mayo, JC}, title = {Interplay between oxidative stress, neuroinflammatory cytokines and melatonin in Alzheimer's disease: Insights from cerebrospinal fluid analysis.}, journal = {Heliyon}, volume = {11}, number = {2}, pages = {e41841}, pmid = {39897852}, issn = {2405-8440}, abstract = {BACKGROUND: Among neurodegenerative disorders Alzheimer's disease (AD) displays the highest prevalence and the projected increase in its incidence will require new advances in early diagnosis and treatment, particularly for distinguishing AD from other dementias. While beta-amyloid (Aβ) and tau biomarkers are currently used to discriminate AD from other tauopathies and dementias, additional indicators could enhance patient stratification for specific dementia types. The present study was designed to find potential associations among the classic neurologic markers, Aβ, total and phospho-tau (T-tau and P-tau), with other biomarkers including melatonin and its oxidative-derived metabolite, Formyl-N-acetyl-5-methoxykynurenamine (AFMK) levels, assayed in patients' cerebrospinal fluid (CSF) taken previously for diagnostic purposes. Other factors previously associated with the aetiology of AD, including redox indicators or proinflammatory biomarkers, were also included.

METHODS: The cross-sectional study included a cohort of 148 patients showing signs of dementia. A group of age-matched patients without neurological disorders were used as controls. CSF levels of Aβ, T-tau and P-tau were assayed, and patients were further classified according to threshold CSF levels of the three markers protein following the criteria of NIA-AA.

RESULTS: Correlational and group analysis showed a positive association between oxidative stress and neuronal damage. TNF-α negatively correlated with CSF Aβ levels (amyloid plaques) while only RANTES/CCL5 correlated positively with T-tau and P-tau. Qualitative analysis of the proinflammatory cytokines assayed showed a higher detection level in Aβ-positive patients. Regarding melatonin in the CSF, indolamine levels did not correlate with its major oxidative-derived metabolite, i.e., AFMK. However, melatonin CSF levels were significantly reduced in AD patients but not in OT. On the contrary, AFMK showed the opposite pattern, with higher levels in samples from patients displaying high T-tau and P-tau levels. Neuroinflammation was associated with Aβ deposits (low concentration in CSF), while oxidative stress significantly correlated with high T-tau and P-tau levels. Finally, among all the parameters assayed in CSF samples from the cohort studied, P-tau, in combination with antioxidant capacity, offered the best ROC curve for the diagnostic capacity to discriminate between AD and OT, showing an 85 % specificity.

CONCLUSION: While oxidative stress is instead associated with high T- and P-tau levels, higher neuroinflammatory cytokines correlate with low CSF Aβ levels. An intriguing lack of correlation between neuroinflammation and melatonin found in this study could be as a result of sample size and requires further studies with a larger sample size. Even though indolamine levels in CSF drop significantly in AD, they do not correlate with AFMK, suggesting a different kynurenine synthesis source. None of them appear to discriminate between AD and OT. Finally, among all the parameters assayed in this study, P-tau in combination with antioxidant capacity, offered the best ROC curve for the diagnostic ability capacity to discriminate between AD and OT, showing an 85 % specificity. This study holds the potential to significantly improve patient stratification and contribute to the early diagnosis and treatment of Alzheimer's disease.}, } @article {pmid39897171, year = {2024}, author = {Sharo, C and Zhang, J and Zhai, T and Bao, J and Garcia-Epelboim, A and Mamourian, E and Shen, L and Huang, Z}, title = {Repurposing FDA-Approved Drugs Against Potential Drug Targets Involved in Brain Inflammation Contributing to Alzheimer's Disease.}, journal = {Targets (Basel)}, volume = {2}, number = {4}, pages = {446-469}, pmid = {39897171}, issn = {2813-3137}, support = {R01 AG071470/AG/NIA NIH HHS/United States ; U01 AG066833/AG/NIA NIH HHS/United States ; U01 AG068057/AG/NIA NIH HHS/United States ; U19 AG074879/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease is a neurodegenerative disease that continues to have a rising number of cases. While extensive research has been conducted in the last few decades, only a few drugs have been approved by the FDA for treatment, and even fewer aim to be curative rather than manage symptoms. There remains an urgent need for understanding disease pathogenesis, as well as identifying new targets for further drug discovery. Alzheimer's disease (AD) is known to stem from a build-up of amyloid beta (Aβ) plaques as well as tangles of tau proteins. Furthermore, inflammation in the brain is known to arise from the degeneration of tissue and the build-up of insoluble material. Therefore, there is a potential link between the pathology of AD and inflammation in the brain, especially as the disease progresses to later stages where neuronal death and degeneration levels are higher. Proteins that are relevant to both brain inflammation and AD thus make ideal potential targets for therapeutics; however, the proteins need to be evaluated to determine which targets would be ideal for potential drug therapeutic treatments, or 'druggable'. Druggability analysis was conducted using two structure-based methods (i.e., Drug-Like Density analysis and SiteMap), as well as a sequence-based approach, SPIDER. The most druggable targets were then evaluated using single-nuclei sequencing data for their clinical relevance to inflammation in AD. For each of the top five targets, small molecule docking was used to evaluate which FDA approved drugs were able to bind with the chosen proteins. The top targets included DRD2 (inhibits adenylyl cyclase activity), C9 (binds with C5B8 to form the membrane attack complex), C4b (binds with C2a to form C3 convertase), C5AR1 (GPCR that binds C5a), and GABA-A-R (GPCR involved in inhibiting neurotransmission). Each target had multiple potential inhibitors from the FDA-approved drug list with decent binding infinities. Among these inhibitors, two drugs were found as top inhibitors for more than one protein target. They are C15H14N2O2 and v316 (Paracetamol), used to treat pain/inflammation originally for cataracts and relieve headaches/fever, respectively. These results provide the groundwork for further experimental investigation or clinical trials.}, } @article {pmid39897094, year = {2025}, author = {Li, Y and Jönsson, L}, title = {The health and economic burden of brain disorders: Consequences for investment in diagnosis, treatment, prevention and R&D.}, journal = {Cerebral circulation - cognition and behavior}, volume = {8}, number = {}, pages = {100377}, pmid = {39897094}, issn = {2666-2450}, abstract = {Brain disorders are prevalent across all age groups but particularly in the elderly, highlighting the importance of preserving brain health in ageing populations. There have been few previous studies to address the complete scope of burden of brain disorders, including direct and indirect costs as well as intangible costs from morbidity and mortality. We seek to illustrate the full health and economic impact of brain disorders by leveraging data from previous large-scale epidemiological and health economic studies to estimate the total direct, indirect and intangible cost of brain disorders in 2019. Two alternative methods were used to estimate indirect costs: the human capital (HC) method (data from the CBDE2010 study), and the willingness-to-pay (WTP) per DALY method (data from GBD2019). Less than 10% of the costs of Alzheimer's disease (AD) and other dementias are incurred by the health care system, while Alzheimer's disease and other dementias is the costliest condition using the HC approach and stroke is the costliest condition due to the large number of life-years lost, followed by AD using the WTP approach. Using per-capita GDP as a proxy for WTP, the indirect costs were nearly four times higher compared to the conventional HC approach. We found that Indirect costs of brain disorders outweigh the direct costs for diagnosis, treatment and care even in high-income countries with advanced, universally accessible systems in Europe. There is likely underinvestment in R&D for brain disorders, and health care systems may lack sufficient incentives to invest in their treatment and prevention.}, } @article {pmid39897039, year = {2025}, author = {Kim, Y and Ha, TY and Lee, MS and Chang, KA}, title = {Regulatory Mechanisms and Therapeutic Implications of Lysosomal Dysfunction in Alzheimer's Disease.}, journal = {International journal of biological sciences}, volume = {21}, number = {3}, pages = {1014-1031}, pmid = {39897039}, issn = {1449-2288}, mesh = {*Lysosomes/metabolism ; Humans ; *Alzheimer Disease/metabolism ; *Autophagy/physiology ; Animals ; Microglia/metabolism ; }, abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs) formed from hyperphosphorylated Tau, and widespread neuronal loss. The autophagy-lysosomal pathway plays a crucial role in maintaining cellular homeostasis by degrading and recycling of damaged organelles and aggregate amyloid proteins implicated in AD. Lysosomes are key effectors of autophagic process, responsible for the breakdown of a variety of damaged organelles and aggregate or dysfunctional proteins. This review examines the role of lysosomal dysfunction in AD pathophysiology, focusing on genetic factors, acidification abnormalities, and other contributing factors. We also explore the involvement of lysosomal dysfunction of microglia in AD pathology, and cover the role of lysosomal stress response (LSR) in cellular response to neuronal injury associated with AD. Furthermore, we discuss potential therapeutic strategies targeting lysosomal proteolysis pathway and addressing lysosomal dysfunction for AD treatment, including the pharmacologically activating lysosomal activity, regulating TFEB, and considering other emerging approaches.}, } @article {pmid39896474, year = {2025}, author = {Pinto, A and Haytural, H and Loss, C and Alvarez, C and Ertas, A and Curtis, O and Williams, AR and Murphy, G and Salleng, K and Gografe, S and Altintas, A and Kafri, T and Barres, R and Deshmukh, AS and van Praag, H}, title = {Muscle Cathepsin B treatment improves behavioral and neurogenic deficits in a mouse model of Alzheimer's Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.01.20.633414}, pmid = {39896474}, issn = {2692-8205}, abstract = {Muscle secretes factors during exercise that enhance cognition. Myokine Cathepsin B (Ctsb) is linked to memory function, but its role in neurodegenerative disease is unclear. Here we show that AAV-vector-mediated Ctsb overexpression in skeletal muscle in an Alzheimer's Disease (AD) mouse model (APP/PS1), improves motor coordination, memory function and adult hippocampal neurogenesis, while plaque pathology and neuroinflammation remain unchanged. Additionally, in AD mice, Ctsb treatment modifies hippocampal, muscle and plasma proteomic profiles to resemble that of wildtype controls. Conversely, in wildtype mice, Ctsb expression causes memory deficits and results in protein profiles across tissues that are comparable to AD control mice. In AD mice, Ctsb treatment increases the abundance of hippocampal proteins involved in mRNA metabolism and protein synthesis, including those relevant to adult hippocampal neurogenesis and memory function. Furthermore, Ctsb treatment enhances plasma metabolic and mitochondrial processes, and reduces inflammatory responses. In muscle, Ctsb expression elevates protein translation in AD mice, whereas in wildtype mice mitochondrial proteins decrease. Overall, the biological changes in the treatment groups are consistent with effects on memory function. Thus, skeletal muscle Ctsb application has potential as an AD therapeutic intervention.}, } @article {pmid39896355, year = {2024}, author = {Henríquez, PA and Araya, N}, title = {Multimodal Alzheimer's disease classification through ensemble deep random vector functional link neural network.}, journal = {PeerJ. Computer science}, volume = {10}, number = {}, pages = {e2590}, pmid = {39896355}, issn = {2376-5992}, abstract = {Alzheimer's disease (AD) is a condition with a complex pathogenesis, sometimes hereditary, characterized by the loss of neurons and synapses, along with the presence of senile plaques and neurofibrillary tangles. Early detection, particularly among individuals at high risk, is critical for effective treatment or prevention, yet remains challenging due to data variability and incompleteness. Most current research relies on single data modalities, potentially limiting comprehensive staging of AD. This study addresses this gap by integrating multimodal data-including clinical and genetic information-using deep learning (DL) models, with a specific focus on random vector functional link (RVFL) networks, to enhance early detection of AD and mild cognitive impairment (MCI). Our findings demonstrate that ensemble deep RVFL (edRVFL) models, when combined with effective data imputation techniques such as Winsorized-mean (Wmean), achieve superior performance in detecting early stages of AD. Notably, the edRVFL model achieved an accuracy of 98.8%, precision of 98.3%, recall of 98.4%, and F1-score of 98.2%, outperforming traditional machine learning models like support vector machines, random forests, and decision trees. This underscores the importance of integrating advanced imputation strategies and deep learning techniques in AD diagnosis.}, } @article {pmid39895108, year = {2025}, author = {Tezen, D and Koçhan Kızılkılıç, E and Akkan Suzan, A and Öz, A and Gulmammadli, N and Arslan, S and Kızılkılıç, O and Konukoğlu, D and Demirbilek, V and Bozluolçay, M}, title = {Correlation between serum YKL-40 and VILIP 1 levels and brain volume in dementia patients.}, journal = {Geriatrics & gerontology international}, volume = {}, number = {}, pages = {}, doi = {10.1111/ggi.15075}, pmid = {39895108}, issn = {1447-0594}, abstract = {AIM: Alzheimer's disease (AD) is a chronic, progressive cognitive disorder characterized by prominent episodic memory impairment. The contribution of neuronal damage and neuroinflammation to this process has been investigated by measuring various substances. Two of the most promising substances in serum and plasma studies are visinin-like protein 1 (VILIP-1) and tyrosine (Y), lysine (K), leucine (L)-40 (YKL-40). These markers may lead to early diagnosis and new treatment options.

METHODS: Serum VILIP-1 and YKL-40 levels were analyzed in 33 probable AD patients and 23 healthy controls. Cranial magnetic resonance imaging (MRI) was used for volumetric measurements. The results were compared with the control group and then the correlation analyze between markers and volumetric measurements of the patient group was achieved.

RESULTS: The right and left hippocampus and amygdala, left medial temporal, right rostral anterior cingulate, total brain, cortex, white matter, gray matter, subcortical gray matter, right and left total cortex volumes of the probable AD group were significantly lower than those of the control group. In the correlation analysis, the YKL-40 level and left posterior cingulate volume and the VILIP-1 level and left amygdala volume were negatively correlated.

CONCLUSIONS: In AD, there is atrophy of the limbic structures, cortex, and white matter. While the relationship between these regions and neurodegenerative markers remains unclear, our findings highlight a notable correlation between YKL-40 and VILIP-1 levels and the left amygdala and left posterior cingulate cortex, respectively. Geriatr Gerontol Int 2025; ••: ••-••.}, } @article {pmid39894909, year = {2025}, author = {Thorwald, MA and Sta Maria, NS and Chakhoyan, A and O'Day, PA and Jacobs, RE and Zlokovic, B and Finch, CE}, title = {Iron chelation by oral deferoxamine treatment decreased brain iron and iron signaling proteins.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877241313031}, doi = {10.1177/13872877241313031}, pmid = {39894909}, issn = {1875-8908}, abstract = {BACKGROUND: Deferoxamine (DFO) and other iron chelators are clinically used for cancer and stroke. They may also be useful for Alzheimer's disease (AD) to diminish iron from microbleeds. DFO may also stimulate antioxidant membrane repair which is impaired during AD. DFO and other chelators do enter the brain despite some contrary reports.

OBJECTIVE: Low dose, oral DFO was given in lab chow to wildtype (WT) C57BL/6 mice to evaluate potential impact on iron levels, iron-signaling and storage proteins, and amyloid-β protein precursor (AβPP) and processing enzymes. Young WT mice do not have microbleeds or disrupted blood-brain barrier of AD mice.

METHODS: Iron was measured by MRI and chemically after two weeks of dietary DFO. Cerebral cortex was examined for changes in iron metabolism, antioxidant signaling, and AβPP processing by western blot.

RESULTS: DFO decreased brain iron 18% (p < 0.01) estimated by R2 MRI and decreased seven major proteins that mediate iron metabolism by at least 25%. The iron storage proteins ferritin light and heavy chain decreased by at least 30%. AβPP and secretase enzymes also decreased by 30%.

CONCLUSIONS: WT mice respond to DFO with decreased AβPP, amyloid processing enzymes, and antioxidant repair. Potential DFO treatment for early-stage AD by DFO should consider the benefits of lowered AβPP and secretase enzymes.}, } @article {pmid39894843, year = {2025}, author = {Chen, L and Shen, Q and Liu, Y and Zhang, Y and Sun, L and Ma, X and Song, N and Xie, J}, title = {Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases.}, journal = {Signal transduction and targeted therapy}, volume = {10}, number = {1}, pages = {31}, pmid = {39894843}, issn = {2059-3635}, support = {32471049//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32170984//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32200802//National Natural Science Foundation of China (National Science Foundation of China)/ ; ZR2020YQ23//Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)/ ; ZR2024MC153//Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)/ ; }, mesh = {Humans ; *Iron/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; *Homeostasis ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Copper/metabolism ; Metals/metabolism ; Ferroptosis/genetics ; Oxidative Stress ; Zinc/metabolism ; Alzheimer Disease/metabolism/genetics/pathology/drug therapy ; Animals ; }, abstract = {As essential micronutrients, metal ions such as iron, manganese, copper, and zinc, are required for a wide range of physiological processes in the brain. However, an imbalance in metal ions, whether excessive or insufficient, is detrimental and can contribute to neuronal death through oxidative stress, ferroptosis, cuproptosis, cell senescence, or neuroinflammation. These processes have been found to be involved in the pathological mechanisms of neurodegenerative diseases. In this review, the research history and milestone events of studying metal ions, including iron, manganese, copper, and zinc in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), will be introduced. Then, the upstream regulators, downstream effector, and crosstalk of mental ions under both physiologic and pathologic conditions will be summarized. Finally, the therapeutic effects of metal ion chelators, such as clioquinol, quercetin, curcumin, coumarin, and their derivatives for the treatment of neurodegenerative diseases will be discussed. Additionally, the promising results and limitations observed in clinical trials of these metal ion chelators will also be addressed. This review will not only provide a comprehensive understanding of the role of metal ions in disease development but also offer perspectives on their modulation for the prevention or treatment of neurodegenerative diseases.}, } @article {pmid39894695, year = {2025}, author = {Leikin, JB}, title = {Foreword for Atypical Alzheimer's dementia: Addressing the subtypes, epidemiology, atypical presentations, diagnostic biomarkers, and treatment updates.}, journal = {Disease-a-month : DM}, volume = {}, number = {}, pages = {101862}, doi = {10.1016/j.disamonth.2025.101862}, pmid = {39894695}, issn = {1557-8194}, } @article {pmid39894694, year = {2025}, author = {Vora, N and Patel, P and Marsool, MDM and Marsool, ADM and Sunasra, R and Ladani, P and Pati, S and Khoont, D and Prajjwal, P and Ranjan, R}, title = {Atypical Alzheimer's dementia: Addressing the subtypes, epidemiology, atypical presentations, diagnostic biomarkers, and treatment updates.}, journal = {Disease-a-month : DM}, volume = {}, number = {}, pages = {101863}, doi = {10.1016/j.disamonth.2025.101863}, pmid = {39894694}, issn = {1557-8194}, abstract = {Alzheimer's disease is a progressive neurodegenerative disorder that primarily affects the elderly population; and is characterized by the gradual loss of memory, cognition, and ability to carry out daily activities. However, a growing body of research indicates that there exists a subtype of Alzheimer's disease known as Atypical Alzheimer's disease. Atypical Alzheimer's disease is a rare form of dementia that differs from the typical presentation of Alzheimer's disease, such as variations in the age of onset, distribution of brain pathology, and clinical symptoms. The patients affected have a younger age of onset and have predominantly visual, language, executive function, motor, and behavioral dysfunction. The diagnosis requires a comprehensive neurological evaluation with specific attention to cognitive and behavioral changes while ruling out other potential causes of dementia. Emerging biomarkers including CSF profiles, amyloid and tau PET imaging, and advanced neuroimaging techniques offer promising avenues for improving diagnostic accuracy and understanding disease mechanisms. In this article, we focus on atypical presentations seen in the posterior cortical variant, frontal variant, progressive aphasic variant, corticobasal syndrome and look at the specific biomarkers used in the diagnosis of each variant along with focusing on the treatment of the disease. We also aim to provide an understanding of Atypical Alzheimer's disease, its clinical features, the biomarkers helping in diagnosing the disease, the current treatment guidelines, and the current scientific advancements in the field.}, } @article {pmid39894421, year = {2025}, author = {Valderrama-Mantilla, AI and Martín-Cuevas, C and Gómez-Garrido, A and Morente-Montilla, C and Crespo-Facorro, B and García-Cerro, S}, title = {Shared molecular signature in Alzheimer's disease and schizophrenia: A systematic review of the reelin signaling pathway.}, journal = {Neuroscience and biobehavioral reviews}, volume = {169}, number = {}, pages = {106032}, doi = {10.1016/j.neubiorev.2025.106032}, pmid = {39894421}, issn = {1873-7528}, mesh = {Humans ; *Reelin Protein ; *Alzheimer Disease/metabolism/genetics ; *Schizophrenia/metabolism/genetics/physiopathology ; *Signal Transduction/physiology ; *Nerve Tissue Proteins/metabolism/genetics ; *Extracellular Matrix Proteins/metabolism/genetics ; *Cell Adhesion Molecules, Neuronal/metabolism/genetics ; *Serine Endopeptidases/genetics/metabolism ; Animals ; }, abstract = {The Reelin signaling pathway, particularly the RELN-APOER2-DAB1 complex, has emerged as a key contributor to the neuropathology of Alzheimer's disease (AD) and Schizophrenia (SZ). Despite being distinct clinical conditions, these disorders exhibit similar patterns of cognitive decline, including early disruptions in synaptic function and memory impairments. Notably, individuals with SZ have a 2-4 fold increased risk of developing AD or other dementias, highlighting potential shared molecular mechanisms, and positioning Reelin as a pivotal link between them. This systematic review explores the role of Reelin and its signaling components across these disorders. In AD, Reelin disruption correlates with hallmark features such as Tau hyperphosphorylation, amyloid-beta accumulation, and cognitive deficits. In SZ, alterations in Reelin signaling, including epigenetic modifications affecting RELN expression, are linked to disruptions in neuronal development and synaptic plasticity, particularly in the parietal and prefrontal cortices. Additionally, genomic studies reveal specific RELN variants and allelic imbalances that may influence disease severity and treatment response in SZ, suggesting RELN's role as a potential biomarker for therapeutic outcomes. Region-specific Reelin alterations in both AD and SZ suggest differing impacts yet underscore a potential common molecular origin. Our findings highlight the Reelin pathway as a molecular convergence point, warranting further investigation as a therapeutic and diagnostic target for AD, SZ, and potentially other neuropsychiatric disorders. The interplay between genetic and epigenetic regulation of RELN may provide novel insights into neurodegeneration, with implications for personalized intervention strategies in AD and SZ.}, } @article {pmid39893357, year = {2025}, author = {Bhatia, V and Chandel, A and Minhas, Y and Kushawaha, SK}, title = {"Advances in biomarker discovery and diagnostics for alzheimer's disease".}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {39893357}, issn = {1590-3478}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by intracellular neurofibrillary tangles with tau protein and extracellular β-amyloid plaques. Early and accurate diagnosis is crucial for effective treatment and management.

OBJECTIVE: The purpose of this review is to investigate new technologies that improve diagnostic accuracy while looking at the current diagnostic criteria for AD, such as clinical evaluations, cognitive testing, and biomarker-based techniques.

METHODS: A thorough review of the literature was done in order to assess both conventional and contemporary diagnostic methods. Multimodal strategies integrating clinical, imaging, and biochemical evaluations were emphasised. The promise of current developments in biomarker discovery was also examined, including mass spectrometry and artificial intelligence.

RESULTS: Current diagnostic approaches include cerebrospinal fluid (CSF) biomarkers, imaging tools (MRI, PET), cognitive tests, and new blood-based markers. Integrating these technologies into multimodal diagnostic procedures enhances diagnostic accuracy and distinguishes dementia from other conditions. New technologies that hold promise for improving biomarker identification and diagnostic reliability include mass spectrometry and artificial intelligence.

CONCLUSION: Advancements in AD diagnostics underscore the need for accessible, minimally invasive, and cost-effective techniques to facilitate early detection and intervention. The integration of novel technologies with traditional methods may significantly enhance the accuracy and feasibility of AD diagnosis.}, } @article {pmid39893320, year = {2025}, author = {Groo, AC and Curel, T and Malzert-Fréon, A and Séguy, L and Bento, O and Corvaisier, S and Culerier, T and Legrand, R and Callizot, N and Henriques, A and Culley, G and Claeysen, S and Rochais, C and Dallemagne, P}, title = {Evidence from a mouse model supports repurposing an anti-asthmatic drug, bambuterol, against Alzheimer's disease by administration through an intranasal route.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {155}, pmid = {39893320}, issn = {2399-3642}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Administration, Intranasal ; Mice ; *Disease Models, Animal ; *Terbutaline/analogs & derivatives/administration & dosage/pharmacology/pharmacokinetics ; *Drug Repositioning ; Anti-Asthmatic Agents/administration & dosage/pharmacology/pharmacokinetics ; Male ; Rats ; Hippocampus/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Neuroprotective Agents/administration & dosage/pharmacology/pharmacokinetics ; Neurons/drug effects/metabolism ; }, abstract = {Bambuterol is a long-acting anti-asthmatic prodrug which releases terbutaline. Terbutaline is an agonist of the β2-adrenergic receptors which is formed by decarbamoylation of bambuterol by butyrylcholinesterase. Inhibition of the latter, as well as activation of β2-AR, are of interest for the treatment of Alzheimer's disease (AD). Combining these two activities, bambuterol could express a good clinical efficacy against AD. The present work firstly confirmed the capacity of bambuterol to display in cellulo neuroprotective activities, reduction of Tau hyperphosphorylation and preservation of synapses in rat hippocampal neuronal cultures intoxicated with Aβ peptides. Further, bambuterol, in the form of a liposomal gel, showed a good bioavailability in CNS after intranasal administration, which should reduce any side effects linked to peripheral terbutaline release. Indeed, even if the latter is more selective than other β2-mimetics towards bronchial β2-AR, cardiovascular effects (tachycardia, arrhythmias…) could occur upon cardiac β1-AR activation. Finally, intranasal administration of low doses of bambuterol gel in mice intoxicated with Aβ peptides, prevented long-term spatial memory impairment and showed beneficial effects on the survival of neurons and on synapse preservation.}, } @article {pmid39893139, year = {2025}, author = {Smith, EE and Phillips, NA and Feldman, HH and Borrie, M and Ganesh, A and Henri-Bhargava, A and Desmarais, P and Frank, A and Badhwar, A and Barlow, L and Bartha, R and Best, S and Bethell, J and Bhangu, J and Black, SE and Bocti, C and Bronskill, SE and Burhan, AM and Calon, F and Camicioli, R and Campbell, B and Collins, DL and Dadar, M and DeMarco, ML and Ducharme, S and Duchesne, S and Einstein, G and Fisk, JD and Gawryluk, JR and Grossman, L and Ismail, Z and Itzhak, I and Joshi, M and Harrison, A and Kroger, E and Kumar, S and Laforce, R and Lanctot, KL and Lau, M and Lee, L and Masellis, M and Massoud, F and Mitchell, SB and Montero-Odasso, M and Myers Barnett, K and Nygaard, HB and Pasternak, SH and Peters, J and Rajah, MN and Robillard, JM and Rockwood, K and Rosa-Neto, P and Seitz, DP and Soucy, JP and Trenaman, SC and Wellington, CL and Zadem, A and Chertkow, H and , }, title = {Use of lecanemab and donanemab in the Canadian healthcare system: Evidence, challenges, and areas for future research.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100068}, doi = {10.1016/j.tjpad.2025.100068}, pmid = {39893139}, issn = {2426-0266}, abstract = {Lecanemab and donanemab are monoclonal antibody therapies that remove amyloid-beta from the brain. They are the first therapies that alter a fundamental mechanism, amyloid-beta deposition, in Alzheimer disease (AD). To inform Canadian decisions on approval and use of these drugs, the Canadian Consortium on Neurodegeneration in Aging commissioned Work Groups to review evidence on the efficacy and safety of these new therapies, as well as their projected impacts on Canadian dementia systems of care. We included persons with lived experience with Alzheimer disease in the discussion about the benefits and harms. Our review of the trial publications found high quality evidence of statistically significant group differences, but also recognized that there are mixed views on the clinical relevance of the observed differences and the value of therapy for individual patients. The drugs are intended for persons with early AD, at a stage of mild cognitive impairment or mild dementia. If patients are treated, then confirmation of AD by positron emission tomography or cerebrospinal fluid analysis and monitoring for risk of amyloid-related imaging abnormalities was recommended, as done in the clinical trials, although it would strain Canadian resource capacity. More data are needed to determine the size of the potentially eligible treatment population in Canada.}, } @article {pmid39892653, year = {2025}, author = {Muratori, BG and da Veiga, IET and Medeiros, GN and Silva, SMSE and Soliani, AG and Prado, CM and Cerutti, SM}, title = {Standardized extract of Ginkgo biloba induced memory consolidation in female mice with hypofunction of vesicular acetylcholine transporter.}, journal = {Behavioural brain research}, volume = {482}, number = {}, pages = {115455}, doi = {10.1016/j.bbr.2025.115455}, pmid = {39892653}, issn = {1872-7549}, abstract = {Basal forebrain cholinergic neurons are pivotal for cholinergic signaling in the neocortex and hippocampal formation, crucially implicated in neurodegenerative diseases like late-onset Alzheimer's disease (LOAD), recognition memory impairments, and decision-making. The acetylcholine transporter (VAChT) is essential for loading acetylcholine into synaptic vesicles. Building on our previous findings showing that Ginkgo biloba extract (EGb) preserves recognition memory, we hypothesized EGb would enhance memory in female mice with varying VAChT reductions. We also explored whether reduced cholinergic signaling induces anxiety-like behavior and whether EGb could alleviate such symptoms. Three-month-old female mice with severe VAChT reduction (knockdown homozygotes; VAChT KD[HOM]), moderate reduction (heterozygotes; VAChT KD[HET]), and wild-type (WT) mice received the vehicle, 5 mg/kg Donepezil, or EGb at doses of 250, 500, and 1000 mg/kg for 30 days. Memory assessments included aversive tasks like discriminative avoidance memory and non-aversive tasks like object recognition and location memory. We assessed VAChT protein expression in the hippocampal formation (HF) using Western blotting and quantified VAChT-immunopositive cells (IR[+]) in specific HF subfields (dCA1, dCA3, dDG) using immunohistochemistry. Chronic EGb treatment significantly improved long-term memory in female VAChT KD[HOM] mice in object recognition and locations memories in a dose-dependent manner, unlike Donepezil. Enhanced memory was correlated with an increase in VAChT-IR[+] cells in the dCA1 of VAChT KD[HOM] mice. Additionally, EGb reduced VAChT-IR[+] cells in the dDG of VAChT KD[HET] mice, which was associated with decreased anxiety-like behavior. These findings suggest that EGb effectively mitigates deficits caused by cholinergic deficiency in hippocampal-dependent memory consolidation, thereby improving our understanding of its role in modulating long-term memory and hippocampal plasticity.}, } @article {pmid39892523, year = {2025}, author = {Kuo, YF and Westra, J and Harvey, EP and Raji, MA}, title = {Use of Medications for Opioid Use Disorder in Older Adults.}, journal = {American journal of preventive medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.amepre.2025.01.019}, pmid = {39892523}, issn = {1873-2607}, abstract = {INTRODUCTION: The American population diagnosed with opioid use disorder (OUD) is growing, particularly those aged ≥65 years. Less than 30% of OUD patients receive medication for opioid use disorder (MOUD), and even fewer older adults.

METHODS: Using 20% national Medicare data, beneficiaries aged over 65 diagnosed with OUD in 2017-2022 were selected to assess the trend and types of MOUD use, including methadone, buprenorphine, or naltrexone. In the 2022 cohort (n=69,380), a multivariable logistic regression model was constructed to examine the factors associated with MOUD use. Analyses were performed in 2024.

RESULTS: MOUD use among older adults increased from 4.8% in 2017, 7.5% in 2019, to 15.0% in 2022. The larger increase coincided with implementation of a new Medicare payment policy covering methadone for OUD. About 79% of OUD patients had chronic pain and arthritis; 50% had anemia, depression, or anxiety. Males, Black patients, Hispanic patients, older patients, and rural residents had lower odds of receiving MOUD. Enrollees with dual coverage from Medicaid had higher odds of receiving MOUD. Patients with alcohol or tobacco use disorders, anxiety, depression, hypothyroidism, or liver disease were more likely to receive MOUD; conversely, those with non-Alzheimer's dementia, cancer, chronic kidney disease, stroke, chronic pain, or arthritis were less likely to receive MOUD.

CONCLUSIONS: The rate of MOUD use was low in older adults. The disparity in MOUD use underscores the need for improved access to comprehensive opioid treatment programs and increased MOUD coverage. Additional studies of treatment patterns are also warranted.}, } @article {pmid39892386, year = {2025}, author = {Vandal, M and Institoris, A and Reveret, L and Korin, B and Gunn, C and Hirai, S and Jiang, Y and Lee, S and Lee, J and Bourassa, P and Mishra, RC and Peringod, G and Arellano, F and Belzil, C and Tremblay, C and Hashem, M and Gorzo, K and Elias, E and Yao, J and Meilandt, B and Foreman, O and Roose-Girma, M and Shin, S and Muruve, D and Nicola, W and Körbelin, J and Dunn, JF and Chen, W and Park, SK and Braun, AP and Bennett, DA and Gordon, GRJ and Calon, F and Shaw, AS and Nguyen, MD}, title = {Loss of endothelial CD2AP causes sex-dependent cerebrovascular dysfunction.}, journal = {Neuron}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuron.2025.01.006}, pmid = {39892386}, issn = {1097-4199}, abstract = {Polymorphisms in CD2-associated protein (CD2AP) predispose to Alzheimer's disease (AD), but the underlying mechanisms remain unknown. Here, we show that loss of CD2AP in cerebral blood vessels is associated with cognitive decline in AD subjects and that genetic downregulation of CD2AP in brain vascular endothelial cells impairs memory function in male mice. Animals with reduced brain endothelial CD2AP display altered blood flow regulation at rest and during neurovascular coupling, defects in mural cell activity, and an abnormal vascular sex-dependent response to Aβ. Antagonizing endothelin-1 receptor A signaling partly rescues the vascular impairments, but only in male mice. Treatment of CD2AP mutant mice with reelin glycoprotein that mitigates the effects of CD2AP loss function via ApoER2 increases resting cerebral blood flow and even protects male mice against the noxious effect of Aβ. Thus, endothelial CD2AP plays critical roles in cerebrovascular functions and represents a novel target for sex-specific treatment in AD.}, } @article {pmid39891801, year = {2025}, author = {Eo, H and Kim, SH and Ju, IG and Lee, JH and Oh, MS and Kim, YJ}, title = {NXP032 Improves Memory Impairment Through Suppression of Tauopathy in PS19 Mice and Attenuates Okadaic Acid-Induced Tauopathy in SH-SY5Y Cells.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {20}, number = {1}, pages = {10}, pmid = {39891801}, issn = {1557-1904}, support = {2022R1A6A3A01087061//National Research Foundation of Korea/ ; NRF-1711194418//National Research Foundation of Korea/ ; GS-5-JO-NON-20222608//the BK21 FOUR program of National Research Foundation of Korea/ ; KHU-20222128//Nexmos/ ; }, mesh = {Animals ; *Tauopathies/drug therapy/pathology/metabolism ; *Okadaic Acid/pharmacology ; Mice ; Humans ; *Mice, Transgenic ; *Memory Disorders/drug therapy/chemically induced ; tau Proteins/metabolism ; Cell Line, Tumor ; Ascorbic Acid/pharmacology/therapeutic use ; Male ; }, abstract = {Tauopathy is widely observed in multiple neurodegenerative diseases such as Alzheimer's disease (AD) and characterized by abnormal tau protein phosphorylation, aggregation and its accumulation as a form of neurofibrillary tangle (NFT) in the brain. However, there are no effective treatments targeting tau pathology in the AD. Vitamin C is known to reduce tauopathy and modulate one of its regulators called glycogen synthase kinase 3 (GSK3) in the body. Nevertheless, vitamin C has a limitation of its stability during metabolism due to its chemical properties. Thus, in the current study, NXP032 (a vitamin C/aptamer complex) was tested as a candidate for tau-targeting treatment because it can preserve antioxidative efficacy of vitamin C before it can reach the target tissue. In this context, the current study aimed to investigate the therapeutic effect of NXP032 on tauopathy in vivo and in vitro. As a result, NXP032 attenuated cognitive and memory decline and reduced NFT and tau hyperphosphorylation in the P301S mutant human tau transgenic mice (or called PS19 mice). In addition, NXP032 suppressed neuroinflammation found in the PS19 mice. Furthermore, NXP032 protected SH-SY5Y human neuroblastoma cells from okadaic acid (OKA)-induced cytotoxicity. Especially, 10 ng/ml of NXP032 reduced tau hyperphosphorylation and GSK3 activation though its phosphorylation at Tyr216 site which were promoted by OKA treatment in the SH-SY5Y cells. Taken together, our results suggest that NXP032 might be a potential therapy for AD and tauopathy-related neurodegenerative disorders as well.}, } @article {pmid39891777, year = {2025}, author = {Abdelhamed, HG and Hassan, AA and Sakraan, AA and Al-Deeb, RT and Mousa, DM and Aboul Ezz, HS and Noor, NA and Khadrawy, YA and Radwan, NM}, title = {Brain interleukins and Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {40}, number = {2}, pages = {116}, pmid = {39891777}, issn = {1573-7365}, mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Interleukins/metabolism ; *Brain/metabolism/pathology ; Animals ; }, abstract = {The central nervous system (CNS) is immune-privileged by several immuno-modulators as interleukins (ILs). ILs are cytokines secreted by immune cells for cell-cell signaling communications and affect the functions of the CNS. ILs were reported to orchestrate different molecular and cellular mechanisms of both physiological and pathological events, through overproduction or over-expression of their receptors. They interact with numerous receptors mediating pro-inflammatory and/or anti-inflammatory actions. Interleukins have been implicated to participate in neurodegenerative diseases. They play a critical role in Alzheimer's disease (AD) pathology which is characterized by the over-production of pro-inflammatory ILs. These may aggravate neurodegeneration, in addition to their contribution to detrimental mechanisms as oxidative stress, and excitotoxicity. However, recent research on the relation between ILs and AD revealed major discrepancies. Most of the major ILs were shown to play both pro- and anti-inflammatory roles in different experimental settings and models. The interactions between different ILs through shared pathways also add to the difficulty of drawing solid conclusions. In addition, targeting the different ILs has not yielded consistent results. The repeated failures of therapeutic drugs in treating AD necessitate the search for novel agents targeting multiple mechanisms of the disease pathology. In this context, the understanding of interleukins and their roles throughout the disease progression and interaction with other systems in the brain may provide promising therapeutic targets for the prevention or treatment of AD.}, } @article {pmid39891738, year = {2025}, author = {Brennan, GS and Goriely, A}, title = {A network aggregation model for amyloid- β dynamics and treatment of Alzheimer's diseases at the brain scale.}, journal = {Journal of mathematical biology}, volume = {90}, number = {2}, pages = {22}, pmid = {39891738}, issn = {1432-1416}, support = {EP/R020205/1//Engineering and Physical Sciences Research Council/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Amyloid beta-Peptides/metabolism ; *Brain/metabolism ; *Mathematical Concepts ; Protein Aggregation, Pathological/metabolism/drug therapy ; Disease Progression ; Models, Neurological ; }, abstract = {Neurodegenerative diseases are associated with the assembly of specific proteins into oligomers and fibrillar aggregates. At the brain scale, these protein assemblies can diffuse through the brain and seed other regions, creating an autocatalytic protein progression. The growth and transport of these assemblies depend on various mechanisms that can be targeted therapeutically. Here, we use spatially-extended nucleation-aggregation-fragmentation models for the dynamics of prion-like neurodegenerative protein-spreading in the brain to study the effect of different drugs on whole-brain Alzheimer's disease progression.}, } @article {pmid39891708, year = {2025}, author = {Knezovic, A and Salkovic-Petrisic, M}, title = {Cholinergic neurotransmission in the brain of streptozotocin-induced rat model of sporadic Alzheimer's disease: long-term follow up.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {39891708}, issn = {1435-1463}, support = {10/64//Unity through Knowledge Fund/ ; 108-1080003-0020//Ministarstvo znanosti i obrazovanja/ ; }, abstract = {Rats treated intracerebroventricularly with streptozotocin (STZ-icv) develop pathologic features, which resemble those in Alzheimer's disease and have been proposed as a non-transgenic model for sporadic type of the disease (sAD). We aimed to characterize cholinergic transmission in the rat brain as a function of STZ-icv dose and time after the treatment. Acetylcholinesterase (AChE) activity and expression of muscarinic (M1, M4) and nicotinic (α7) receptors, cholin acetyltransferase (ChAT) and glial fibrillary acidic protein (GFAP) were measured in hippocampus (HPC) and parietotemporal cortex (CTX) of STZ-icv and age-matched control rats one week, and one, three, six and nine months after the icv administration of STZ (0.3, 1 and 3 mg/kg), respectively. Cholinergic and astroglial changes were found most pronounced with a highest STZ dose in time-dependent manner. The cortex and hippocampus exhibited specific alterations in cholinergic transmission following STZ-icv administration, with either similar or distinct patterns depending on the parameter observed: increased AChE activity in HPC and invariable in CTX; increased M4 and ChAT levels in both regions; substantial cortical M1 level increment and moderate hippocampal M1 decrement; and decreased α7 levels in both regions, with subsequent increase observed only in HPC. Alterations in cerebral cholinergic neurotransmission in STZ-icv rat model were mostly following a threephasic time pattern: acute response (Phase I), complete/partial compensation (Phase II), and reappearance/progression of changes (Phase III). Staging structure of cholinergic changes in STZ-icv rat model might be speculated to partly correlate with cholinergic pathology in clinical AD stages.}, } @article {pmid39891319, year = {2025}, author = {Canet, G and Zussy, C and Vitalis, M and Morin, F and Chevallier, N and Hunt, H and Claeysen, S and Blaquière, M and Marchi, N and Planel, E and Meijer, OC and Desrumaux, C and Givalois, L}, title = {Advancing Alzheimer's disease pharmacotherapy: efficacy of glucocorticoid modulation with dazucorilant (CORT113176) in preclinical mouse models.}, journal = {British journal of pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bph.17457}, pmid = {39891319}, issn = {1476-5381}, support = {SM2016#1512//Association France Alzheimer & Fédération pour la Recherche sur le Cerveau/ ; MND202003011477-OPA//Fondation pour la Recherche Médicale/ ; ANR-11-LABEX-0021-LipSTIC//Agence Nationale de la Recherche/ ; ANR-AAP2022-R22102FF-EpiNeurAge//Agence Nationale de la Recherche/ ; Postdoctoral fellowship//Alzheimer Society of Canada/ ; CBS2 PhD program//Université de Montpellier/ ; MUSE-AAP20REC-FRS09-GAiA//Université de Montpellier/ ; }, abstract = {BACKGROUND AND PURPOSE: Exposure to chronic stress and high levels of glucocorticoid hormones in adulthood has been associated with cognitive deficits and increased risk of Alzheimer's disease (AD). Dazucorilant has recently emerged as a selective glucocorticoid receptor (NR3C1) modulator, exhibiting efficacy in counteracting amyloid-β toxicity in an acute model of AD. We aim to assess the therapeutic potential of dazucorilant in reversing amyloid and tau pathologies through the inhibition of glucocorticoid receptor pathological activity, and providing additional evidence for its consideration in AD treatment.

EXPERIMENTAL APPROACH: The efficacy of dazucorilant was evaluated in two transgenic mouse models of amyloid pathology. The slowly progressing J20 and the aggressively pathological 5xFAD mice. Behavioural analysis was conducted to evaluate welfare, cognitive performances and anxiety levels. The activity of the glucocorticoid receptor system, neuroinflammation, amyloid burden and tau phosphorylation were examined in hippocampi.

KEY RESULTS: In both AD models, chronic treatment with dazucorilant improved working and long-term spatial memories along with the inhibition of glucocorticoid receptor-dependent pathogenic processes and the normalization of plasma glucocorticoid levels. Dazucorilant treatment also resulted in a reduction in tau hyperphosphorylation and amyloid production and aggregation. Additionally, dazucorilant seemed to mediate a specific re-localization of activated glial cells onto amyloid plaques in J20 mice, suggesting a restoration of physiological neuroinflammatory processes.

CONCLUSION AND IMPLICATIONS: Dazucorilant exhibited sustained disease-modifying effects in two AD models. Given that this compound has demonstrated safety and tolerability in human subjects, our results provide pre-clinical support for conducting clinical trials to evaluate its potential in AD.}, } @article {pmid39890844, year = {2025}, author = {Xie, Z and Situ, Y and Deng, L and Liang, M and Ding, H and Guo, Z and Xu, Q and Liang, Z and Shao, Z}, title = {Identification of therapeutic targets for Alzheimer's Disease Treatment using bioinformatics and machine learning.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {3888}, pmid = {39890844}, issn = {2045-2322}, mesh = {*Alzheimer Disease/drug therapy/genetics/metabolism/pathology ; Humans ; *Machine Learning ; *Computational Biology/methods ; Gene Expression Profiling/methods ; Gene Regulatory Networks ; Molecular Targeted Therapy/methods ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder that currently lacks effective treatment options. This study aimed to identify potential therapeutic targets for the treatment of AD using comprehensive bioinformatics methods and machine learning algorithms. By integrating differential gene expression analysis, weighted gene co-expression network analysis, Mfuzz clustering, single-cell RNA sequencing, and machine learning algorithms including LASSO regression, SVM-RFE, and random forest, five hub genes related to AD, including PLCB1, NDUFAB1, KRAS, ATP2A2, and CALM3 were identified. PLCB1, in particular, exhibited the highest diagnostic value in AD and showed significant correlation with Braak stages and neuronal expression. Furthermore, Noscapine, PX-316, and TAK-901 were selected as potential therapeutic drugs for AD based on PLCB1. This research provides a comprehensive and reliable method for the discovery of AD therapeutic targets and the construction of diagnostic models, offering important insights and directions for future AD treatment strategies and drug development.}, } @article {pmid39887820, year = {2025}, author = {Lu, X and Bai, S and Feng, L and Yan, X and Lin, Y and Huang, J and Liao, X and Wang, H and Li, L and Yang, Z and Yan, LYC and Yang, B and Wang, M and Jin, J and Zong, Z and Jiang, Z and Huang, C and Liu, C and Zhang, X and Su, H and Wang, Y and Lee, WY and Jiang, X and Tortorella, MD and Lin, S and Ko, H and Li, G}, title = {Cranial bone maneuver ameliorates Alzheimer's disease pathology via enhancing meningeal lymphatic drainage function.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {e14518}, doi = {10.1002/alz.14518}, pmid = {39887820}, issn = {1552-5279}, support = {82172430//National Natural Science Foundation of China/ ; 82272505//National Natural Science Foundation of China/ ; 82472454//National Natural Science Foundation of China/ ; 81874000//National Natural Science Foundation of China/ ; 82122001//National Natural Science Foundation of China/ ; 14108720//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; 14121721//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; 14202920//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; 14100122//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; 14119124//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; 14113723//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; N_CUHK472/22//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; C7030-18G//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; C6027-19GF//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; C7074-21GF//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; T13-402/17-N//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; AoE/M-402/20//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; AoE/M-604/16//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; 17180831//Heath Medical Research Fund (HMRF) of Food and Health Bureau Hong Kong/ ; 08190416//Heath Medical Research Fund (HMRF) of Food and Health Bureau Hong Kong/ ; 09203436//Heath Medical Research Fund (HMRF) of Food and Health Bureau Hong Kong/ ; PRP/050/19FX//Hong Kong Innovation Technology Commission Funds/ ; 2023A1515011040//Natural Science Foundation of Guangdong Province/ ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disease and the leading cause of dementia. Recent research highlights meningeal lymphatics as key regulators in neurological diseases, suggesting that enhancing their drainage function could be a potential therapeutic strategy for AD. Our proof-of-concept study demonstrated that cranial bone transport can improve meningeal lymphatic drainage function and promote ischemic stroke recovery.

METHODS: This study defined cranial bone maneuver (CBM) technique. After osteotomy, a small circular bone flap was made and attached to an external fixator for subsequent maneuver in a controlled fashion for a defined period using 5xFAD mice.

RESULTS: CBM treatment improved memory functions, reduced amyloid deposits, and promoted meningeal lymphatic drainage function. CBM induced cascades of inflammatory and lymphangiogenic processes in skull and meninges. Meningeal lymphatics are indispensable elements for the therapeutic effects of CBM.

DISCUSSION: CBM might be a promising innovative therapy for AD management, warranting further clinical investigation.

HIGHLIGHTS: Cranial bone maneuver (CBM) alleviated memory deficits and amyloid depositions. CBM promoted meningeal lymphangiogenesis and lymphatic drainage function. The beneficial effects of CBM lasted for a long time following the CBM procedures. CBM induced cascades of inflammatory and lymphangiogenic processes in the meninges. Meningeal lymphatic vessels are indispensable elements for CBM therapeutic effects.}, } @article {pmid39887549, year = {2025}, author = {Andrews, D and Ducharme, S and Chertkow, H and Sormani, MP and Collins, DL and , }, title = {The higher benefit of lecanemab in males compared to females in CLARITY AD is probably due to a real sex effect.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14467}, pmid = {39887549}, issn = {1552-5279}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; //Brain Canada Foundation/ ; //McGill University/ ; FRN-165921/CAPMC/CIHR/Canada ; //Famille Louise & André Charron/ ; }, mesh = {Humans ; Male ; Female ; *Alzheimer Disease ; Aged ; Cognitive Dysfunction ; Sex Characteristics ; Sex Factors ; Disease Progression ; }, abstract = {INTRODUCTION: The phase 3 trial CLARITY AD found lecanemab slowed cognitive decline by 27%. However, subgroup analyses indicated a significant 31% sex difference in the effect and suggested no or limited effectiveness in females. We used simulations constrained by the trial design to determine whether that difference reflects a pre-existing sex difference in Alzheimer's disease progression or was a random event.

METHODS: Simulations were generated using linear mixed models of cognitive decline fit to data from Alzheimer's Disease Neuroimaging Initiative participants satisfying CLARITY AD inclusion criteria.

RESULTS: The statistically non-significant 7.9% smaller cognitive decline rate in our cohort's males versus females does not explain CLARITY AD's 31% sex difference in lecanemab's effect. A ≥ 31% difference occurred randomly in only 12 of our 10,000 simulations (0.0012 probability).

DISCUSSION: CLARITY AD's sex difference was probably not random. Lecanemab is likely less effective in females than males, but we cannot conclude the drug is ineffective in females.

HIGHLIGHTS: Lecanemab is more clinically effective in males than in females. Forest plots should only report subgroup-specific effects in well-powered subgroups. Trial simulations based on real data enable investigation of subgroup drug effects. We cannot conclude that lecanemab is clinically ineffective in females. A sex difference in lecanemab's efficacy could be linked to its action mechanism.}, } @article {pmid39887500, year = {2025}, author = {Bittner, T and Tonietto, M and Klein, G and Belusov, A and Illiano, V and Voyle, N and Delmar, P and Scelsi, MA and Gobbi, S and Silvestri, E and Barakovic, M and Napolitano, A and Galli, C and Abaei, M and Blennow, K and Barkhof, F}, title = {Biomarker treatment effects in two phase 3 trials of gantenerumab.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {e14414}, doi = {10.1002/alz.14414}, pmid = {39887500}, issn = {1552-5279}, support = {//F. Hoffmann-La Roche AG/ ; }, abstract = {INTRODUCTION: We report biomarker treatment effects in the GRADUATE I and II phase 3 studies of gantenerumab in early Alzheimer's disease (AD).

METHODS: Amyloid and tau positron emission tomography (PET), volumetric magnetic resonance imaging (vMRI), cerebrospinal fluid (CSF), and plasma biomarkers used to assess gantenerumab treatment related changes on neuropathology, neurodegeneration, and neuroinflammation over 116 weeks.

RESULTS: Gantenerumab reduced amyloid PET load, CSF biomarkers of amyloid beta (Aβ)40, total tau (t-tau), phosphorylated tau 181 (p-tau181), neurogranin, S100 calcium-binding protein B (S100B), neurofilament light (NfL), alpha-synuclein (α-syn), neuronal pentraxin-2 (NPTX2), and plasma biomarkers of t-tau, p-tau181, p-tau217, and glial fibrillary acidic protein (GFAP) while increasing plasma Aβ40, Aβ42. vMRI showed increased reduction in whole brain volume and increased ventricular expansion, while hippocampal volume was unaffected. Tau PET showed no treatment effect.

DISCUSSION: Robust treatment effects were observed for multiple biomarkers in GRADUATE I and II. Comparison across anti-amyloid antibodies indicates utility of p-tau and GFAP as biomarkers of amyloid plaque removal while NfL and tau PET seem unsuitable as consistent indicators of clinical efficacy. vMRI might be confounded by non-neurodegenerative brain volume changes. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV IDENTIFIER): NCT03444870 and NCT03443973.

HIGHLIGHTS: Gantenerumab significantly reduced brain amyloid load. Tau positron emission tomography showed no treatment effect in a small subset of participants. Volumetric magnetic resonance imaging showed increased whole brain volume reduction under treatment while hippocampal volume was unaffected. Robust treatment effects on cerebrospinal fluid and plasma biomarkers were found, despite lack of clinical efficacy.}, } @article {pmid39887156, year = {2025}, author = {Ellakwa, DE and Rashed, LA and Ali, OS and El-Sabbagh, NA}, title = {A study to determine the effect of nano-selenium and thymoquinone on the Nrf2 gene expression in Alzheimer's disease.}, journal = {Future science OA}, volume = {11}, number = {1}, pages = {2458434}, pmid = {39887156}, issn = {2056-5623}, abstract = {INTRODUCTION: Alzheimer's disease is a developing public health concern in aging communities that affects a sizable section of the global population. The risk of Alzheimer's disease increases with age; it affects one-third of males and two-thirds of women[.] This research attempts to assess the effect of nano-selenium and thymoquinone on Nrf2 gene expression levels in Alzheimer's disease (AD).

METHODS: There were five identical groups of 50 albino male rats: a control group that was healthy; an AD positive control group; an AD group that received nano-selenium (5 mg/kg); an AD group that received thymoquinone (2 mg/kg); and an AD group that received both. The duration of treatment was 4 weeks. The levels of Nrf2 in brain tissues were evaluated using real-time PCR.

RESULTS: Nrf2 mean expression levels in the nano-selenium-treated rats, the thymoquinone-treated rats, and the rats that were given both treatments all increased significantly compared to AD rats with no treatment.

CONCLUSIONS: This study showed that nano-selenium and thymoquinone elevated Nrf2 gene expression levels in AD.}, } @article {pmid39886794, year = {2025}, author = {Gupta, B and Malviya, R and Sundram, S and Sridhar, SB and Singh, DP}, title = {Melatonin Overexpression in the Management of Alzheimer's Disease: Therapeutic Exploration.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266327614241121050448}, pmid = {39886794}, issn = {1873-4294}, abstract = {Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is characterized by the accumulation of neurofibrillary tangles and β-amyloid plaques, leading to a decline in cognitive function. AD is characterized by tau protein hyperphosphorylation and extracellular β-amyloid accumulation. Even after much research, there are still no proven cures for AD. The neuroprotective, anti-inflammatory, and antioxidant qualities of melatonin, a hormone mostly produced by the pineal gland, have drawn interest as a possible treatment option for AD. This study looks at new evidence that suggests melatonin overexpression to be a promising therapy option for AD. Melatonin levels naturally decline with age and decrease more significantly in individuals with AD, worsening neurodegenerative processes. Melatonin has therapeutic potential as it inhibits Aβ formation, prevents amyloid fibril extension through structure-dependent interactions, and protects neurons from Aβ-induced toxicity. Melatonin promotes neurogenesis, which is decreased in AD, suggesting it may treat the disease's many pathologies. The review emphasizes the importance of melatonin's mechanisms of action, including its capacity to reduce neuroinflammation, regulate mitochondrial function, scavenge free radicals, and influence apoptotic pathways. As research into AD continues, this article provides a forward-looking perspective on how future studies could leverage melatonin's multifaceted neuroprotective properties to develop more effective treatments for AD.}, } @article {pmid39886562, year = {2024}, author = {Nouh, CD and Younes, K}, title = {Diagnosis and Management of Progressive Corticobasal Syndrome.}, journal = {Current treatment options in neurology}, volume = {26}, number = {7}, pages = {319-338}, pmid = {39886562}, issn = {1092-8480}, support = {P30 AG066515/AG/NIA NIH HHS/United States ; }, abstract = {PURPOSE OF REVIEW: The purpose of this review is to discuss the clinical, radiological, and neuropathological heterogeneity of corticobasal syndrome (CBS), which can complicate the determination of underlying etiology and lead to inaccurate treatment decisions. Though the most common diagnosis is corticobasal degeneration (CBD), the spectrum of underlying pathologies expands beyond CBD and can overlap with other neurodegenerative diseases and even the neuroimmunology field. We will review possible clinical presentations and cues that can point towards the etiology. We will also discuss the most recent available biomarkers to facilitate a more accurate diagnosis. Additionally, we will examine current and future potential therapeutic options.

RECENT FINDINGS: The range of available fluid and neuroimaging biomarkers is increasing and some are already being used in clinical practice. While the treatment of neurodegenerative diseases is largely aimed at managing symptoms, early detection and accurate diagnosis are crucial for initiating early management and enrollment in clinical trials. The recent approval of a disease-modifying therapy for Alzheimer's disease (AD) has raised hopes for the development of more therapeutic options for other proteinopathies. Several candidates are currently being studied in clinical trial pipelines, particularly those targeting tau pathology.

SUMMARY: Recent advancements in understanding the genetic and neuropathological diversity of CBS, along with the promising development of fluid and imaging biomarkers, are driving clinical trial research forward, instilling optimism for creating more effective disease-modifying treatments for brain proteinopathies.}, } @article {pmid39886067, year = {2025}, author = {Vecchio, D and Piras, F and Natalizi, F and Banaj, N and Pellicano, C and Piras, F}, title = {Evaluating conversion from mild cognitive impairment to Alzheimer's disease with structural MRI: a machine learning study.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcaf027}, pmid = {39886067}, issn = {2632-1297}, abstract = {Alzheimer's disease is a disabling neurodegenerative disorder for which no effective treatment currently exists. To predict the diagnosis of Alzheimer's disease could be crucial for patients' outcome, but current Alzheimer's disease biomarkers are invasive, time consuming or expensive. Thus, developing MRI-based computational methods for Alzheimer's disease early diagnosis would be essential to narrow down the phenotypic measures predictive of cognitive decline. Amnestic mild cognitive impairment (aMCI) is associated with higher risk for Alzheimer's disease, and here, we aimed to identify MRI-based quantitative rules to predict aMCI to possible Alzheimer's disease conversion, applying different machine learning algorithms sequentially. At baseline, T1-weighted brain images were collected for 104 aMCI patients and processed to obtain 146 volumetric measures of cerebral grey matter regions [regions of interest (ROIs)]. One year later, patients were classified as converters (aMCI-c = 32) or non-converters, i.e. clinically and neuropsychologically stable (aMCI-s = 72) based on cognitive performance. Feature selection was performed by random forest (RF), and the identified seven ROIs volumetric data were used to implement support vector machine (SVM) and decision tree (DT) classification algorithms. Both SVM and DT reached an average accuracy of 86% in identifying aMCI-c and aMCI-s. DT found a critical threshold volume of the right entorhinal cortex (EC-r) as the first feature for differentiating aMCI-c/aMCI-s. Almost all aMCI-c had an EC-r volume <1286 mm[3], while more than half of the aMCI-s patients had a volume above the identified threshold for this structure. Other key regions for the classification between aMCI-c/aMCI-s were the left lateral occipital (LOC-l), the middle temporal gyrus and the temporal pole cortices. Our study reinforces previous evidence suggesting that the morphometry of the EC-r and LOC-l best predicts aMCI to Alzheimer's disease conversion. Further investigations are needed prior to deeming our findings as a broadly applicable predictive framework. However, here, a first indication was derived for volumetric thresholds that, being easy to obtain, may assist in early identification of Alzheimer's disease in clinical practice, thus contributing to establishing MRI as a useful non-invasive prognostic instrument for dementia onset.}, } @article {pmid39886010, year = {2024}, author = {Petersen, KK and Nallapu, BT and Lipton, RB and Grober, E and Ezzati, A}, title = {MRI-guided clustering of patients with mild dementia due to Alzheimer's disease using self-organizing maps.}, journal = {Neuroimage. Reports}, volume = {4}, number = {4}, pages = {}, pmid = {39886010}, issn = {2666-9560}, support = {R21 AG056920/AG/NIA NIH HHS/United States ; R01 AG062622/AG/NIA NIH HHS/United States ; R01 AG048642/AG/NIA NIH HHS/United States ; K23 AG063993/AG/NIA NIH HHS/United States ; U10 NS077308/NS/NINDS NIH HHS/United States ; RF1 AG054548/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; R01 AG060933/AG/NIA NIH HHS/United States ; U24 NS113847/NS/NINDS NIH HHS/United States ; UG3 FD006795/FD/FDA HHS/United States ; R56 AG057548/AG/NIA NIH HHS/United States ; RF1 AG057531/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a phenotypically and pathologically heterogenous neurodegenerative disorder. This heterogeneity can be studied and disentangled using data-driven clustering techniques.

METHODS: We implemented a self-organizing map clustering algorithm on baseline volumetric MRI measures from nine brain regions of interest (ROIs) to cluster 1041 individuals enrolled in the placebo arm of the EXPEDITION3 trial. Volumetric MRI differences were compared among clusters. Demographics as well as baseline and longitudinal cognitive performance metrics were used to evaluate cluster characteristics.

RESULTS: Three distinct clusters, with an overall silhouette coefficient of 0.491, were identified based on MRI volumetrics. Cluster 1 (N = 400) had the largest baseline volumetric measures across all ROIs and the best cognitive performance at baseline. Cluster 2 (N = 269) had larger hippocampal and medial temporal lobe volumes, but smaller parietal lobe volumes in comparison with the third cluster (N = 372). Significant between-group mean differences were observed between Clusters 1 and 2 (difference, 2.38; 95% CI, 1.85 to 2.91; P < 0.001), Clusters 1 and 3 (difference, 1.93; 95% CI, 1.41 to 2.44; P < 0.001), but not between Clusters 2 and 3 (difference, 0.45; 95% CI, -0.11 to 1.02; P = 0.146) in ADAS-14.

CONCLUSIONS: Volumetric MRI can be used to identify homogenous clusters of amyloid positive individuals with mild dementia. The groups identified differ in baseline and longitudinal characteristics. Cluster 1 shows little ADAS-14 change over the first 40 weeks of study on placebo treatment and may be unsuitable for identifying early benefits of treatment.}, } @article {pmid39885146, year = {2025}, author = {Fang, LP and Lin, CH and Medlej, Y and Zhao, R and Chang, HF and Guo, Q and Wu, Z and Su, Y and Zhao, N and Gobbo, D and Wyatt, A and Wahl, V and Fiore, F and Tu, SM and Boehm, U and Huang, W and Bian, S and Agarwal, A and Lauterbach, MA and Yi, C and Niu, J and Scheller, A and Kirchhoff, F and Bai, X}, title = {Oligodendrocyte precursor cells facilitate neuronal lysosome release.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1175}, pmid = {39885146}, issn = {2041-1723}, support = {BA 8014/1-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; SFB1158//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; SPP 1757//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; HOMFORexzellent2018//Universität des Saarlandes (Saarland University)/ ; NanoBioMed Young Investigator grant 2021//Universität des Saarlandes (Saarland University)/ ; GradUS global2019 and 2020//Universität des Saarlandes (Saarland University)/ ; Mini-proposal of SFB1027//Universität des Saarlandes (Saarland University)/ ; HOMFORexzellent2020//Universität des Saarlandes (Saarland University)/ ; NanoBioMed Young Investigator grant 2020//Universität des Saarlandes (Saarland University)/ ; H2020-MSCA-ITN EU-GliaPhD//European Commission (EC)/ ; }, mesh = {Animals ; *Lysosomes/metabolism ; *Oligodendrocyte Precursor Cells/metabolism/cytology ; *Neurons/metabolism ; Mice ; *Alzheimer Disease/metabolism/pathology ; Exocytosis/physiology ; Oligodendroglia/metabolism/cytology ; Mice, Inbred C57BL ; Humans ; Disease Models, Animal ; Male ; Cells, Cultured ; }, abstract = {Oligodendrocyte precursor cells (OPCs) shape brain function through many non-canonical regulatory mechanisms beyond myelination. Here we show that OPCs form contacts with their processes on neuronal somata in a neuronal activity-dependent manner. These contacts facilitate exocytosis of neuronal lysosomes. A reduction in the number or branching of OPCs reduces these contacts, which is associated with lysosome accumulation and altered metabolism in neurons and more senescent neurons with age. A similar reduction in OPC branching and neuronal lysosome accumulation is seen in an early-stage mouse model of Alzheimer's disease. Our findings have implications for the prevention of age-related pathologies and the treatment of neurodegenerative diseases.}, } @article {pmid39884636, year = {2025}, author = {Bajad, NG and Jangra, J and T A, G and Kumar, A and Krishnamurthy, S and Singh, SK}, title = {Discovery of pyrazoline analogs as multi-targeting cholinesterase, β-secretase and Aβ aggregation inhibitors through lead optimization strategy.}, journal = {International journal of biological macromolecules}, volume = {301}, number = {}, pages = {140436}, doi = {10.1016/j.ijbiomac.2025.140436}, pmid = {39884636}, issn = {1879-0003}, abstract = {The multi-target directed ligands (MTDLs) strategy has been evolved as the propitious approach for the development of therapeutics for Alzheimer's disease (AD). In an earlier report, we described the novel series of chalcone derivatives bearing N-aryl piperazine scaffold as MTDLs for the treatment of AD. Herein, we report the lead optimization of the series culminating in potent, multi-targeting compounds (32-57), evaluated through in-vitro and in-vivo biological studies. The optimal compound 48 exhibited potent inhibitory activities against AChE (IC50 = 2.89 ± 0.706 μM), BuChE (IC50 = 0.151 ± 0.089 μM), along with BACE-1 (% inhibition = 36.64 ± 1.343 %) and amyloid-β aggregation inhibition. Compound 48 showed excellent blood-brain barrier permeability (Pe = 7.28 ± 0.474 × 10[-6] cm s[-1]) in PAMPA assay and was found safe in the in vivo acute oral toxicity study. The molecular binding interaction pattern and protein-ligand stability was displayed by lead compound 48 with selected targets. Furthermore, in-vivo behavioural studies demonstrated the amelioration of cognitive dysfunctions and significant memory improvement in Y-maze test (scopolamine-induced amnesia model) in mice on the administration of compound 48 at a dose of 20 mg/kg. The reduction in the level of AChE and increased in ACh activity was observed in ex vivo biochemical analysis. Moreover, compound 48 displayed antioxidant potential on measurement of catalase (CAT) and malondialdehyde (MDA) activity in ex vivo analysis. We anticipate that compound 48, from the pyrazoline series, may be a lead molecule for the discovery of safe and effective therapeutic agents for AD.}, } @article {pmid39884492, year = {2025}, author = {Pinky, and Anwar, S and Neha, and Parvez, S}, title = {Paeoniflorin inhibits pyruvate dehydrogenase kinase 3 and promotes BDNF activity by modulating neuronal activity and TNF-α.}, journal = {Brain research}, volume = {1851}, number = {}, pages = {149476}, doi = {10.1016/j.brainres.2025.149476}, pmid = {39884492}, issn = {1872-6240}, abstract = {Metabolic dysregulation causes diseases like diabetes and cancer, making PDKs attractive targets. However, a thorough investigation into the unique roles played by the different members of the PDK family, especially PDK3, about memory loss and related diseases like Alzheimer's disease (AD) is still lacking. The current study investigates PF's potential to reduce PDK3-associated toxicity in neurodegenerative illnesses, including AD. The association between PF and PDK3 presents a significant opportunity for medication development and AD therapy approaches. PF efficiently suppresses PDK3 activity, as demonstrated by molecular docking and biophysical characterization, providing an in-depth understanding of their molecular interactions. PF significantly inhibited PDK3 in a concentration-dependent manner with an IC50 value of 4.88 µM. Considering this, the current investigation also explores the biological component of PF, which exhibits potential in treating AD and is primarily associated with neuroprotection. In the present study, a 3-hour pre-treatment of PF was administered at varying concentrations (4, 6, and 8 µM) in response to the 24-hour SCP (2 mM)-mediated toxicity. Based on the results of in silico and biophysical characterization, it is concluded that PF inhibits the PDK3 activity. Additionally, it can enhance cell viability, suppress ROS expression, impede apoptosis, and downregulate TNF-α expression. When combined, these actions help to prevent neuronal death in an in vitro model of SCP. PF strengthens the memory marker, which is confirmed through BDNF expression. This study found that all results were more effective at lower and moderate doses of PF. Our research indicates that PF boosts memory, decelerates the progression of oxidative stress, and could potentially serve as a dose-dependent treatment for AD.}, } @article {pmid39884484, year = {2025}, author = {Lai, B and Wu, D and Xiao, Q and Wang, Z and Niu, Q and Chen, Q and Long, Q and He, L}, title = {Qiangji decoction mitigates neuronal damage, synaptic and mitochondrial dysfunction in SAMP8 mice through the regulation of ROCK2/Drp1-mediated mitochondrial dynamics.}, journal = {Journal of ethnopharmacology}, volume = {342}, number = {}, pages = {119424}, doi = {10.1016/j.jep.2025.119424}, pmid = {39884484}, issn = {1872-7573}, abstract = {Qiangji Decoction (QJD), a Chinese medicine, is widely used in Traditional Chinese Medicine to treat amnesia and Alzheimer's disease (AD), showing significant anti-AD effects. However, the precise mechanisms behind these effects are not well understood and require more research.

AIM OF THE STUDY: This study aims to elucidate the mechanisms by which QJD ameliorates neuronal damage, synaptic dysfunction, and mitochondrial impairment in AD through the regulation of ROCK2/Drp1-mediated mitochondrial dynamics.

MATERIALS AND METHODS: UPLC-Q-TOF-MS/MS was used to identify active components in QJD extract. The study used SAMP8 mice for AD modeling and SAMR1 mice as controls. Cognitive function in SAMP8 mice was assessed with the Morris Water Maze after following treatment with QJD and the mitochondrial fission inhibitor Mdivi-1. Nissl and FJB staining evaluated QJD's effect on hippocampal injury. Synaptic integrity was examined with Golgi-Cox staining, transmission electron microscopy, and immunofluorescence. Mitochondrial function in hippocampal neurons was assessed using electron microscopy, JC-1 staining, and reagent kits. Western blot analyzed expression of proteins related to mitochondrial fission (ROCK2, Drp1, Fis1, Mff) and fusion (Mfn1, Mfn2, OPA1).

RESULTS: The analysis of QJD extract via UPLC-Q-TOF-MS/MS led to the identification of 46 active compounds. In SAMP8 mice, administration of QJD resulted in decreased escape latency, increased platform crossings, and extended duration in the target quadrant. Additionally, QJD exhibited neuroprotective effects on the hippocampus of SAMP8 mice, effectively preventing neuronal loss and damage. QJD also facilitated the extension and thickening of dendritic spines, enhanced the ultrastructure of hippocampal synapses, and upregulated synaptic function-related proteins, including PSD95 and SYN1. Furthermore, QJD ameliorated mitochondrial damage, improved mitochondrial membrane potential and ATP content, and reduced ROS expression in hippocampal neurons of SAMP8 mice. These effects were mediated through the downregulation of ROCK2, phosphorylated Drp1 (Ser616), Fis1, and Mff, as well as the upregulation of Mfn1, Mfn2, and OPA1.

CONCLUSIONS: QJD may reduce neuronal damage, synaptic dysfunction, and mitochondrial impairment in SAMP8 mice by regulating mitochondrial dynamics through the ROCK2/Drp1 pathway.}, } @article {pmid39884096, year = {2025}, author = {He, F and Guo, Y and Shen, X and Li, L and Li, D and Liu, X and Gao, P}, title = {Design and synthesis three novel series of derivatives using natural acetylcholinesterase inhibitor-RLMS as template and in vitro, in vivo and in silico activities verification.}, journal = {European journal of medicinal chemistry}, volume = {286}, number = {}, pages = {117309}, doi = {10.1016/j.ejmech.2025.117309}, pmid = {39884096}, issn = {1768-3254}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Drug Design ; Humans ; *Acetylcholinesterase/metabolism ; Animals ; *Zebrafish ; Structure-Activity Relationship ; *Molecular Docking Simulation ; Molecular Structure ; Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; Dose-Response Relationship, Drug ; Cell Line, Tumor ; Alzheimer Disease/drug therapy ; Biological Products/pharmacology/chemistry/chemical synthesis ; Apoptosis/drug effects ; }, abstract = {Acetylcholinesterase (AChE) is a pivotal enzyme in nerve conduction, controlling its activity with its inhibitor (AChEI) is crucial for the treatment of Alzheimer's disease (AD). However, current AChEIs are associated with considerable adverse effects. Previous work has identified 2α,3β,19α,23-tetrahydroxy-12-ene-28-oic acid (RLMS) as a promising natural AChEI. This study synthesized three novel series of AChEIs to elucidate the interaction mechanisms between the title enzyme and RLMS. Among the compounds, 1 and 22 emerged as the most potent and selective inhibitors exhibiting both irreversible and mixed competitive inhibition types against AChE. Molecular docking studies at the AChE active sites revealed binding modes that justify its potent enzyme inhibitory effects. Additionally, molecular dynamic simulations demonstrated robust and stable interactions of 1 and 22 with the binding sites of their target. In vitro assays showed derivates, especially 22, exhibited potential neuroprotective activities on H2O2-induced SH-SY5Y cell injury model. In vivo experiments showed that zebrafish models of AD treated with varying concentrations of 22 displayed obviously increased movement distance and speed, notably, at 25 μM level, 22 effectively reduced apoptosis in zebrafish brain cells. Collectively, this research delineates the intricate relationship between AChE and 22, suggesting its potential as a therapeutic agent for combating AD.}, } @article {pmid39883631, year = {2025}, author = {Guerguer, FZ and Rossafi, B and Abchir, O and Raouf, YS and Albalushi, DB and Samadi, A and Chtita, S}, title = {Potential Azo-8-hydroxyquinoline derivatives as multi-target lead candidates for Alzheimer's disease: An in-depth in silico study of monoamine oxidase and cholinesterase inhibitors.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0317261}, pmid = {39883631}, issn = {1932-6203}, mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy ; *Monoamine Oxidase Inhibitors/chemistry/pharmacology/therapeutic use ; *Monoamine Oxidase/metabolism/chemistry ; Humans ; *Molecular Dynamics Simulation ; *Molecular Docking Simulation ; *Acetylcholinesterase/chemistry/metabolism ; Butyrylcholinesterase/metabolism/chemistry ; Oxyquinoline/chemistry/analogs & derivatives ; Computer Simulation ; Azo Compounds/chemistry/pharmacology ; }, abstract = {Cognitive dysfunction in Alzheimer's disease results from a complex interplay of various pathological processes, including the dysregulation of key enzymes such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidase B (MAO-B). This study proposes and designs a series of novel molecules derived from 8-hydroxyquinoline (Azo-8HQ) as potential multi-target lead candidates for treating AD. An exhaustive in silico analysis was conducted, encompassing docking studies, ADMET analysis, density functional theory (DFT) studies, molecular dynamics simulations, and subsequent MM-GBSA calculations to examine the pharmacological potential of these molecules with the specific targets of interest. Out of the 63 Azo-8HQ derivatives analysed, two molecules, 14c and 17c, demonstrated strong affinities for AChE, BuChE, and MAO-B, along with favourable pharmacokinetic profiles and electronic properties. Molecular dynamics simulations confirmed the stability of these molecules within the active sites of the targets, and MM-GBSA calculations revealed low binding energies, indicating robust interactions. These findings identify molecules 14c and 17c as promising multi-target candidates for the treatment of AD, based on an in-depth computational study aimed at minimizing drug development costs and time. Future work will include the synthesis of these molecules followed by in-depth in vitro and in vivo testing to validate their potential therapeutic efficacy.}, } @article {pmid39882364, year = {2024}, author = {Sun, X and Zhu, J and Li, R and Peng, Y and Gong, L}, title = {The global research of magnetic resonance imaging in Alzheimer's disease: a bibliometric analysis from 2004 to 2023.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1510522}, pmid = {39882364}, issn = {1664-2295}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disorder worldwide and the using of magnetic resonance imaging (MRI) in the management of AD is increasing. The present study aims to summarize MRI in AD researches via bibliometric analysis and predict future research hotspots.

METHODS: We searched for records related to MRI studies in AD patients from 2004 to 2023 in the Web of Science Core Collection (WoSCC) database. CiteSpace was applied to analyze institutions, references and keywords. VOSviewer was used for the analysis of countries, authors and journals.

RESULTS: A total of 13,659 articles were obtained in this study. The number of published articles showed overall exponential growth from 2004 to 2023. The top country and institution were the United States and the University of California System, accounting for 40.30% and 9.88% of the total studies, respectively. Jack CR from the United States was the most productive author. The most productive journal was the Journal of Alzheimers Disease. Keyword burst analysis revealed that "machine learning" and "deep learning" were the keywords that frequently appeared in the past 6 years. Timeline views of the references revealed that "#0 tau pathology" and "#1 deep learning" are currently the latest research focuses.

CONCLUSION: This study provides an in-depth overview of publications on MRI studies in AD. The United States is the leading country in this field with a concentration of highly productive researchers and high-level institutions. The current research hotspot is deep learning, which is being applied to develop noninvasive diagnosis and safer treatment of AD.}, } @article {pmid39880699, year = {2025}, author = {Dumurgier, J and Paquet, C and Hugon, J and Planche, V and Gaubert, S and Epelbaum, S and Bombois, S and Teichmann, M and Levy, R and Baudouin, E and Vrillon, A and Hourrègue, C and Cognat, E and Sabia, S and Singh-Manoux, A}, title = {MemScreen: A smartphone application for detection of mild cognitive impairment: A validation study: Smartphone App for MCI Detection.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100077}, doi = {10.1016/j.tjpad.2025.100077}, pmid = {39880699}, issn = {2426-0266}, abstract = {BACKGROUND AND OBJECTIVES: Primary care is often the first point of contact for patients with cognitive complaints, making initial cognitive screening an essential step to avoid delays in diagnosing Alzheimer's disease (AD) at an early stage. We developed MemScreen, a self-administered smartphone application that assesses overall cognition and verbal memory, and evaluated its ability to detect mild cognitive impairment (MCI) in both general and clinical populations.

METHODS: We conducted two validation cohort studies: (1) UK-based Whitehall II cohort study (13th wave, 2018-2022) involving a general population (MCI defined by poor performance on a global cognitive score), and (2) five French memory clinics involving patients without dementia (amnestic MCI defined by the Free and Cued Selective Reminding Test). MemScreen, MMSE, and TMT-A effectiveness was assessed using Area Under the Curve (AUC) values from unadjusted and adjusted logistic regression models.

RESULTS: In Whitehall II (n = 2118, mean age 75.9 years, 23.9 % women, 14.5 % MCI), median MemScreen completion time was 4 min 18 s. MemScreen had the highest AUC (0.87; 95 % CI: 0.82-0.89) for distinguishing MCI, outperforming MMSE (AUC = 0.79; 0.76-0.82; p = 0.018) and TMT-A (AUC = 0.77; 0.74-0.80; p = 0.023). MemScreen sensitivity and specificity were 78.6 % and 78.7 %, respectively. In memory clinics (n = 303, mean age 70.5 years, 53 % women, 46.9 % amnestic MCI), median completion time was 5 min 17 s. MemScreen showed superior performance (AUC = 0.87; 0.83-0.91) compared to MMSE (AUC = 0.72; 0.67-0.78; p < 0.001) and TMT-A (AUC = 0.63; 0.56-0.69; p < 0.001), with 93.0 % sensitivity and 54.0 % specificity for amnestic MCI.

DISCUSSION: MemScreen outperformed traditional tests in identifying MCI in both general and clinical populations. Its self-administration and short completion time suggest potential as an effective screening tool to optimize memory clinic referrals for AD diagnosis and treatment.}, } @article {pmid39880333, year = {2025}, author = {Izrael, M and Chebath, J and Molakandov, K and Revel, M}, title = {Clinical perspective on pluripotent stem cells derived cell therapies for the treatment of neurodegenerative diseases.}, journal = {Advanced drug delivery reviews}, volume = {218}, number = {}, pages = {115525}, doi = {10.1016/j.addr.2025.115525}, pmid = {39880333}, issn = {1872-8294}, abstract = {Self-renewal capacity and potential to differentiate into almost any cell type of the human body makes pluripotent stem cells a valuable starting material for manufacturing of clinical grade cell therapies. Neurodegenerative diseases are characterized by gradual loss of structure or function of neurons, often leading to neuronal death. This results in gradual decline of cognitive, motor, and physiological functions due to the degeneration of the central nervous systems. Over the past two decades, comprehensive preclinical efficacy (proof-of-concept) and safety studies have led to the initiation of First-in-Human phase I-II clinical trials for a range of neurodegenerative diseases. In this review, we explore the fundamentals and challenges of neural-cell therapies derived from pluripotent stem cells for treating neurodegenerative diseases. Additionally, we highlight key preclinical investigations that paved the way for regulatory approvals of these trials. Furthermore, we provide an overview on progress and status of clinical trials done so far in treating neurodegenerative diseases such as spinal cord injury (SCI), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), as well as advances in retina diseases such as Stargardt disease (a.k.a fundus flavimaculatus), retinitis pigmentosa (RP) and age-related macular degeneration (AMD). These trials will pave the way for the development of new cell-based therapies targeting additional neurological conditions, including Alzheimer's disease and epilepsy.}, } @article {pmid39878947, year = {2025}, author = {Zhang, Y and Sereika, S and Seaman, J and Pettigrew, C and Albert, M and Lingler, J}, title = {Caregivers' Perspectives on Discussions of Medical Treatment Preferences for People Living with Dementia Are Associated with Their Dementia Health Literacy and the Caregiving Relationship.}, journal = {The Gerontologist}, volume = {}, number = {}, pages = {}, doi = {10.1093/geront/gnaf033}, pmid = {39878947}, issn = {1758-5341}, abstract = {BACKGROUND AND OBJECTIVES: People living with dementia experience progressive functional decline and increased dependence on caregivers. This study examined the influence of caregivers' dementia health literacy on perceptions of medical care preferences and advanced care planning (ACP) in people living with dementia.

RESEARCH DESIGN AND METHODS: This analysis used data from a cross-sectional survey, "Care Planning for Individuals with Dementia", administered nationwide by Alzheimer's Disease Centers. We conducted binary, ordinal, and multinomial logistic regression.

RESULTS: On average, surveyed caregivers (n=431) were 78.3 years, had 16 years of education, and were mainly white (88.5%). Most lived with (76.8%) and were the designated healthcare proxy (95.1%), with high dementia knowledge scores (mean=8.4/10). As caregivers' dementia knowledge scores increased, they were 1.27 times more likely (p=0.02) to endorse comfort care. Caregivers with greater knowledge about severe dementia were less likely to need further treatment preference-related discussions (knowing a lot: OR=0.17, p<0.001; knowing some things: OR=0.37, p=0.006). Caregivers live apart from patients were 2.71 times more likely to know about such discussions (p<0.001). Caregivers of people in earlier stages endorsed greater needs for further conversations with clinicians (no impairment & MCI: OR=7.38, p=0.002; mild impairment: OR=5.32, p=0.005) and their care recipients (no impairment & MCI: OR=5.24, p=0.02).

DISCUSSION AND IMPLICATIONS: These findings highlight the role of dementia-specific education in ACP discussions among people living with dementia, caregivers, and healthcare clinicians. These findings are important since evidence suggests that ACP may promote quality of life, reduce iatrogenic harm, minimize healthcare overutilization, and alleviate care-related burdens.}, } @article {pmid39878879, year = {2025}, author = {Du, K and Su, Y and Song, Q and Chen, S and Wu, R and Teng, X and Huang, R and Wang, L and Zou, C}, title = {2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione protects against MPP[+]-induced neurotoxicity by ameliorating oxidative stress, apoptosis and autophagy in SH-SY5Y cells.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {113}, pmid = {39878879}, issn = {1573-7365}, support = {2024JJA140684 and 2024JJA141221//the Joint Project on Regional High-Incidence Diseases Research of Guangxi Natural Science Foundation/ ; Guike AB2302602//Guangxi Key Technologies R&D Program/ ; 81971191 and 81670750//National Natural Science Foundation of China/ ; 2014GXNSFDA118030//Guangxi Natural Science Foundation/ ; ZR2019ZD39//Natural Science Foundation of Shandong Province/ ; }, mesh = {Humans ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; *Autophagy/drug effects ; *Neuroprotective Agents/pharmacology ; Cell Line, Tumor ; *1-Methyl-4-phenylpyridinium/toxicity ; Reactive Oxygen Species/metabolism ; Cell Survival/drug effects ; }, abstract = {2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) is a cyclohexanedione compound extracted from the roots of Averrhoa carambola L. Several studies have documented its beneficial effects on diabetes, Alzheimer's disease, and cancer. However, its potential neuroprotective effects on Parkinson's disease (PD) have not yet been explored. The present study aimed to investigate the protective effects and underlying mechanisms of DMDD in a cellular model of PD. In this study, SH-SY5Y cells were incubated with or without DMDD following intoxication with the parkinsonian neurotoxin 1-methyl-4-phenylpyridine (MPP[+]). Cell viability and apoptosis were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium (MTS) assay and Hoechst 33,342 staining, respectively. The mitochondrial membrane potential (Δψm) was assessed through the JC-10 assay. The activities of superoxide dismutase (SOD) and the levels of reactive oxygen species (ROS) were measured using WST-8 and DCFH-DA assays. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore significant biological processes and pathways influenced by DMDD. Molecular docking was employed to predict the domains of potential protein targets interacting with DMDD. Western blotting was subsequently conducted to determine the protein expression levels of TH, Nrf2, Bax, Bcl-2, Caspase-3, Beclin-1, PARP, LC3-II, LC3-I, p-PI3K, PI3K, p-mTOR and mTOR. Our study showed that DMDD treatment significantly increased cell viability and reduced apoptosis in MPP[+]-treated SH-SY5Y cells. In addition, DMDD treatment reversed the loss of TH expression and Δψm in MPP[+]-exposed SH-SY5Y cells. Moreover, DMDD treatment reduced MPP+-induced ROS production by promoting SOD activity. Additionally, compared with those in the MPP[+] group, the protein expression levels of Beclin-1, Caspase-3, and PARP and the LC3II/I ratio were significantly decreased, whereas the protein expression levels of Nrf2 and the Bcl-2/Bax, p-PI3K/PI3K, and p-mTOR/mTOR ratios were significantly increased in the DMDD-treated group. In conclusion, DMDD protects against MPP[+]-induced cytotoxicity by mitigating oxidative stress, apoptosis, and autophagy. PI3K/mTOR signaling at least partly mediates the cytoprotective effect of DMDD.}, } @article {pmid39878109, year = {2025}, author = {Mir, M and Khosravani, P and Ramezannezhad, E and Saadabad, FP and Falahati, M and Ghanbarian, M and Saberian, P and Sadeghi, M and Niknam, N and Ghejelou, SE and Jafari, M and Gulisashvili, D and Mayeli, M}, title = {Association Between Metabolomics Findings and Brain Hypometabolism in Mild Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050350196250110092338}, pmid = {39878109}, issn = {1875-5828}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative condition with rising prevalence due to the aging global population. Existing methods for diagnosing AD are struggling to detect the condition in its earliest and most treatable stages. One early indicator of AD is a substantial decrease in the brain's glucose metabolism. Metabolomics can detect metabolic disturbances in biofluids, which may be advantageous for early detection of some ADrelated changes. The study aims to predict brain hypometabolism in Alzheimer's disease using metabolomics findings and develop a predictive model based on metabolomic data.

METHODS: The data used in this study were acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI) project. We conducted a longitudinal cohort study with three assessment time points to investigate the predictive ability of baseline metabolomic data for modeling longitudinal fluorodeoxyglucose-positron emission tomography (FDG-PET) trajectory changes in AD patients. A total number of 44 participants with AD were included. The cognitive abilities of participants were evaluated using the Alzheimer's Disease Assessment Scale (ADAS) and the Mini-Mental State Examination (MMSE), while the overall severity of dementia was measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB). We employed the ADNI's FDG MetaROIs (Meta Regions of Interest) dataset to identify AD-associated hypometabolism in the brain. These MetaROIs were selected based on areas frequently mentioned in FDG-PET studies of AD and MCI subjects.

RESULTS: Across models, we observed consistent positive relationships between specific cholesterol esters - CE (20:3) (p = 0.005) and CE (18:3) (p = 0.0039) - and FDG-PET metrics, indicating these baseline metabolites may be valuable indicators of future PET score changes. Selected triglycerides like DG-O (16:0-20:4) also showed time-specific positive associations (p = 0.017).

CONCLUSION: This research provides new insights into the disruptions in the metabolic network linked to AD pathology. These findings could pave the way for identifying novel biomarkers and potential treatment targets for AD.}, } @article {pmid39878108, year = {2025}, author = {Wang, C and Chen, X and Yu, Z}, title = {Trafficking of Muscarinic 1 Acetylcholine Receptor Regulated by VPS35 in Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050356990250111200217}, pmid = {39878108}, issn = {1875-5828}, abstract = {INTRODUCTION: Muscarinic 1 acetylcholine receptor (M1AChR) is a member of the Gprotein- coupled receptor superfamily, with the dysfunction being linked to the onset of Alzheimer's Disease (AD).

AIMS: Retromer complex with Vacuolar Protein Sorting-35 (VPS35) as the core plays an important role in the transport of biological proteins and has been confirmed to be closely related to the pathogenesis of AD. This study was designed to determine whether VPS35 could affect the trafficking mechanism of M1AChRs.

METHOD: The interaction between VPS35 and M1AChR was studied by co-immunoprecipitation method, and the recycling of M1AChR influence by VPS35 was analyzed using biotinylation technology.

RESULTS: It was found that VPS35 affected the localization of M1AChR on the cell membrane by regulating intracellular M1AChR transport, thus controlling the M1AChR-mediated cholinergic signaling pathway.

CONCLUSION: The findings presented here provide a potential pathogenesis and pathway for the treatment of AD.}, } @article {pmid39878107, year = {2025}, author = {Mehrabadi, S}, title = {Extracellular Vesicles: A Promising Therapeutic Approach to Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050365314250112042136}, pmid = {39878107}, issn = {1875-5828}, abstract = {Extracellular vesicles (EVs) are nano-sized membranous particles that are secreted by various cell types and play a critical role in intercellular communication. Their unique properties and remarkable ability to deliver bioactive cargo to target cells have made them promising tools in the treatment of various diseases, including Alzheimer's disease (AD). AD is a devastating neurodegenerative disease characterized by progressive cognitive decline and neuropathological hallmarks, such as amyloid-beta plaques and neurofibrillary tangles. Despite extensive research, no disease-modifying therapy for AD is currently available. However, EVs have emerged as a potential therapeutic agent in AD due to their ability to cross the blood-brain barrier, deliver bioactive cargo, and modulate neuroinflammation. This review provides a comprehensive overview of the current knowledge on the role of EVs in AD and discusses their potential as a therapeutic approach. It covers the mechanisms of action, potential therapeutic targets, and challenges and limitations of EV-based therapies for AD.}, } @article {pmid39877983, year = {2025}, author = {Thirumalai, S and Livesey, FJ and Patani, R and Hung, C}, title = {APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC-derived trisomy 21 astrocytes.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14560}, pmid = {39877983}, issn = {1552-5279}, support = {//Alzheimer's Research UK/ ; }, mesh = {Humans ; *Induced Pluripotent Stem Cells/drug effects ; *Down Syndrome/metabolism ; *Astrocytes/drug effects/metabolism ; *Mitochondria/drug effects/metabolism ; *Amyloid beta-Protein Precursor/genetics ; *Oligonucleotides, Antisense/pharmacology ; Phenotype ; Cell Differentiation/drug effects ; Alzheimer Disease/metabolism ; Cells, Cultured ; Superoxides/metabolism ; }, abstract = {INTRODUCTION: Antisense oligonucleotides (ASOs) have shown promise in reducing amyloid precursor protein (APP) levels in neurons, but their effects in astrocytes, key contributors to neurodegenerative diseases, remain unclear. This study evaluates the efficacy of APP ASOs in astrocytes derived from an individual with Down syndrome (DS), a population at high risk for Alzheimer's disease (AD).

METHODS: Human induced pluripotent stem cells (hiPSCs) from a healthy individual and an individual with DS were differentiated into astrocytes. Astrocytes were treated with APP ASOs for 10 days, and APP levels were quantified. Mitochondrial morphology and superoxide production in DS astrocytes were analyzed using super-resolution and confocal microscopy.

RESULTS: APP ASOs significantly reduced APP levels in astrocytes from both control and DS individuals. In DS astrocytes, treatment restored mitochondrial health, increasing mitochondrial number and size while reducing superoxide production.

DISCUSSION: APP ASOs effectively reduce APP levels and improve mitochondrial health in astrocytes, suggesting their potential as a therapeutic approach for DS and DS-related AD. Further in vivo studies are required to confirm these findings.

HIGHLIGHTS: APP ASOs reduce APP levels in human iPSC-derived astrocytes. APP ASO treatment rescues mitochondrial phenotypes in trisomy 21 astrocytes. This study supports ASOs as a potential therapy for Down syndrome-related Alzheimer's disease.}, } @article {pmid39877657, year = {2024}, author = {Wang, J and Bai, X and Chen, X and Liu, S and Sun, M and Li, K and Zheng, Y and Wang, Z}, title = {Effects of acupuncture at the Taichong (LIV3) and Hegu (LI4) points on functional connectivity with the retrosplenial cortex in patients with Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1511183}, pmid = {39877657}, issn = {1662-4548}, abstract = {BACKGROUND: Acupuncture has been demonstrated to have a promising effect on Alzheimer's disease (AD), but the underlying neural mechanisms remain unclear. The retrosplenial cortex (RSC) is one of the earliest brain regions affected in AD, and changes in its functional connectivity (FC) are reported to underlie disease-associated memory impairment. The aim of this study was to examine the effect of acupuncture on FC with the RSC in patients with AD.

METHODS: Demographic data, neuropsychological assessments, and resting-state functional magnetic resonance imaging (fMRI) data were collected from 14 AD patients and 14 normal controls (NCs) matched by age, sex, and educational level at baseline. After the baseline MRI scan, acupuncture stimulation on the Taichong (LIV3) and Hegu (LI4) points was performed for 3 min. Then, another 10 min of fMRI data were acquired after the needle was withdrawn. A dataset that included 100 healthy participants was also included to construct a reliable FC map of the RSC. Two sets of regions of interest (ROIs) in the RSC were selected to assess the sustained effect of acupuncture on FC with the RSC in AD patients and NCs.

RESULTS: Two sets of RSC ROI-based analyses demonstrated robust positive connectivity with the hippocampus (HPC). Furthermore, multiple brain regions, including the bilateral thalamus, bilateral posterior cingulate cortex (PCC), bilateral subcallosal cingulate gyrus (SCG), bilateral orbitofrontal cortex (OFC), and right precuneus, showed decreased FC with the RSC in the AD group and increased FC with the RSC in the NC group after acupuncture compared to that at baseline. Acupuncture also specifically elicited increased FC between the RSC and the HPC as well as between the RSC and the parahippocampal gyrus in AD patients and decreased FC between the RSC and the visual cortices in NCs. Additionally, diminished FC with the RSC was correlated with neuropsychological scale scores in the AD group before acupuncture treatment.

CONCLUSION: These findings confirm and extend previous studies suggesting that acupuncture at Taichong (LIV3) and Hegu (LI4) can exert bidirectional and benign regulatory effects on RSC connectivity in AD patients.}, } @article {pmid39877076, year = {2024}, author = {Shu, H and Ding, G and Xu, X and Huang, X and He, R}, title = {Association of CSF soluble TREM1 levels with hippocampal atrophy in cognitively impaired older adults.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1481526}, pmid = {39877076}, issn = {1663-4365}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; RF1 AG053303/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; RF1 AG074007/AG/NIA NIH HHS/United States ; U01 AG058922/AG/NIA NIH HHS/United States ; R01 AG044546/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; RF1 AG058501/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Recent studies have shown that cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 1 (sTREM1) are elevated in individuals with Alzheimer's disease (AD), though the relationship between CSF sTREM1 and hippocampal atrophy remains to be elucidated. The primary aim of this study was to investigate the association between CSF sTREM1 levels and longitudinal changes in hippocampal volumes, and to determine if this relationship is moderated by cognitive status.

METHODS: We included 576 participants, comprising 152 cognitively unimpaired (CU) and 424 cognitively impaired (CI) individuals. In the cross-sectional analyses, Pearson's correlation tests were conducted to examine the relationship between baseline CSF sTREM1 levels and hippocampal volumes in both CU and CI participants. For the longitudinal analyses, a linear mixed-effects model was employed to assess the significance of the three-way interaction between CSF sTREM1 levels, cognitive status, and follow-up time on adjusted hippocampal volume (aHV). Further stratified analyses based on cognitive status were performed to dissect the specific effects within each group.

RESULTS: Our findings revealed significantly elevated baseline CSF sTREM1 levels in CI participants compared to CU participants. Cross-sectional analyses demonstrated that CSF sTREM1 levels were negatively associated with hippocampal volumes in both CU and CI participants. In the longitudinal analyses, the three-way interaction between CSF sTREM1 levels, cognitive status, and follow-up time was found to be significant for aHV. Stratified analyses indicated that, in CI participants, higher CSF sTREM1 levels were associated with a more accelerated rate of hippocampal atrophy, whereas no such association was observed in CU participants.

CONCLUSION: These results underscore the complex interplay between neuroinflammation, as reflected by CSF sTREM1 levels, hippocampal atrophy, and cognitive decline. The data suggest that neuroinflammation may contribute differently to hippocampal atrophy rates in CI versus CU individuals, highlighting the potential for targeted anti-inflammatory interventions in the prevention and treatment of AD.}, } @article {pmid39876884, year = {2025}, author = {Chen, XH and Xia, W and Ma, JB and Chen, J and Hu, J and Shi, X and Yu, JJ and Gong, J and Liu, L and Sun, YA and Liu, ZG}, title = {Rare mixed dementia: A case report.}, journal = {World journal of radiology}, volume = {17}, number = {1}, pages = {102579}, pmid = {39876884}, issn = {1949-8470}, abstract = {BACKGROUND: Autoimmune encephalitis (AE) is a rare and recently described neuroinflammatory disease associated with specific autoantibodies. Anti-leucine-rich glioma inactivated 1 (anti-LGI1) encephalitis is a rare but treatable type of AE discovered in recent years. Alzheimer's disease (AD) is a degenerative brain disease and the most common cause of dementia. AD may undergo a series of pathological physiological changes in brain tissue 20 years before the onset of typical symptoms. The stage of mild cognitive impairment (MCI) that occurs during this process, known as MCI due to AD, is the earliest stage with clinical symptoms. MCI is typically categorized into two subtypes: Amnestic MCI (aMCI) and non-aMCI.

CASE SUMMARY: This report describes a patient with rapid cognitive impairment, diagnosed with anti-LGI1 antibody-mediated AE and aMCI, and treated at Peking University Shenzhen Hospital in March 2023. The patient was hospitalized with acute memory decline for more than 3 months. Both the cerebrospinal fluid and serum were positive for anti-LGI1 antibodies, biomarkers of AD coexisting in the patient's cerebrospinal fluid. Following combination treatment with immunoglobulin therapy and glucocorticoid, plus inhibition of acetylcholinesterase, the patient's cognitive function significantly improved. Throughout the 3-month follow-up period, a sustained improvement in cognitive function was observed. The results of serum anti-LGI1 antibody were negative.

CONCLUSION: This case has raised awareness of the possible interaction between AE and early AD (including MCI due to AD), and alerted clinicians to the possibility of concurrent rare and common diseases in patients presenting with cognitive impairment.}, } @article {pmid39875073, year = {2025}, author = {Géraudie, A and De Rossi, P and Canney, M and Carpentier, A and Delatour, B}, title = {Effects of blood-brain barrier opening using ultrasound on tauopathies: A systematic review.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {379}, number = {}, pages = {1029-1044}, doi = {10.1016/j.jconrel.2025.01.056}, pmid = {39875073}, issn = {1873-4995}, abstract = {UNLABELLED: Blood-brain barrier opening with ultrasound can potentiate drug efficacy in the treatment of brain pathologies and also provides therapeutic effects on its own. It is an innovative tool to transiently, repeatedly and safely open the barrier, with studies showing beneficial effects in both preclinical models for Alzheimer's disease and recent clinical studies. The first preclinical and clinical work has mainly shown a decrease in amyloid burden in mice models and in patients. However, Alzheimer's disease pathology also encompasses tauopathy, which is closely related to cognitive decline, making it a crucial therapeutic target. The effects of blood-brain barrier opening with ultrasound have been rarely assessed on tau and are still unclear.

METHODS: This systematic review, conducted through searches using Pubmed, Embase, Web of Science and Cochrane Central databases, extracted results of 15 studies reporting effects of blood-brain barrier opening using ultrasound on tau proteins.

RESULTS: This review of the literature indicates that blood-brain barrier opening using ultrasound can decrease the extent of the tau pathology or potentialize the effect of a therapeutic drug. However, selected studies report paradoxically that blood-brain barrier opening can increase tau pathology burden and induce brain damage.

DISCUSSION: Apparent discrepancies between reports could originate from the variability in protocols or analytical methods that may impact the effects of blood-brain barrier opening with ultrasound on tauopathies, glial populations, tissue integrity and functional outcomes.

CONCLUSION: This calls for a better standardization effort combined with improved methodologies allowing between-studies comparisons, and for further understanding of the effects of blood-brain barrier opening on tau pathology as an essential prerequisite before translation to clinic.}, } @article {pmid39875069, year = {2025}, author = {Zuo, Y and Ding, X and Liu, Z and Xie, Y and Liu, G and Liu, C}, title = {Diverse pathways for the treatment of Parkinson's disease: Integration and development of traditional and emerging therapies.}, journal = {Neuroscience}, volume = {568}, number = {}, pages = {388-398}, doi = {10.1016/j.neuroscience.2025.01.045}, pmid = {39875069}, issn = {1873-7544}, abstract = {Parkinson's disease (PD) is the second most common central neurodegenerative disease in the world after Alzheimer's disease (AD), which mainly occurs in middle-aged and elderly people, and is increasing with the aging of the population. With the increasing incidence of PD, it is particularly important to explore its pathology and provide effective interventions and treatments. The pathogenesis of PD involves a variety of factors such as genetics, environment, and age, and is not yet fully understood. The main pathogenic mechanisms include neuronal degeneration, abnormal aggregation of α-synuclein, formation of Lewy bodies and oxidative stress, etc. In recent years, gene therapy, stem cell therapy, and immunotherapy, along with traditional drugs and surgical treatments, have become widely used. Currently, all treatments for PD are symptomatic and there is no radical cure. This paper reviews existing traditional and emerging treatments for PD to provide a theoretical basis for the in-depth study of PD pathogenesis and therapeutic approaches. Meanwhile, the application of gene editing and delivery, stem cell transplantation, immunotherapy and multi-target therapy laid the foundation for the development of safer, more effective and more comprehensive treatments for PD.}, } @article {pmid39874644, year = {2025}, author = {Park, E and He, C and Abbasi, AZ and Tian, M and Huang, S and Wang, L and Georgiou, J and Collingridge, GL and Fraser, PE and Henderson, JT and Wu, XY}, title = {Brain microenvironment-remodeling nanomedicine improves cerebral glucose metabolism, mitochondrial activity and synaptic function in a mouse model of Alzheimer's disease.}, journal = {Biomaterials}, volume = {318}, number = {}, pages = {123142}, doi = {10.1016/j.biomaterials.2025.123142}, pmid = {39874644}, issn = {1878-5905}, abstract = {The development of disease-modifying therapeutics for Alzheimer's disease remains challenging due to the complex pathology and the presence of the blood-brain barrier. Previously we have described the investigation of a brain-penetrating multifunctional bioreactive nanoparticle system capable of remodeling the hypoxic and inflammatory brain microenvironment and reducing beta-amyloid plaques improving cognitive function in a mouse model of Alzheimer's disease. Despite the linkage of hypoxia and inflammation to metabolic alteration, the effects of this system on modulating cerebral glucose metabolism, mitochondrial activity and synaptic function remained to be elucidated. To examine this, a transgenic mouse model of Alzheimer's disease (TgCRND8) in vivo were treated intravenously with beta-amyloid antibody-conjugated (Ab), blood-brain barrier-crossing terpolymer (TP) containing polymer-lipid based manganese dioxide nanoparticles (Ab-TP-MDNPs). Alterations in cerebral glucose utilization were determined by [[1][8]F]FDG-PET imaging in vivo, with glucose metabolism and mitochondrial activity analyzed by biomarkers and studies with primary neurons in vitro. Synaptic function was evaluated by both biomarkers and electrophysiologic analysis. Current study shows that intravenously administered Ab-TP-MDNPs enhanced cerebral glucose utilization, improved glucose metabolism, mitochondrial activity, and increased the levels of neprilysin, O-glycosylation. The consequence of this was enhanced glucose and ATP availability, resulting in improved long-term potentiation for promoting neuronal synaptic function. This study highlights the importance of targeting the metabolism of complex disease pathologies in addressing disease-modifying therapeutics for neurodegenerative disorders such as Alzheimer's disease.}, } @article {pmid39874376, year = {2025}, author = {Lu, H and Ni, X and Man Chan, SS and Cheng, CPW and Chan, W and Lam, LCW}, title = {Pre-treatment subjective sleep quality as a predictive biomarker of tDCS effects in preclinical Alzheimer's disease patients: Secondary analysis of a randomised clinical trial.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0317700}, pmid = {39874376}, issn = {1932-6203}, mesh = {Humans ; *Alzheimer Disease/therapy/psychology/physiopathology ; *Transcranial Direct Current Stimulation/methods ; Male ; Female ; Aged ; *Sleep Quality ; *Cognition/physiology ; Biomarkers ; Memory, Short-Term/physiology ; Middle Aged ; Cognitive Dysfunction/therapy ; Aged, 80 and over ; Treatment Outcome ; }, abstract = {BACKGROUND: Despite transcranial direct current stimulation (tDCS) has demonstrated encouraging potential for modulating the circadian rhythm, little is known about how well and sustainably tDCS might improve the subjective sleep quality in older adults. This study sought to determine how tDCS affected sleep quality and cognition, as well as how well pre-treatment sleep quality predicted tDCS effects on domain-specific cognitive functions in patients with mild neurocognitive disorder due to Alzheimer's disease (NCD-AD).

METHODS: This clinical trial aimed to compare the effectiveness of tDCS and cognitive training in mild NCD-AD patients (n =  201). Over the course of four weeks, patients were randomized to receive either tDCS plus working memory training, or sham tDCS plus working memory training, or tDCS plus controlled cognitive training. The Pittsburgh Sleep Quality Index (PSQI) was used to measured subjective sleep quality. The Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog) was used to evaluate domain-specific cognitive functions.

RESULTS: Recurrent tDCS treatments enhanced subjective sleep quality and cognition considerably. The poor sleepers (i.e., PSQI >  5) who received tDCS treatment had more cognitive benefits (p =  0.031, Cohen's d =  0.605) and sleep improvements (p <  0.001, Cohen's d =  1.209) in comparison to cognitive training. Pre-treatment subjective sleep quality was linked to tDCS-induced improvement in memory function.

CONCLUSION: During the course of two months, repeated tDCS could considerably enhance subjective sleep quality. For the cognitive benefits of the treatments, the status of pre-treatment subjective sleep quality is crucial. More thorough research is necessary to explore an efficient approach to managing comorbidities for preclinical AD patients.}, } @article {pmid39874173, year = {2025}, author = {Aksu, K and Ayvaz, MÇ and Çelik, ÖF and Serdaroğlu, G and Üstün, E and Kelebekli, L}, title = {Synthesis, Biological Activities, DFT Calculations, and Molecular Docking Studies of O-Methyl-Inositols.}, journal = {Chemistry & biodiversity}, volume = {}, number = {}, pages = {e202402346}, doi = {10.1002/cbdv.202402346}, pmid = {39874173}, issn = {1612-1880}, support = {ODU/BAP Grant AR-1324//Ordu University Scientific Research Projects Coordination Unit/ ; //Scientific and Technological Research Council of Turkey (TUBITAK)/ ; }, abstract = {The concise synthesis of O-methyl-d-inositol derivative and conduritol derivatives was obtained starting from p-benzoquinone. Spectroscopic methods have been performed for the characterization of newly synthesized compounds. Cyclitols are useful molecules with anticancer, antibiotic, antinutrient, and antileukemic activities. Inositol class molecules, known as the most important cyclitol derivatives, were examined in this study for their 1,1-diphenyl-2-picrylhydrazyl (DPPH) and nitric oxide radical scavenging and butyrylcholinesterase (BChE) and glycosidase inhibition activities. It was observed that compound 5, in particular, showed efficacy that competed with the standards in terms of both antioxidant activity and enzyme inhibitor potential. Additionally, compound 5 shows effective antimicrobial activity. The water-soluble characteristics and lipophilic properties of the compounds were also considered and discussed. Moreover, the quantum chemical analyses were performed in light of the DFT/B3LYP/6-311G** level computations to elucidate/compare the studied inositols' possible reactivity directions. Additionally, the interactions of the molecules were analyzed against acetylcholinesterase (AChE), peroxiredoxin 5, and DNA gyrase by molecular docking methods. Cholinesterase inhibitors have an important status as the most important drug group used in the treatment of Alzheimer's disease today. Considering the effects of inhibition of the α-glucosidase enzyme by inhibitors, such molecules can also be used as therapeutic components in the treatment of diabetes.}, } @article {pmid39873362, year = {2025}, author = {Zhang, L and An, H and Zhen, R and Zhang, T and Ding, M and Zhang, M and Sun, Y and Gu, C}, title = {Di Huang Yi Zhi Fang improves cognitive function in APP/PS1 mice by inducing neuronal mitochondrial autophagy through the PINK1-parkin pathway.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {2}, pages = {372-382}, doi = {10.1177/13872877241299832}, pmid = {39873362}, issn = {1875-8908}, mesh = {Animals ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Mice, Transgenic ; Mice ; *Mitochondria/drug effects/metabolism ; *Autophagy/drug effects ; *Amyloid beta-Protein Precursor/genetics ; *Protein Kinases/metabolism ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Neurons/drug effects/metabolism ; *Ubiquitin-Protein Ligases/metabolism/genetics ; Presenilin-1/genetics ; Cognition/drug effects ; Maze Learning/drug effects ; Disease Models, Animal ; Male ; Amyloid beta-Peptides/metabolism ; Signal Transduction/drug effects ; Hippocampus/drug effects/metabolism/pathology ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is an irreversible age-related neurodegenerative condition characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles. Di Huang Yi Zhi (DHYZ) formula, a traditional Chinese herbal compound comprising several prescriptions, demonstrates properties that improve cognitive abilities in clinical. Nonetheless, its molecular mechanisms on treating AD through improving neuron cells mitochondria function have not been deeply investigated.

OBJECTIVE: This study administered DHYZ to APP/PS1 mice to explore its potential therapeutic mechanisms in AD treatment.

METHODS: APP/PS1 transgenic mice were given DHYZ (L, M, H), donepezil, or distilled water for a consecutive 12-week period. The Morris water maze test was used to assess memory capacity, transmission electron microscopy was used to observe mitochondrial and synaptic structures, immunohistochemistry and western blot detected proteins involved in the mitochondrial autophagy pathway, ELISA measured serum Aβ content, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assessed neuronal cell apoptosis.

RESULTS: DHYZ demonstrates a notable therapeutic impact on mice with AD, effectively improving cognitive and memory impairments. DHYZ decreases Aβ accumulation in the hippocampus by reducing BACE1 activity and enhancing Aβ clearance through the blood-brain barrier. Additionally, DHYZ significantly suppresses neuronal apoptosis, enhances synaptic structure, and increases synapse numbers, processes strongly linked to the activation of mitochondrial PINK1-Parkin autophagy.

CONCLUSIONS: DHYZ enhances cognitive function in APP/PS1 mice by stimulating neuronal mitochondrial autophagy through the PINK1-Parkin pathway.}, } @article {pmid39873275, year = {2025}, author = {Liang, F and Ma, L and Zhang, G and Han, J and Zhu, M and Zhu, C and Jin, Y and Wang, Z}, title = {Mapping of Amyloid-β Aggregates In Vivo by a Fluorescent Probe with Dual Recognition Moieties.}, journal = {Analytical chemistry}, volume = {97}, number = {5}, pages = {3108-3116}, doi = {10.1021/acs.analchem.4c06385}, pmid = {39873275}, issn = {1520-6882}, mesh = {*Fluorescent Dyes/chemistry/chemical synthesis ; *Amyloid beta-Peptides/metabolism/analysis ; Animals ; Mice ; Alzheimer Disease/metabolism/diagnosis/pathology ; Humans ; Brain/diagnostic imaging/metabolism/pathology ; Protein Aggregates ; Peptide Fragments/chemistry/metabolism ; Molecular Structure ; Mice, Transgenic ; Optical Imaging ; }, abstract = {The spontaneous aggregation of amyloid-β (Aβ) leads to neuronal cell death in the brain and causes the development of Alzheimer's disease (AD). The efficient detection of the aggregation state of Aβ holds significant promise for the early diagnosis and subsequent treatment of this neurodegenerative disorder. Currently, most of the fluorescent probes used for the detection of Aβ fibrils share similar recognition moieties, such as the N,N-dimethylamino group, N,N-diethylamino group, and piperidyl group. The development of fluorescent probes incorporating novel recognition groups will, in principle, bring new properties for the detection and imaging of Aβ aggregates. Herein, we designed and synthesized three fluorescent probes (1 CarbCN, 2 NTCN, and 3 NCarbCN) based on dicyanoisophorone. The probe 3 NCarbCN, which integrated two recognition moieties, a carbamate unit (a new recognition group) together with a N,N-dimethylamino group, showed a sensitive turn-on fluorescence response toward the early aggregation state of Aβ, along with a high binding affinity (Kd = 59 nM) and recognition selectivity for Aβ fibrils. Theoretical calculations revealed that the carbamate unit of 3 NCarbCN could provide an additional three hydrogen bonding interaction with Aβ42 fibrils. Furthermore, the probe 3 NCarbCN efficiently crossed the blood-brain barrier and exhibited a higher response in the brains of AD model mice. Co-staining of isolated brain sections with monoclonal antibody further demonstrated specific binding of 3 NCarbCN to Aβ plaques in the brains of AD model mice, thus demonstrating its great potential for the early diagnosis of such neurodegenerative disorders.}, } @article {pmid39873194, year = {2025}, author = {Kumar, N and Devi, B and Jangid, K and Kumar, V}, title = {Pharmacophore-based virtual screening of the chromone derivatives as potential therapeutic for Alzheimer's disease.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/07391102.2025.2458327}, pmid = {39873194}, issn = {1538-0254}, abstract = {Alzheimer's disease is one of the most complex neurological disorders and millions of people are suffering from this disease all over the world. In the past two decades acetylcholinesterase (AChE) has been the most explored pathological hallmark. The generation of potent AChE inhibitors has grown as a rapid pathological tool for the efficacious treatment of the disease. Hence, AChE enzyme is extensively explored as a drug discovery tool for the development of potent therapeutics. We have used chromone derivatives with known biological activities for developing a Gaussian field-based 3D QSAR pharmacophore model using PHASE module of Schrodinger with statistically significant R[2] and Q[2] values of 0.92 and 0.9209, respectively. ChEMBL and MCULE databases were screened using the best pharmacophore hypothesis model (AAHHRR_4) with features of two hydrogen bond acceptors (A1, A2), two hydrophobic regions (H1, H2), and two aromatic regions (R1, R2). These were subjected to structure-based virtual screening using extra precision, MM/GBSA and ADME calculations for calculating the binding free energies and pharmacokinetic properties, respectively. Subsequently, two hit molecules i.e. CHEMBL1319989 and MCULE-2246633290 were identified. The leads exhibited higher docking score (-8.859 and -9.984 kcal/mol) and ΔGbinding (-57.63 and -56.45 kcal/mol) as compared to the reference (ΔGbinding= -53.79 kcal/mol). MD simulation study exhibited stable interactions with the binding free energy (ΔGMMPBSA) of -27.29 and -21.26 kcal/mol for CHEMBL1319989 and MCULE-2246633290, respectively. So, the generated pharmacophore model may be considered as a valuable tool for the development of potent AChE inhibitors for the treatment of AD.}, } @article {pmid39873047, year = {2025}, author = {Son, SH and Lee, SW and Chung, G}, title = {Loss of dental pulp potentially increased the risk of Alzheimer's dementia.}, journal = {Journal of dental sciences}, volume = {20}, number = {1}, pages = {310-318}, pmid = {39873047}, issn = {2213-8862}, abstract = {BACKGROUND/PURPOSE: Chronic periodontitis and tooth loss contribute to cognitive decline. Since many biological processes are shared by loss of teeth and loss of pulps, this study investigated the potential association between loss of pulp and the development of dementia.

MATERIALS AND METHODS: A retrospective cohort analysis was conducted to investigate the association between dental treatment and the development of dementia. The records of dental treatment during the 10 years prior to the first diagnosis of dementia were extracted from the Elderly Cohort Database of the National Health Information Sharing Service of Korea. The independence of dementia compared to the number of pulps or teeth removed was evaluated using the chi-squared test. The subjects were grouped by the number of teeth or pulps treated, and their odds ratio for dementia was calculated.

RESULTS: Analysis of 591,592 sessions for pulpectomy and 710,722 sessions for tooth extraction from 558,147 individuals revealed a significant association with Alzheimer's dementia, but not with vascular or unspecified dementia. The number of dementia patients based on the number of pulps or teeth extracted were significantly different across age groups. The odds ratios demonstrated a tendency to increase with the number of dental treatments and decrease with age at the time of diagnosis of dementia. The number of pulps removed to achieve a notable impact on Alzheimer's dementia was found to be lower than the number of teeth extracted.

CONCLUSION: The loss of pulp increased incidence of Alzheimer's dementia, with the impact being more pronounced in younger geriatric groups.}, } @article {pmid39872995, year = {2024}, author = {Fine, JM and Kosyakovsky, J and Bowe, TT and Faltesek, KA and Stroebel, BM and Abrahante, JE and Kelly, MR and Thompson, EA and Westby, CM and Robertson, KM and Frey, WH and Hanson, LR}, title = {Low-dose intranasal deferoxamine modulates memory, neuroinflammation, and the neuronal transcriptome in the streptozotocin rodent model of Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1528374}, pmid = {39872995}, issn = {1662-4548}, abstract = {INTRODUCTION: Intranasal (IN) deferoxamine (DFO) has emerged over the past decade as a promising therapeutic in preclinical experiments across neurodegenerative and neurovascular diseases. As an antioxidant iron chelator, its mechanisms are multimodal, involving the binding of brain iron and the consequent engagement of several pathways to counter pathogenesis across multiple diseases. We and other research groups have shown that IN DFO rescues cognitive impairment in several rodent models of Alzheimer Disease (AD).

METHODS: This study was designed to probe dosing regimens to inform future clinical trials, while exploring mechanisms within the intracerebroventricular (ICV) streptozotocin (STZ) model.

RESULTS: Five weeks of daily IN dosing of Long Evans rats with 15 μL of a 1% (0.3 mg), but not 0.1% (0.03 mg), solution of DFO rescued cognitive impairment caused by ICV STZ administration as assessed with the Morris Water Maze (MWM) test of spatial memory and learning. Furthermore, IN DFO modulated several aspects of the neuroinflammatory milieu of the ICV STZ model, which was assessed through a novel panel of brain cytokines and immunohistochemistry. Using RNA-sequencing and pathway analysis, STZ was shown to induce several pathways of cell death and neuroinflammation, and IN DFO engaged multiple transcriptomic pathways involved in hippocampal neuronal survival.

DISCUSSION: To our knowledge this study is the first to assess the transcriptomic pathways and mechanisms associated with either the ICV STZ model or DFO treatment, and the first to demonstrate efficacy at this low dose.}, } @article {pmid39872848, year = {2024}, author = {Wang, X and He, X and Zhong, B}, title = {Oral microbiota: the overlooked catalyst in cancer initiation and progression.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1479720}, pmid = {39872848}, issn = {2296-634X}, abstract = {The advancement of high-throughput sequencing technology in recent decades has led to a greater understanding of the components of the oral microbiota, providing a solid foundation for extensive research in this field. The oral microbiota plays an important role in an individual's overall health. It has been shown to be significantly correlated with chronic human diseases, including diabetes, rheumatoid arthritis, cardiovascular disease, periodontal disease, and Alzheimer's disease. Furthermore, tumor occurrence and development are closely related to the oral microbiome. Specific bacteria, such as Fusobacterium nucleatum (F. nucleatum), Porphyromonas gingivalis (P. gingivalis), Streptococcus, Streptomyces, Prevotella, and Fibrophagy gingivalis, play critical roles in cancer development. The oral microbiota has various oncogenic mechanisms, including bacterial inflammation, immunological suppression, tumor growth mediated by bacterial toxins, antiapoptotic activity, and carcinogenic effects. This paper reviews the role of the oral microbiota in the occurrence and progression of cancer and systematically elucidates the molecular mechanisms by which dysbiosis influences tumorigenesis and tumor progression. This information can provide a theoretical basis for exploring cancer treatment strategies and offer new insights for cancer prevention.}, } @article {pmid39872720, year = {2025}, author = {Graur, A and Erickson, N and Kabbani, N}, title = {Using Protein Painting Mass Spectrometry to Define Ligand Receptor Interaction Sites for Acetylcholine Binding Protein.}, journal = {Bio-protocol}, volume = {15}, number = {2}, pages = {e5163}, pmid = {39872720}, issn = {2331-8325}, abstract = {Nicotinic acetylcholine receptors (nAChRs) are a family of ligand-gated ion channels expressed in nervous and non-nervous system tissue important for memory, movement, and sensory processes. The pharmacological targeting of nAChRs, using small molecules or peptides, is a promising approach for the development of compounds for the treatment of various human diseases including inflammatory and neurogenerative disorders such as Alzheimer's disease. Using the Aplysia californica acetylcholine binding protein (Ac-AChBP) as an established structural surrogate for human homopentameric α7 nAChRs, we describe an innovative protein painting mass spectrometry (MS) method that can be used to identify interaction sites for various ligands at the extracellular nAChR site. We describe how the use of small molecule dyes can be optimized to uncover contact sites for ligand-protein interactions based on MS detection. Protein painting MS has been recently shown to be an effective tool for the identification of residues within Ac-AChBP involved in the binding of know ligands such as α-bungarotoxin. This strategy can be used with computational structural modeling to identify binding regions involved in drug targeting at the nAChR. Key features • Identify binding ligands of nicotinic receptors based on similarity with the acetylcholine binding protein. • Can be adapted to test various ligands and binding conditions. • Mass spectrometry identification of specific amino acid residues that contribute to protein binding. • Can be effectively coupled to structural modeling analysis.}, } @article {pmid39871894, year = {2024}, author = {Ren, Y and Chen, M and Wang, Z and Han, JJ}, title = {Oral microbiota in aging and diseases.}, journal = {Life medicine}, volume = {3}, number = {3}, pages = {lnae024}, pmid = {39871894}, issn = {2755-1733}, abstract = {Human microbiomes are microbial populations that form a symbiotic relationship with humans. There are up to 1000 species on the surface of human skin and mucosal system, among which gut microbiota attracts the most interest. As the beginning of the digestive tract, oral cavity is also an important microbial habitat in the human body which is the first line of defense against pathogens entering the body. Many studies have revealed that oral microbial dysbiosis could not only contribute to oral diseases but also whole-body systemic diseases and health status. Oral microorganisms can enter the gastrointestinal tract with saliva and food, or enter the blood circulation through mouth breakage, thus causing systemic inflammation and aging-related diseases including some causal links to Alzheimer's disease. A series of changes take place in oral microbial composition during development, with different age stages marked by different dominant microbial species. Despite a lack of comprehensive studies on aging oral microbiota, through systemic inflammation, oral pathogenic microbes are likely to contribute inflammatory aging. As inflammaging is a key signature and one of the causes for accelerated aging, improving the structure of oral microbiome may be not only a new strategy for disease prevention and treatment, but also for aging intervention.}, } @article {pmid39871563, year = {2025}, author = {Guo, J and Liu, XY and Yang, SS and Li, Q and Duan, Y and Zhu, SS and Zhou, K and Yan, YZ and Zeng, P}, title = {Roles of C/EBPβ/AEP in Neurodegenerative Diseases.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266357822250119172351}, pmid = {39871563}, issn = {1873-4294}, abstract = {In recent years, an increasing number of studies have shown that increased activation of aspartic endopeptidases (AEPs) is a common symptom in neurodegenerative diseases (NDDs). AEP cleaves amyloid precursor protein (APP), tau (microtubule-associated protein tau), α- synuclein (α-syn), SET (a 39-KDa phosphoprotein widely expressed in various tissues and localizes predominantly in the nucleus), and TAR DNA-binding protein 43 (TDP-43), and promotes their aggregation, contributing to Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) pathogenesis. Abundant evidence supports the notion that CCAAT/enhancer-binding protein β (C/EBPβ)/AEP may play an important role in NDDs. Developing its small molecule inhibitors is a promising treatment of NDDs. However, current research suggests that the pathophysiological mechanism of the C/EBPβ/AEP pathway is very complex in NDDs. This review summarizes the structure of C/EBPβ and AEP, their major physiological functions, potential pathogenesis, their small molecule inhibitors, and how C/EBPβ/AEP offers a novel pathway for the treatment of NDDs.}, } @article {pmid39871559, year = {2025}, author = {Rani, S and Tuteja, M}, title = {Chaperones as Potential Pharmacological Targets for Treating Protein Aggregation Illness.}, journal = {Current protein & peptide science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892037338028241230092414}, pmid = {39871559}, issn = {1875-5550}, abstract = {The three-dimensional structure of proteins, achieved through the folding of the nascent polypeptide chain in vivo, is largely facilitated by molecular chaperones, which are crucial for determining protein functionality. In addition to aiding in the folding process, chaperones target misfolded proteins for degradation, acting as a quality control system within the cell. Defective protein folding has been implicated in a wide range of clinical conditions, including neurodegenerative and metabolic disorders. It is now well understood that the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and Creutzfeldt-Jakob disease shares a common mechanism: the accumulation of misfolded proteins, which aggregate and become toxic to cells. Among the family of molecular chaperones, Heat Shock Proteins (HSPs) are highly expressed in response to cellular stress and play a pivotal role in preventing protein aggregation. Specific chaperones, particularly HSPs, are now recognized as critical in halting the accumulation and aggregation of misfolded proteins in these conditions. Consequently, these chaperones are increasingly considered promising pharmacological targets for the treatment of protein aggregation-related diseases. This review highlights research exploring the potential roles of specific molecular chaperones in disorders characterized by the accumulation of misfolded proteins.}, } @article {pmid39871402, year = {2025}, author = {Li, S and Li, M and Li, G and Li, L and Yang, X and Zuo, Z and Zhang, L and Hu, X and He, X}, title = {Physical Exercise Decreases Complement-Mediated Synaptic Loss and Protects Against Cognitive Impairment by Inhibiting Microglial Tmem9-ATP6V0D1 in Alzheimer's Disease.}, journal = {Aging cell}, volume = {}, number = {}, pages = {e14496}, doi = {10.1111/acel.14496}, pmid = {39871402}, issn = {1474-9726}, support = {2024A04J4861//Guangzhou Science and Technology Planning Project/ ; 82272609//National Natural Science Foundation of China/ ; 2022YFC3601200//National Key Research and Development Program of China/ ; }, abstract = {Physical exercise is known to slow synaptic neurodegeneration and cognitive aging in Alzheimer's disease (AD). The benefits of physical exercise are related to reduced amyloid beta (Aβ) deposition and increased synaptic plasticity. Yet little is known about the mechanisms that mediate these effects. Here, we show that physical exercise down-regulated the microglial Tmem9 protein, inhibited C1q activation, and decreased C1q-dependent microglial synapse engulfment, eventually ameliorating cognitive impairment in 5xFAD mice. Furthermore, using oAβ cultured-BV2 in vitro, we show that downregulation of microglial Tmem9 was sufficient to restrain complement activity and decrease microglia-mediated synaptic loss, whereas overexpression of microglial Tmem9 tended to promote complement activation and induced synaptic loss, abolishing exercise-associated protection. Finally, we show that microglial Tmem9 contributed to complement activation by regulating ATP6V0D1, a vesicular (H[+]) ATP-dependent proton pump (V-ATPase) subunit that regulates V-ATPase assembly. Together, our results demonstrate that exercise is a potential treatment for AD patients. In an AD mouse model, it decreased the levels of microglial Tmem9 to inhibit the activation of complement, alleviated complement-dependent synaptic loss, and eventually ameliorated emotional and cognitive disorders.}, } @article {pmid39871348, year = {2025}, author = {He, S and Xu, Z and Han, X}, title = {Lipidome disruption in Alzheimer's disease brain: detection, pathological mechanisms, and therapeutic implications.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {11}, pmid = {39871348}, issn = {1750-1326}, support = {Methodist Hospital Foundation//Methodist Hospital Foundation/ ; University of Texas Health Science Center at San Antonio//University of Texas Health Science Center at San Antonio/ ; William and Ella Owens Medical Research Foundation//William and Ella Owens Medical Research Foundation/ ; P30 AG013319/AG/NIA NIH HHS/United States ; R01 AG061872/AG/NIA NIH HHS/United States ; P30 AG044271/AG/NIA NIH HHS/United States ; RF1 AG061729/AG/NIA NIH HHS/United States ; Cure Alzheimer's Fund//Cure Alzheimer's Fund/ ; R01 AG085545/AG/NIA NIH HHS/United States ; T32 AG021890/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism ; Humans ; *Brain/metabolism/pathology ; *Lipidomics/methods ; *Lipid Metabolism/physiology ; Animals ; }, abstract = {Alzheimer's disease (AD) is among the most devastating neurodegenerative disorders with limited treatment options. Emerging evidence points to the involvement of lipid dysregulation in the development of AD. Nevertheless, the precise lipidomic landscape and the mechanistic roles of lipids in disease pathology remain poorly understood. This review aims to highlight the significance of lipidomics and lipid-targeting approaches in the diagnosis and treatment of AD. We summarized the connection between lipid dysregulation in the human brain and AD at both genetic and lipid species levels. We briefly introduced lipidomics technologies and discussed potential challenges and areas of future advancements in the lipidomics field for AD research. To elucidate the central role of lipids in converging multiple pathological aspects of AD, we reviewed the current knowledge on the interplay between lipids and major AD features, including amyloid beta, tau, and neuroinflammation. Finally, we assessed the progresses and obstacles in lipid-based therapeutics and proposed potential strategies for leveraging lipidomics in the treatment of AD.}, } @article {pmid39870228, year = {2025}, author = {Dahiya, M and Kumar, A and Yadav, M and Chauhan, S}, title = {β-pinene ameliorates ICV-STZ induced Alzheimer's pathology via antioxidant, anticholinesterase, and mitochondrial protective effects: In-silico and in-vivo studies.}, journal = {European journal of pharmacology}, volume = {991}, number = {}, pages = {177307}, doi = {10.1016/j.ejphar.2025.177307}, pmid = {39870228}, issn = {1879-0712}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a leading cause of dementia, characterized by progressive neurodegeneration and cognitive dysfunction. The disease aetiology is closely associated with proteinopathies, mitochondrial abnormalities, and elevated ROS generation, which are some of the primary markers for AD brains.

OBJECTIVES: The current research was intended to elucidate the chemical interaction of β-pinene against potential targets and evaluate its neuroprotective potential in ICV-STZ-induced sAD.

METHODOLOGY: The potential binding interactions of β-pinene and galantamine were evaluated against the active sites of PP2A, SOD1, catalase-3, and AChE using AutoDock vina. Additionally, the β-pinene and galantamine were subjected to tests of their ADMET by employing the Swiss ADME and Protox-II web servers. To assess the neuroprotective potential, β-pinene (50, 100, and 200 mg/kg) and galantamine (2 mg/kg) was administered p.o in ICV-STZ-treated wistar rats for 21 days. Moreover, behavioral parameters (NOR & MWM), biochemical, AChE activities, and mitochondrial complexes were performed.

RESULTS: Molecular docking study showed that β-pinene can interact with human PP2A, SOD1, Catalase-3, and AChE with better ligand efficiency as compared to galantamine. In-vivo data showed that β-pinene treatment (100, and 200 mg/kg) for 21 days exhibited significantly enhanced cognitive performance, as shown in behavioral studies. Additionally, β-pinene treatment significantly re-established antioxidant levels and mitochondrial capacities and attenuated altered AChE activity as compared to ICV-STZ-induced groups.

CONCLUSIONS: In-silico studies revealed that β-pinene shared the same binding pocket as galantamine, supporting its neuroprotective effects in the ICV-STZ-induced animal model by alleviating oxidative stress and mitochondrial dysfunction and reducing AChE activity.}, } @article {pmid39869613, year = {2025}, author = {Li, X and Gong, B and Chen, X and Li, H and Yuan, G}, title = {Alzheimer's disease image classification based on enhanced residual attention network.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0317376}, pmid = {39869613}, issn = {1932-6203}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis/classification ; Humans ; *Deep Learning ; Early Diagnosis ; Neural Networks, Computer ; Attention ; }, abstract = {With the increasing number of patients with Alzheimer's Disease (AD), the demand for early diagnosis and intervention is becoming increasingly urgent. The traditional detection methods for Alzheimer's disease mainly rely on clinical symptoms, biomarkers, and imaging examinations. However, these methods have limitations in the early detection of Alzheimer's disease, such as strong subjectivity in diagnostic criteria, high detection costs, and high misdiagnosis rates. To address these issues, this study proposes a deep learning model to detect Alzheimer's disease; it is called Enhanced Residual Attention Network (ERAN) that can classify medical images. By combining residual learning, attention mechanism, and soft thresholding, the feature representation ability and classification accuracy of the model have been improved. The accuracy of the model in detecting Alzheimer's disease has reached 99.36%, with a loss rate of only 0.0264. The experimental results indicate that the Enhanced Residual Attention Network has achieved excellent performance on the Alzheimer's disease test dataset, providing strong support for the early diagnosis and treatment of Alzheimer's disease.}, } @article {pmid39868844, year = {2025}, author = {Elyaman, W and Stern, LJ and Jiang, N and Dressman, D and Bradley, P and Klatzmann, D and Bradshaw, EM and Farber, DL and Kent, SC and Chizari, S and Funk, K and Devanand, D and Thakur, KT and Raj, T and Dalahmah, OA and Sarkis, RA and Weiner, HL and Shneider, NA and Przedborski, S}, title = {Exploring the role of T cells in Alzheimer's and other neurodegenerative diseases: Emerging therapeutic insights from the T Cells in the Brain symposium.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {e14548}, doi = {10.1002/alz.14548}, pmid = {39868844}, issn = {1552-5279}, support = {AG R01AG055422/NH/NIH HHS/United States ; R35GM141457/NH/NIH HHS/United States ; R01AI137198/NH/NIH HHS/United States ; R01AG076018/NH/NIH HHS/United States ; AI106697/NH/NIH HHS/United States ; R01AG067581/NH/NIH HHS/United States ; R13AG090018-01/NH/NIH HHS/United States ; T32AI148099-4/NH/NIH HHS/United States ; }, abstract = {This proceedings article summarizes the inaugural "T Cells in the Brain" symposium held at Columbia University. Experts gathered to explore the role of T cells in neurodegenerative diseases. Key topics included characterization of antigen-specific immune responses, T cell receptor (TCR) repertoire, microbial etiology in Alzheimer's disease (AD), and microglia-T cell crosstalk, with a focus on how T cells affect neuroinflammation and AD biomarkers like amyloid beta and tau. The symposium also examined immunotherapies for AD, including the Valacyclovir Treatment of Alzheimer's Disease (VALAD) trial, and two clinical trials leveraging regulatory T cell approaches for multiple sclerosis and amyotrophic lateral sclerosis therapy. Additionally, single-cell RNA/TCR sequencing of T cells and other immune cells provided insights into immune dynamics in neurodegenerative diseases. This article highlights key findings from the symposium and outlines future research directions to further understand the role of T cells in neurodegeneration, offering innovative therapeutic approaches for AD and other neurodegenerative diseases. HIGHLIGHTS: Researchers gathered to discuss approaches to study T cells in brain disorders. New technologies allow high-throughput screening of antigen-specific T cells. Microbial infections can precede several serious and chronic neurological diseases. Central and peripheral T cell responses shape neurological disease pathology. Immunotherapy can induce regulatory T cell responses in neuroinflammatory disorders.}, } @article {pmid39868840, year = {2025}, author = {Wen, B and Han, X and Gong, J and Wang, P and Sun, W and Xu, C and Shan, A and Wang, X and Luan, H and Li, S and Li, R and Guo, J and Chen, R and Li, C and Sun, Y and Lv, S and Wei, C}, title = {Nutrition: A non-negligible factor in the pathogenesis and treatment of Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {e14547}, doi = {10.1002/alz.14547}, pmid = {39868840}, issn = {1552-5279}, support = {2021ZD0201802//STI2030-Major Projects/ ; 82471450//National Natural Science Foundation of China/ ; }, abstract = {Alzheimer's disease (AD) is a degenerative disease characterized by progressive cognitive dysfunction. The strong link between nutrition and the occurrence and progression of AD pathology has been well documented. Poor nutritional status accelerates AD progress by potentially aggravating amyloid beta (Aβ) and tau deposition, exacerbating oxidative stress response, modulating the microbiota-gut-brain axis, and disrupting blood-brain barrier function. The advanced stage of AD tends to lead to malnutrition due to cognitive impairments, sensory dysfunctions, brain atrophy, and behavioral and psychological symptoms of dementia (BPSD). This, in turn, produces a vicious cycle between malnutrition and AD. This review discusses how nutritional factors and AD deteriorate each other from the early stage of AD to the terminal stages of AD, focusing on the potential of different levels of nutritional factors, ranging from micronutrients to diet patterns. This review provides novel insights into reducing the risk of AD, delaying its progression, and improving prognosis. HIGHLIGHTS: Two-fifths of Alzheimer's disease (AD) cases worldwide have been attributed to potentially modifiable risk factors. Up to ≈26% of community-dwelling patients with AD are malnourished, compared to 7%∼76% of institutionalized patients. Undernutrition effects the onset, progression, and prognosis of AD through multiple mechanisms. Various levels of nutritional supports were confirmed to be protective factors for AD via specific mechanisms.}, } @article {pmid39868701, year = {2025}, author = {Keränen, E and Rysä, J and Tiihonen, M and Hartikainen, S and Tolppanen, AM}, title = {HELICOBACTER PYLORI ERADICATION TREATMENTS AND RISK OF ALZHEIMER DISEASE: A CASE-CONTROL STUDY NESTED IN THE FINNISH POPULATION.}, journal = {Epidemiology (Cambridge, Mass.)}, volume = {}, number = {}, pages = {}, doi = {10.1097/EDE.0000000000001831}, pmid = {39868701}, issn = {1531-5487}, abstract = {BACKGROUND: Helicobacter pylori (H. pylori) has been inconsistently associated with risk of Alzheimer disease. The exposure assessment period has often overlapped with the prodromal time of Alzheimer disease. Cognitive disorders might increase vulnerability to infectious pathogens, complicating the ascertainment of temporal relationship between H. pylori infection and Alzheimer disease.

METHODS: This Finnish nested case-control study included 70,520 persons with incident Alzheimer disease diagnosed between 2005-2011 and 281,233 age-, sex-, and region of residence-matched controls. We obtained information on comorbidities and drug use from the national healthcare registers. We identified dispensed H. pylori eradication treatments from the Prescription register. We considered exposure at least 5 years before Alzheimer disease diagnosis in the main analysis. We compared risk of Alzheimer disease between H. pylori eradication treatment users and nonusers using confounder-adjusted (comorbidities and other drug use) conditional logistic regression. We assessed cumulative exposure by calculating the number of eradication treatments.

RESULTS: The prevalence of exposure to H. pylori eradication treatment at least 5 years before the outcome was 4.1% in cases and 3.9% in controls. The odds ratio (95% confidence interval) was 1.06 (1.02-1.11) in the crude and 1.03 (0.99-1.07) in the confounder-adjusted model. We observed no association between cumulative exposure and risk of Alzheimer disease.

CONCLUSION: Our results, reflecting diagnosed and treated H. pylori infection late in life, do not support the hypothesis of H. pylori as an independent risk factor for Alzheimer disease. The previously reported association may be explained by reverse association and confounding.}, } @article {pmid39868614, year = {2025}, author = {Liu, KY and Senn, S and Howard, R}, title = {Avoiding causal fraud in the evaluation of clinical benefits of treatments for Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {e14457}, doi = {10.1002/alz.14457}, pmid = {39868614}, issn = {1552-5279}, support = {MR/S021418/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Recent regulatory approvals of three amyloid-lowering monoclonal antibody therapies for the treatment of Alzheimer's disease (AD) have triggered a polarizing debate in the field on the clinical meaningfulness of their reported effects. The question of how to define clinical meaningfulness for any treatment that has a modest effect size is important and will likely be subject to influence from interested stakeholders. We warn of claims of evaluating meaningful within-individual change from randomized parallel-group trials of AD treatments, sometimes purportedly assessed by a commonly recognized "responder" analysis approach, and explain why it is likely to mislead and should simply be avoided. The average between-group difference in score change is where the debate and research efforts should be focused to contextualize and evaluate the clinical meaningfulness of the true treatment effect. The statistical and communication principles we consider and would recommend are applicable to the evaluation of most interventions in medicine. HIGHLIGHTS: Dichotomized outcome analysis approaches purporting to evaluate within-individual meaningful change are highly likely to mislead. In our view, the most valid statistical approach to understanding the true treatment effect is to analyze the average between-group difference in outcome scores. The average between-group difference in score change is where the debate and research efforts should be focused to contextualize and evaluate the clinical meaningfulness of the true treatment effect.}, } @article {pmid39868189, year = {2025}, author = {Kalecký, K and Buitrago, L and Alarcon, JM and Singh, A and Bottiglieri, T and Kaddurah-Daouk, R and Hernández, AI and , }, title = {Rescue of hippocampal synaptic plasticity and memory performance by Fingolimod (FTY720) in APP/PS1 model of Alzheimer's disease is accompanied by correction in metabolism of sphingolipids, polyamines, and phospholipid saturation composition.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39868189}, issn = {2692-8205}, support = {R01 AG046171/AG/NIA NIH HHS/United States ; U19 AG063744/AG/NIA NIH HHS/United States ; RF1 AG059093/AG/NIA NIH HHS/United States ; U01 AG061359/AG/NIA NIH HHS/United States ; RF1 AG058942/AG/NIA NIH HHS/United States ; RF1 AG051550/AG/NIA NIH HHS/United States ; }, abstract = {Previously, our metabolomic, transcriptomic, and genomic studies characterized the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease, and we demonstrated that FTY720, a sphingosine-1-phospahate receptor modulator approved for treatment of multiple sclerosis, recovers synaptic plasticity and memory in APP/PS1 mice. To further investigate how FTY720 rescues the pathology, we performed metabolomic analysis in brain, plasma, and liver of trained APP/PS1 and wild-type mice. APP/PS1 mice showed area-specific brain disturbances in polyamines, phospholipids, and sphingolipids. Most changes were completely or partially normalized in FTY720-treated subjects, indicating rebalancing the "sphingolipid rheostat", reactivating phosphatidylethanolamine synthesis via mitochondrial phosphatidylserine decarboxylase pathway, and normalizing polyamine levels that support mitochondrial activity. Synaptic plasticity and memory were rescued, with spermidine synthesis in temporal cortex best corresponding to hippocampal CA3-CA1 plasticity normalization. FTY720 effects, also reflected in other pathways, are consistent with promotion of mitochondrial function, synaptic plasticity, and anti-inflammatory environment, while reducing pro-apoptotic and pro-inflammatory signals.}, } @article {pmid39868172, year = {2025}, author = {Rao, SP and Imam-Fulani, AO and Xie, W and Phillip, S and Chennavajula, K and Lind, EB and Zhang, Y and Vince, R and Lee, MK and More, SS}, title = {Oral prodrug of a novel glutathione surrogate reverses metabolic dysregulation and attenuates neurodegenerative process in APP/PS1 mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39868172}, issn = {2692-8205}, support = {R01 AG062469/AG/NIA NIH HHS/United States ; R01 AG077743/AG/NIA NIH HHS/United States ; RF1 AG062135/AG/NIA NIH HHS/United States ; }, abstract = {Glycation-induced oxidative stress underlies the numerous metabolic ravages of Alzheimer's disease (AD). Reduced glutathione levels in AD lead to increased oxidative stress, including glycation-induced pathology. Previously, we showed that the accumulation of reactive 1,2-dicarbonyls such as methylglyoxal, the major precursor of non-enzymatic glycation products, was reduced by the increased function of GSH-dependent glyoxalase-1 enzyme in the brain. In this two-pronged study, we evaluate the therapeutic efficacy of an orally bioavailable prodrug of our lead glyoxalase substrate, pro-ψ-GSH, for the first time in a transgenic Alzheimer's disease mouse model. This prodrug delivers pharmacodynamically relevant brain concentrations of ψ-GSH upon oral delivery. Chronic oral dosing of pro-ψ-GSH effectively reverses the cognitive decline observed in the APP/PS1 mouse model. The prodrug successfully mirrors the robust effects of the parent drug i.e., reducing amyloid pathology, glycation stress, neuroinflammation, and the resultant neurodegeneration in these mice. We also report the first metabolomics study of such a treatment, which yields key biomarkers linked to the reversal of AD-related metabolic dysregulation. Collectively, this study establishes pro-ψ-GSH as a viable, disease-modifying therapy for AD and paves the way for further preclinical advancement of such therapeutics. Metabolomic signatures identified could prove beneficial in the development of treatment-specific clinically translatable biomarkers.}, } @article {pmid39867586, year = {2025}, author = {Yepes, AF and Cardona-Galeano, W and Herrera-Ramírez, A and Rada, MS and Osorio, E and Gonzalez-Molina, LA and Miranda-Brand, Y and Posada-Duque, R}, title = {Novel multipotent conjugate bearing tacrine and donepezil motifs with dual cholinergic inhibition and neuroprotective properties targeting Alzheimer's disease.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {39867586}, issn = {2632-8682}, abstract = {In this work, we developed potential multifunctional agents to combat Alzheimer's disease. According to our strategy, fragments of tacrine and donepezil were merged in a unique hybrid structure. After successfully synthesizing the compounds, they were evaluated for their dual AChE/BuChE inhibitor potential and neuroprotector response using a glutamate-induced excitotoxicity model. Most of the compounds showed promising activity. Among them, the hybrid with 2,5-dimetoxysubstitution (3b) was the most potent analogue, triggering dual potent AChE/BuChE inhibition with low nanomolar affinity (IC50 ∼ 300 nM) and low toxicity to human liver cancer cells (HepG2). This analogue prevented the glutamate excitotoxic stimulus during pre/post treatment testing, maintained ATP levels, possessed an astrocytic protective response, and abolished the glutamate-induced excitotoxicity. Besides, the hit compound 3b exhibited suitable permeability in the blood-brain barrier (BBB) and low degradability in human blood-plasma. In addition, the docking studies suggested that the neuroprotectant response exhibited by 3b can be related to the direct blockage of the NMDA channel pore. Finally, an ideal neuropharmacokinetic profile was estimated for 3b. Overall, the designed conjugates provide a novel multifunctional molecular scaffold that can be used as a prototype drug in further investigations toward novel multipotent therapeutics for treating AD.}, } @article {pmid39867516, year = {2025}, author = {Roy, S and Biswas, S and Nandy, A and Guha, D and Dasgupta, R and Bagchi, A and Sil, PC}, title = {An approach to predict and inhibit Amyloid Beta dimerization pattern in Alzheimer's disease.}, journal = {Toxicology reports}, volume = {14}, number = {}, pages = {101879}, pmid = {39867516}, issn = {2214-7500}, abstract = {Alzheimer's Disease (AD) is one of the leading neurodegenerative diseases that affect the human population. Several hypotheses are in the pipeline to establish the commencement of this disease; however, the amyloid hypothesis is one of the most widely accepted ones. Amyloid plaques are rich in Amyloid Beta (Aβ) proteins, which are found in the brains of Alzheimer's patients. They are the spliced product of a transmembrane protein called Amyloid Precursor Protein (APP); when they enter into the amylogenic pathway, they get cleaved simultaneously by Beta and Gamma Secretase and produce Aβ protein. Appearances of Amyloid plaques are the significant clinical hallmarks of this disease. AD is mainly present in two genetically distinct forms; sporadic and familial AD. Sporadic Alzheimer's Disease (sAD) is marked by a later clinical onset of the disease, whereas, familial Alzheimer's Disease (fAD) is an early onset of the disease with mendelian inheritance. Several mutations have been clinically reported in the last decades that have shown a direct link with fAD. Many of those mutations are reported to be present in the APP. In this study, we selected a few significant mutations present in the Aβ stretch of the APP and tried to differentiate the wild-type Aβ dimers formed in sAD and the mutant dimers formed in fAD through molecular modelling as there are no structures available from wet-lab studies till date. We analysed the binding interactions leading to formations of the dimers. Our next aim was to come up with a solution to treat AD using the method of drug repurposing. For that we used virtual screening and molecular docking simulations of the already existing anti-inflammatory drugs and studied their potency in resisting the formation of Aβ dimers. This is the first such report of drug repurposing for the treatment of AD, which might pave new pathways in therapy.}, } @article {pmid39867382, year = {2025}, author = {Poulet, PE and Tran, M and Tezenas du Montcel, S and Dubois, B and Durrleman, S and Jedynak, B}, title = {Prediction-powered Inference for Clinical Trials.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.01.15.25320578}, pmid = {39867382}, abstract = {Prediction-powered inference (PPI) [1] and its subsequent development called PPI++ [2] provide a novel approach to standard statistical estimation leveraging machine learning systems to enhance unlabeled data with predictions. We use this paradigm in clinical trials. The predictions are provided by disease progression models, providing prognostic scores for all the participants as a function of baseline covariates. The proposed method would empower clinical trials by providing untreated digital twins of the treated patients while remaining statistically valid. The potential implications of this new estimator of the treatment effect in a two-arm randomized clinical trial (RCT) are manifold. First, it leads to an overall reduction of the sample size required to reach the same power as a standard RCT. Secondly, it advocates for an imbalance of controls and treated patients, requiring fewer controls to achieve the same power. Finally, this technique directly transfers any disease prediction model trained on large cohorts to practical and scientifically valid use. In this paper, we demonstrate the theoretical properties of this estimator and illustrate them through simulations. We show that it is asymptotically unbiased for the Average Treatment Effect and derive an explicit formula for its variance. An application to an Alzheimer's disease clinical trial showcases the potential to reduce the sample size.}, } @article {pmid39865978, year = {2025}, author = {Theofanopoulou, C}, title = {Dancing towards speech improvement: Repurposing dance for motor speech deficits in neurodegenerative diseases.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877241313304}, doi = {10.1177/13872877241313304}, pmid = {39865978}, issn = {1875-8908}, abstract = {Dance or rhythmic movement-based training has demonstrated significant efficacy in addressing a range of motor and cognitive deficits associated with neurodegenerative diseases like Parkinson's and Alzheimer's diseases. Leveraging both human and non-human animal behavioral and neurobiological evidence, I hypothesize a possible untapped role of dance training in mitigating impairments in the motor control of speech, a complex sensorimotor behavior affected in these conditions. Here, this hypothesis is supported by an in-depth examination of motor speech deficits in Parkinson's and Alzheimer's diseases, at a behavioral, physiological, and neural level. Additionally, literature on the impact of dance training on behaviors and brain pathways possibly relevant to speech motor control in populations with neurodegenerative diseases is thoroughly reviewed. Synthesizing these findings, I propose repurposing dance as a novel treatment for motor speech deficits and outline specific experiments to test this hypothesis. By comprehensively investigating the full spectrum of the effects of a motor-based training, i.e., dance, on often overlooked motor-based behaviors, such as speech, we may uncover novel therapeutic avenues of a practice that has already shown promising implications.}, } @article {pmid39865938, year = {2025}, author = {Takeo, Y and Crite, M and Mehmood, K and DiMaio, D}, title = {γ-secretase facilitates retromer-mediated retrograde transport.}, journal = {Journal of cell science}, volume = {}, number = {}, pages = {}, doi = {10.1242/jcs.263538}, pmid = {39865938}, issn = {1477-9137}, support = {AI150897//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {Retromer mediates retrograde transport of protein cargos from endosomes to the trans-Golgi network (TGN). γ-secretase is a protease that cleaves the transmembrane domain of its target proteins. Although retromer can form a stable complex with γ-secretase, the functional consequences of this interaction are not known. Here, we report that retromer-mediated retrograde protein trafficking in cultured human epithelial cells is impaired by the γ-secretase inhibitor XXI or by knockout of the catalytic subunit of γ-secretase. These treatments inhibited endosome to TGN trafficking of retromer-dependent retrograde cellular cargos, divalent metal transporter 1 isoform II, cation-independent mannose-6-phosphate receptor, and shiga toxin, whereas trafficking of retromer-independent cargos cholera toxin and a mutant CIMPR unable to bind retromer was not affected. Moreover, we found that g-secretase associates with retromer cargos even in the absence of retromer. XXI treatment and PS1 knockout did not inhibit the ability of retromer or g-secretase to associate with cargo and did not affect the expression of retromer subunits or Rab7-GTP, which regulates retromer-cargo interaction. These results imply that the γ-secretase-retromer interaction facilitates retromer-mediated retrograde trafficking of cellular transmembrane proteins.}, } @article {pmid39865820, year = {2025}, author = {Vecchio, I and Colica, C}, title = {New Research on Biomarkers in Alzheimer's Continuum.}, journal = {Reviews on recent clinical trials}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115748871331138250114052615}, pmid = {39865820}, issn = {1876-1038}, abstract = {Alzheimer's disease (AD) is a multifactorial pathology, responsible for neurodegenerative disorders which in more than 60% of patients evolve into dementia. Comprehension of the molecular mechanisms underlying the pathology and the development of reliable diagnostic methods have made new and more effective therapies possible. In recent years, in addition to the classic anticholinesterases (AChEs), which can control the clinical symptoms of the disease, compounds able to reduce deposits of amyloid-β (Aβ) and/or tau (τ) protein aggregates, which are disease-modifying therapeutics (DMTs), have been studied. The results have shown that symptomatic therapy works best when administered in the disease's mild to moderate clinical phase. On the other hand, treatment with DMTs has been found to be more effective in the preclinical stage of AD, when Aβ and τ protein neurofibrillary tangles have not yet been compromised and patients still have a normal quality of life. This innovative approach requires the identification of specific biomarkers predictive of the disease, detectable many years before clinical signs are evident. Biomarkers allow early diagnosis, give indications of the possible development of dementia in the future, and make it possible to study the evolution of the disease. New scenarios, involving different pathways and approaches, could emerge and provide effective therapies to treat the very early stages of the disease and hamper its progression. The specific biomarkers studied so far have been reported here.}, } @article {pmid39865819, year = {2025}, author = {Zhang, D and Khan, MU and Safir Ullah, }, title = {Harmony in Motion: The Role of Exercise in Orchestrating Neuroprotection for Individuals with Alzheimer's Disease and Diabetes Examined from a Psychological Perspective.}, journal = {Current pharmaceutical biotechnology}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892010340895250119183021}, pmid = {39865819}, issn = {1873-4316}, abstract = {According to epidemiological studies, diabetes is more common in patients with AD, which suggests that diabetes is a significant risk factor for AD. Accelerating brain cell degeneration, worsening cognitive decline, and increasing susceptibility to AD can be attributed to pathogenic mechanisms linked to diabetes, such as impaired insulin signaling in the brain, neuroinflammation, oxidative stress, mitochondrial dysfunction, and vascular impairment. These factors can also lead to the accumulation of β-amyloid and tau protein phosphorylation. New research suggests that certain drugs used to manage diabetes have different levels of effectiveness in treating or preventing Alzheimer's disease. Exercise has numerous advantages, including the reduction of neuroinflammation, alleviation of oxidative stress and mitochondrial dysfunction, improvement of endothelial and cerebrovascular function, stimulation of neurogenesis, and prevention of pathological changes associated with diabetes-related Alzheimer's disease through various internal mechanisms. This study examined the development of Alzheimer's disease (AD) in relation to diabetes, evaluated the ability of specific antidiabetic drugs to prevent and treat AD, and investigated the impacts and underlying processes of exercise interventions in improving AD treatment for individuals with diabetes.}, } @article {pmid39865687, year = {2025}, author = {Gillman, A and Bourgeat, P and Cox, T and Villemagne, VL and Fripp, J and Huang, K and Williams, R and Shishegar, R and O'Keefe, G and Li, S and Krishnadas, N and Feizpour, A and Bozinovski, S and Rowe, CC and Doré, V}, title = {Digital detector PET/CT increases Centiloid measures of amyloid in Alzheimer's disease: A head-to-head comparison of cameras.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877241313063}, doi = {10.1177/13872877241313063}, pmid = {39865687}, issn = {1875-8908}, abstract = {BACKGROUND: The introduction of therapeutics for Alzheimer's disease has led to increased interest in precisely quantifying amyloid-β (Aβ) burden for diagnosis, treatment monitoring, and further clinical research. Recent positron emission tomography (PET) hardware innovations including digital detectors have led to superior resolution and sensitivity, improving quantitative accuracy. However, the effect of PET scanner on Centiloid remains relatively unexplored and is assumed to be minimized by harmonizing PET resolutions.

OBJECTIVE: To quantify the differences in Centiloid between scanners in a paired cohort.

METHODS: 36 participants from the Australian Imaging, Biomarker and Lifestyle study (AIBL) cohort were scanned within a year on two scanners. Each participant underwent [18]F-NAV4694 imaging on two of the three scanners investigated, the Siemens Vision, the Siemens mCT and the Philips Gemini. We compared Aβ Centiloid quantification between scanners and assessed the effectiveness of post-reconstruction PET resolution harmonization. We further compared the scanner differences in target sub-regions and with different reference regions to assess spatial variability.

RESULTS: Centiloid from the Vision camera was found to be significantly higher compared to the Gemini and mCT; the difference was greater at high-Centiloid levels. Post-reconstruction resolution harmonization only accounted for and corrected ∼20% of the Centiloid (CL) difference between scanners. We further demonstrated that residual differences have effects that vary spatially between different subregions of the Centiloid mask.

CONCLUSIONS: We have demonstrated that the type of PET scanner that a participant is scanned on affects Centiloid quantification, even when scanner resolution is harmonized. We conclude by highlighting the need for further investigation into harmonization techniques that consider scanner differences.}, } @article {pmid39865315, year = {2025}, author = {Lentzen, M and Vairavan, S and Muurling, M and Alepopoulos, V and Atreya, A and Boada, M and de Boer, C and Conde, P and Curcic, J and Frisoni, G and Galluzzi, S and Gjestsen, MT and Gkioka, M and Grammatikopoulou, M and Hausner, L and Hinds, C and Lazarou, I and de Mendonça, A and Nikolopoulos, S and Religa, D and Scebba, G and Jelle Visser, P and Wittenberg, G and Narayan, VA and Coello, N and Brem, AK and Aarsland, D and Fröhlich, H and , }, title = {RADAR-AD: assessment of multiple remote monitoring technologies for early detection of Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {29}, pmid = {39865315}, issn = {1758-9193}, support = {806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnosis ; Female ; Male ; Aged ; *Early Diagnosis ; Aged, 80 and over ; Remote Sensing Technology/methods/instrumentation ; Machine Learning ; Neuropsychological Tests ; Middle Aged ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide, leading to cognitive and functional decline. Early detection and intervention are crucial for enhancing the quality of life of patients and their families. Remote Monitoring Technologies (RMTs) offer a promising solution for early detection by tracking changes in behavioral and cognitive functions, such as memory, language, and problem-solving skills. Timely detection of these symptoms can facilitate early intervention, potentially slowing disease progression and enabling appropriate treatment and care.

METHODS: The RADAR-AD study was designed to evaluate the accuracy and validity of multiple RMTs in detecting functional decline across various stages of AD in a real-world setting, compared to standard clinical rating scales. Our approach involved a univariate analysis using Analysis of Covariance (ANCOVA) to analyze individual features of six RMTs while adjusting for variables such as age, sex, years of education, clinical site, BMI and season. Additionally, we employed four machine learning classifiers - Logistic Regression, Decision Tree, Random Forest, and XGBoost - using a nested cross-validation approach to assess the discriminatory capabilities of the RMTs.

RESULTS: The ANCOVA results indicated significant differences between healthy and AD subjects regarding reduced physical activity, less REM sleep, altered gait patterns, and decreased cognitive functioning. The machine-learning-based analysis demonstrated that RMT-based models could identify subjects in the prodromal stage with an Area Under the ROC Curve of 73.0 %. In addition, our findings show that the Amsterdam iADL questionnaire has high discriminatory abilities.

CONCLUSIONS: RMTs show promise in AD detection already in the prodromal stage. Using them could allow for earlier detection and intervention, thereby improving patients' quality of life. Furthermore, the Amsterdam iADL questionnaire holds high potential when employed remotely.}, } @article {pmid39865265, year = {2025}, author = {Kim, BH and Kim, S and Nam, Y and Park, YH and Shin, SM and Moon, M}, title = {Second-generation anti-amyloid monoclonal antibodies for Alzheimer's disease: current landscape and future perspectives.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {6}, pmid = {39865265}, issn = {2047-9158}, support = {RS-2023-00240010//National Research Foundation of Korea/ ; NRF-2022R1A6A3A13053190//National Research Foundation of Korea/ ; RS-2024-00450135//National Research Foundation of Korea/ ; RS-2023-00212388//National Research Foundation of Korea/ ; RS-2023-00273557//National Research Foundation of Korea/ ; RS-2023-KH138733//Korea Health Industry Development Institute/Republic of Korea ; }, mesh = {*Alzheimer Disease/drug therapy/immunology ; Humans ; *Antibodies, Monoclonal/therapeutic use ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors/metabolism ; Antibodies, Monoclonal, Humanized/therapeutic use ; Animals ; }, abstract = {Alzheimer's disease (AD) is the most common type of dementia. Monoclonal antibodies (MABs) serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors, such as amyloid-β (Aβ) peptide, tau protein, and neuroinflammation. Specifically, based on their efficacy in removing Aβ plaques from the brains of patients with AD, the U.S. Food and Drug Administration has approved three anti-amyloid MABs, aducanumab (Aduhelm®), lecanemab (Leqembi®), and donanemab (Kisunla™). Notably, lecanemab received traditional approval after demonstrating clinical benefit, supporting the Aβ cascade hypothesis. These MABs targeting Aβ are categorized based on their affinity to diverse conformational features of Aβ, including monomer, fibril, protofibril, and plaque forms of Aβ as well as pyroglutamate Aβ. First-generation MABs targeting the non-toxic monomeric Aβ, such as solanezumab, bapineuzumab, and crenezumab, failed to demonstrate clinical benefit for AD in clinical trials. In contrast, second-generation MABs, including aducanumab, lecanemab, donanemab, and gantenerumab directed against pathogenic Aβ species and aggregates have shown that reducing Aβ deposition can be an effective strategy to slow cognitive impairment in AD. In this review, we provide a comprehensive overview of the current status, mechanisms, outcomes, and limitations of second-generation MABs for the clinical treatment of AD. Moreover, we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD.}, } @article {pmid39864933, year = {2025}, author = {Videnovic, A and Cai, A}, title = {Irregular sleep-wake rhythm disorder: From the pathophysiologic perspective to the treatment.}, journal = {Handbook of clinical neurology}, volume = {206}, number = {}, pages = {71-87}, doi = {10.1016/B978-0-323-90918-1.00006-X}, pmid = {39864933}, issn = {0072-9752}, mesh = {Humans ; *Sleep Disorders, Circadian Rhythm/therapy/physiopathology/diagnosis ; Circadian Rhythm/physiology ; }, abstract = {Irregular sleep-wake rhythm disorder (ISWRD) is an intrinsic circadian rhythm disorder caused by loss of the brain's circadian regulation, through changes of the input and/or output to the suprachiasmatic nucleus (SCN), or of the SCN itself. Although there are limited prevalence data for this rare disease, ISWRD is associated with neurodegenerative disorders, including the Alzheimer disease (AD) and the Parkinson disease (PD), which will become increasingly prevalent in an aging population. It additionally presents in childhood developmental disorders, psychiatric disorders, and traumatic brain injury (TBI). Patients present with unpredictable, short sleep periods over a 24-h period, with significant day-to-day and weekly variability. Symptoms manifest as insomnia and excessive daytime sleepiness. Sleep logs and actigraphy monitoring capture rest-activity patterns required for diagnosis. Treatment aims to enhance external circadian cues through timed light therapy, behavioral activity regimens, and melatonin, but efficacy remains quite limited. Pathophysiology of ISWRD in association with various diseases and their specific management are discussed. There is a need for further investigation of disease pathophysiology, development of widely applicable tools for diagnosis, and development of treatments.}, } @article {pmid39864928, year = {2025}, author = {Liu, YJ and Swaab, DF and Zhou, JN}, title = {Sleep-wake modulation and pathogenesis of Alzheimer disease: Suggestions for postponement and treatment.}, journal = {Handbook of clinical neurology}, volume = {206}, number = {}, pages = {211-229}, doi = {10.1016/B978-0-323-90918-1.00001-0}, pmid = {39864928}, issn = {0072-9752}, mesh = {Humans ; *Alzheimer Disease/therapy ; *Melatonin/metabolism/therapeutic use ; *Circadian Rhythm/physiology ; *Sleep Wake Disorders/therapy/etiology ; *Sleep/physiology ; Animals ; }, abstract = {Sleep-wake disorders are recognized as one of the earliest symptoms of Alzheimer disease (AD). Accumulating evidence has highlighted a significant association between sleep-wake disorders and AD pathogenesis, suggesting that sleep-wake modulation could be a promising approach for postponing AD onset. The suprachiasmatic nucleus (SCN) and the pineal hormone melatonin are major central modulating components of the circadian rhythm system. Cerebrospinal fluid (CSF) melatonin levels are dramatically decreased in AD. Interestingly, the number of neurofibrillary tangles in the hippocampus, which is one of the two major neuropathologic AD biomarkers, increases in parallel with the decrease in CSF melatonin levels. Furthermore, a decrease in salivary melatonin levels in middle-aged persons is a significant risk factor for the onset of the early stages of AD. Moreover, the disappearance of rhythmic fluctuations in melatonin may be one of the best biomarkers for AD diagnosis. Light therapy combined with melatonin supplementation is the recommended first-line treatment for sleep-wake disorders in AD patients and may be beneficial for ameliorating cognitive impairment. Sleep-wake cycle modulation based on AD risk gene presence is a promising early intervention for AD onset postponement.}, } @article {pmid39864834, year = {2025}, author = {Zhou, Y and Dou, L and Wang, L and Chen, J and Mao, R and Zhu, L and Liu, D and Zheng, K}, title = {Growth and differentiation factor 15: An emerging therapeutic target for brain diseases.}, journal = {Bioscience trends}, volume = {}, number = {}, pages = {}, doi = {10.5582/bst.2024.01305}, pmid = {39864834}, issn = {1881-7823}, abstract = {Growth and differentiation factor 15 (GDF15), a member of the transforming growth factor-βsuperfamily, is considered a stress response factor and has garnered increasing attention in recent years due to its roles in neurological diseases. Although many studies have suggested that GDF15 expression is elevated in patients with neurodegenerative diseases (NDDs), glioma, and ischemic stroke, the effects of increased GDF15 expression and the potential underlying mechanisms remain unclear. Notably, many experimental studies have shown the multidimensional beneficial effects of GDF15 on NDDs, and GDF15 overexpression is able to rescue NDD-associated pathological changes and phenotypes. In glioma, GDF15 exerts opposite effects, it is both protumorigenic and antitumorigenic. The causes of these conflicting findings are not comprehensively clear, but inhibiting GDF15 is helpful for suppressing tumor progression. GDF15 is also regarded as a biomarker of poor clinical outcomes in ischemic stroke patients, and targeting GDF15 may help prevent this disease. Thus, we systematically reviewed the synthesis, transcriptional regulation, and biological functions of GDF15 and its related signaling pathways within the brain. Furthermore, we explored the potential of GDF15 as a therapeutic target and assessed its clinical applicability in interventions for brain diseases. By integrating the latest research findings, this study provides new insights into the future treatment of neurological diseases.}, } @article {pmid39864832, year = {2025}, author = {Kim, JS and Cho, Y and Lee, J and Cho, H and Han, S and Lee, Y and Jeon, Y and Kim, TK and Hong, JM and Im, J and Chae, M and Lee, Y and Kim, H and Park, SY and Kim, SH and Yim, JH and Jo, DG}, title = {N[5]-((perfluorophenyl)amino)glutamine regulates BACE1, tau phosphorylation, synaptic function, and neuroinflammation in Alzheimer's disease models.}, journal = {Bioscience trends}, volume = {}, number = {}, pages = {}, doi = {10.5582/bst.2024.01360}, pmid = {39864832}, issn = {1881-7823}, abstract = {Alzheimer's disease (AD) is the most common type of dementia. Its incidence is rising rapidly as the global population ages, leading to a significant social and economic burden. AD involves complex pathologies, including amyloid plaque accumulation, synaptic dysfunction, and neuroinflammation. This study explores the therapeutic potential of N [5] -((perfluorophenyl)amino)glutamine (RA-PF), a derivative of γ-glutamyl-N'-(2-hydroxyphenyl)hydrazide (Ramalin), a compound with antioxidant and anti-inflammatory properties. Administration of RA-PF to 5xFAD mice decreases BACE1, reduces Aβ plaque deposition, inhibits microglial activation, restores synaptic transmission, and improves mitochondrial motility, leading to the recovery of cognitive function. Additionally, RA-PF treatment in 3xTg-AD mice alleviates anxiety-like behaviors, tau phosphorylation via inactivating GSK-3β, and BACE1 expression. Further transcriptomic analysis reveals RA-PF treatment in AD mice models recovers phagosome, inflammation, NOD-like receptor, presynaptic membrane, and postsynaptic membrane related signaling pathways. These findings suggest that RA-PF effectively targets multiple aspects of AD pathology, offering a novel multi-target approach for AD treatment.}, } @article {pmid39864562, year = {2025}, author = {Hong, X and Chen, T and Liu, Y and Li, J and Huang, D and Ye, K and Liao, W and Wang, Y and Liu, M and Luan, P}, title = {Design, current states, and challenges of nanomaterials in anti-neuroinflammation: A perspective on Alzheimer's disease.}, journal = {Ageing research reviews}, volume = {105}, number = {}, pages = {102669}, doi = {10.1016/j.arr.2025.102669}, pmid = {39864562}, issn = {1872-9649}, abstract = {Alzheimer's disease (AD), an age-related neurodegenerative disease, brings huge damage to the society, to the whole family and even to the patient himself. However, until now, the etiological factor of AD is still unknown and there is no effective treatment for it. Massive deposition of amyloid-beta peptide(Aβ) and hyperphosphorylation of Tau proteins are acknowledged pathological features of AD. Recent studies have revealed that neuroinflammation plays a pivotal role in the pathology of AD. With the rise of nanomaterials in the biomedical field, researchers are exploring how the unique properties of these materials can be leveraged to develop effective treatments for AD. This article has summarized the influence of neuroinflammation in AD, the design of nanoplatforms, and the current research status and inadequacy of nanomaterials in improving neuroinflammation in AD.}, } @article {pmid39863332, year = {2025}, author = {Leng, Y and Ding, H and Ang, TFA and Au, R and Doraiswamy, PM and Liu, C}, title = {Identifying proteomic prognostic markers for Alzheimer's disease with survival machine learning: The Framingham Heart Study.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {2}, pages = {100021}, doi = {10.1016/j.tjpad.2024.100021}, pmid = {39863332}, issn = {2426-0266}, mesh = {Humans ; *Machine Learning ; Female ; Male ; *Alzheimer Disease/diagnosis ; Middle Aged ; *Biomarkers/blood ; *Proteomics ; Prognosis ; Aged ; Adult ; Longitudinal Studies ; Proportional Hazards Models ; }, abstract = {BACKGROUND: Protein abundance levels, sensitive to both physiological changes and external interventions, are useful for assessing the Alzheimer's disease (AD) risk and treatment efficacy. However, identifying proteomic prognostic markers for AD is challenging by their high dimensionality and inherent correlations.

METHODS: Our study analyzed 1128 plasma proteins, measured by the SOMAscan platform, from 858 participants 55 years and older (mean age 63 years, 52.9 % women) of the Framingham Heart Study (FHS) Offspring cohort. We conducted regression analysis and machine learning models, including LASSO-based Cox proportional hazard regression model (LASSO) and generalized boosted regression model (GBM), to identify protein prognostic markers. These markers were used to construct a weighted proteomic composite score, the AD prediction performance of which was assessed using time-dependent area under the curve (AUC). The association between the composite score and memory domain was examined in 339 (of the 858) participants with available memory scores, and in a separate group of 430 participants younger than 55 years (mean age 46, 56.7 % women).

RESULTS: Over a mean follow-up of 20 years, 132 (15.4 %) participants developed AD. After adjusting for baseline age, sex, education, and APOE ε4 + status, regression models identified 309 proteins (P ≤ 0.2). After applying machine learning methods, nine of these proteins were selected to develop a composite score. This score improved AD prediction beyond the factors of age, sex, education, and APOE ε4 + status across 15-25 years of follow-up, achieving its peak AUC of 0.84 in the LASSO model at the 22-year follow-up. It also showed a consistent negative association with memory scores in the 339 participants (beta = -0.061, P = 0.046), 430 participants (beta = -0.060, P = 0.018), and the pooled 769 samples (beta = -0.058, P = 0.003).

CONCLUSION: These findings highlight the utility of machine learning method in identifying proteomic markers in improving AD prediction and emphasize the complex pathology of AD. The composite score may aid early AD detection and efficacy monitoring, warranting further validation in diverse populations.}, } @article {pmid39863322, year = {2025}, author = {Cox, CG and Brush, BL and Kobayashi, LC and Roberts, JS}, title = {Determinants of dementia diagnosis in U.S. primary care in the past decade: A scoping review.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {2}, pages = {100035}, doi = {10.1016/j.tjpad.2024.100035}, pmid = {39863322}, issn = {2426-0266}, mesh = {Humans ; *Primary Health Care ; United States/epidemiology ; *Dementia/diagnosis/epidemiology ; Alzheimer Disease/diagnosis/epidemiology ; }, abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) are chronically underdiagnosed in the U.S., particularly among minoritized racial and ethnic groups. Primary care providers are at the forefront of diagnosis given the increasing prevalence of cases and shortage of dementia specialists. Advances in policy, detection, and treatment in the past decade necessitate an updated review of the current state of determinants of ADRD diagnosis in U.S. primary care settings.

METHODS: Following Joanna Briggs Institute guidelines, we conducted a scoping literature review on ADRD diagnosis among older adults in U.S. primary care settings. Studies published in English from January 2010 to January 2024 were retrieved from PubMed, PsycINFO, and CINAHL. We extracted primary data on study characteristics and synthesized key findings according to facilitators, barriers, and rates of diagnosis in primary care.

RESULTS: Of 563 articles retrieved, 12 met eligibility criteria. Three studies reported rates of diagnosis, and all but one reported facilitators and/or barriers to diagnosis. ADRD remains underdiagnosed in primary care settings, especially in the earliest symptomatic stage (i.e., mild cognitive impairment). Multi-level barriers and facilitators were identified including individual beliefs about ADRD (e.g., value of early diagnosis), interpersonal relationships between patients and their family members and providers (e.g., importance of an established clinical relationship), and healthcare system limitations (e.g., insufficient resources and training).

CONCLUSION: Despite national policy efforts to improve timely diagnosis of ADRD, underdiagnosis remains a clinical and public health challenge. Increased attention to social and community contexts will be important for future research and intervention.}, } @article {pmid39863320, year = {2025}, author = {Srisuwan, P and Nakawiro, D and Kuha, O and Kengpanich, S and Gesakomol, K and Chansirikarnjana, S}, title = {Efficacy of a group-based 8-week multicomponent cognitive training on cognition, mood and activities of daily living among healthy older adults: A two-year follow-up of a randomized controlled trial.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {2}, pages = {100033}, doi = {10.1016/j.tjpad.2024.100033}, pmid = {39863320}, issn = {2426-0266}, mesh = {Humans ; Aged ; *Activities of Daily Living ; Female ; Male ; *Affect/physiology ; *Cognition/physiology ; Single-Blind Method ; Follow-Up Studies ; Thailand ; Cognitive Dysfunction/therapy/psychology ; Executive Function/physiology ; Cognitive Behavioral Therapy/methods ; Neuropsychological Tests ; Middle Aged ; Mental Status and Dementia Tests ; Independent Living ; Cognitive Training ; }, abstract = {BACKGROUND: Cognitive training (CT) has been one of the important non-pharmaceutical interventions that could delay cognitive decline. Currently, no definite CT methods are available. Furthermore, little attention has been paid to the effect of CT on mood and instrumental activities of daily living (IADL).

OBJECTIVES: To assess the effectiveness of a multicomponent CT using a training program of executive functions, attention, memory and visuospatial functions (TEAM-V Program) on cognition, mood and instrumental ADL.

DESIGN: A randomized, single-blinded, treatment-as-usual controlled trial.

SETTING: Geriatric clinic in Bangkok, Thailand.

PARTICIPANTS: 80 nondemented community-dwelling older adults (mean age 65.7 ± 4.3 years).

INTERVENTION: The CT (TEAM-V) Program or the treatment-as-usual controlled group. The TEAM-V intervention was conducted over 5 sessions, with a 2-week interval between each session. A total of 80 participants were randomized (n = 40 the TEAM-V Program; n = 40 the control group).

MEASUREMENTS: The Thai version of Montreal Cognitive Assessment (MoCA), The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), Thai version of Hospital Anxiety and Depression Scale (HADS) and The Chula ADL were used to assess at baseline, 6 months, 1 year and 2 years.

RESULTS: Compared with the control arm (n = 36), the TEAM-V Program (n = 39) was associated with significantly improved general cognition (MoCA, P = 0.02) at 2 years. Compared with baseline, participants receiving the TEAM-V Program were associated with significantly improved immediate recall (word recall task, P < 0.001), retrieval and retention of memory processes (word recognition task, P = 0.01) and attention (number cancellation part A, P = 0.01) at 2 years. No training effects on anxiety (P = 0.94), depression (P = 0.093) and IADL (P = 0.48) were detected.

CONCLUSIONS: The TEAM-V Program was effective in improving global cognitive function. Even though, the program did not significantly improve anxiety, depression and IADL compared with the control group, memory and attention improved in the intervention group compared with baseline. Further studies incorporating a larger sample size, longitudinal follow-up and higher-intensity CT should be conducted.}, } @article {pmid39863318, year = {2025}, author = {LoBue, C and Chiang, HS and Salter, A and McClintock, S and Nguyen, TP and Logan, R and Smernoff, E and Pandya, S and Hart, J}, title = {High definition transcranial direct current stimulation as an intervention for cognitive deficits in Alzheimer's dementia: A randomized controlled trial.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {2}, pages = {100023}, doi = {10.1016/j.tjpad.2024.100023}, pmid = {39863318}, issn = {2426-0266}, support = {K23 AG075261/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Transcranial Direct Current Stimulation/methods ; *Alzheimer Disease/therapy ; Double-Blind Method ; Female ; Male ; Aged ; *Cognitive Dysfunction/therapy ; Pilot Projects ; Prefrontal Cortex ; Neuropsychological Tests ; Executive Function/physiology ; Aged, 80 and over ; Treatment Outcome ; }, abstract = {BACKGROUND: Recent disease-modifying treatments for Alzheimer's disease show promise to slow cognitive decline, but show no efficacy towards reducing symptoms already manifested.

OBJECTIVES: To investigate the efficacy of a novel noninvasive brain stimulation technique in modulating cognitive functioning in Alzheimer's dementia (AD).

DESIGN: Pilot, randomized, double-blind, parallel, sham-controlled study SETTING: Clinical research site at UT Southwestern Medical Center PARTICIPANTS: Twenty-five participants with clinical diagnoses of AD were enrolled from cognition specialty clinics.

INTERVENTION: Treatment consisted of high definition transcranial direct current stimulation (HD-tDCS) delivered for 20 min over the medial prefrontal cortex. Ten sessions of sham, 1 mA, or 2 mA stimulation were received.

MEASUREMENTS: Cognitive outcomes were measured at baseline, after the last HD-tDCS session, and 8-weeks post-treatment. The primary outcome was change in total learning and delayed recall on the Rey Auditory Verbal Learning Test (RAVLT) immediately post-treatment and at 8-weeks. Secondary outcomes included measures of language, processing speed, and executive functioning. A multi-stage approach was used to examine cognitive outcomes, which included evaluation of effect sizes, statistical effects, and rate of clinically meaningful responses.

RESULTS: In this pilot trial, no statistically significant differences on cognitive outcomes were found between sham and active HD-tDCS immediately post-treatment (p's > 0.05). However, moderate-to-large effect sizes were identified for enhanced RAVLT total learning (Cohen's d = 0.69-0.93) and phonemic fluency (d = 1.08-1.49) for both active HD-tDCS conditions compared to sham, with rates of clinically relevant improvement between 25 and 33%. Meaningful enhancement persisted to 8 weeks only for the 1 mA condition.

CONCLUSIONS: Multiple sessions of HD-tDCS over the medial prefrontal cortex appears to have potential to produce meaningful cognitive enhancements in a proportion of patients having AD with improvements maintained for at least 8 weeks in some.

ClinicalTrials.gov (NCT05270408). Registered December 30, 2021.}, } @article {pmid39862174, year = {2025}, author = {Chekani, F and Mirchandani, K and Zaki, S and Goswami, S and Sharma, M}, title = {Utilization of Potentially Inappropriate Sedative-Hypnotic and Atypical Antipsychotic Medications among Elderly Individuals with Insomnia and Alzheimer's Disease.}, journal = {Sleep}, volume = {}, number = {}, pages = {}, doi = {10.1093/sleep/zsaf003}, pmid = {39862174}, issn = {1550-9109}, abstract = {STUDY OBJECTIVES: This study assessed the utilization of potentially inappropriate medications (PIM) including oral sedative-hypnotic and atypical antipsychotic (OSHAA), healthcare resource utilization (HCRU), and costs among elderly individuals with insomnia and in the subpopulation with Alzheimer's Disease (AD) who also had a diagnosis of insomnia.

METHODS: Using claims database containing International Classification of Diseases, 10th Revision (ICD-10) codes, the cohort included individuals aged ≥ 65 with incident insomnia (EI, N=152,969) and AD insomnia subpopulation (ADI, N=4,888). Proportion of patients utilizing atypical antipsychotics or oral sedative-hypnotic medications, namely z-drugs, benzodiazepines, doxepin, Dual Orexin Receptor Antagonists (DORAs), and melatonin agonists, were assessed. Inappropriate OSHAA utilization was defined as per the American Geriatrics Society (AGS) Beers criteria. Multivariable models were utilized to compare HCRU and costs between PIM-OSHAA and no PIM-OSHAA groups.

RESULTS: Among the EI cohort, z-drugs (13.39%) were the most commonly utilized OSHAA, and in the ADI cohort, it was AAPs (29.97%). PIM-OSHAA was utilized by 20% of the EI and 35% of the ADI cohorts. Patients with PIM-OSHAA use among the EI cohort had a higher annualized adjusted mean HCRU (pharmacy visits: 31.21 vs. 23.68; ambulatory & outpatient visits: 18.55 vs. 16.85) and costs, primarily due to medical costs (mean total cost: $36,676.08 vs. $31,346.54) compared to those without.

CONCLUSIONS: Substantial utilization of PIM-OSHAA was observed in EI and ADI cohorts. PIM-OSHAA use was associated with higher HCRU and costs. These findings underscore the importance of appropriate treatment strategies for insomnia in the elderly population especially in those with concurrent AD.}, } @article {pmid39862109, year = {2025}, author = {Lu, X and Shan, G}, title = {Adaptive promising zone design for sequential parallel comparison design with continuous outcomes.}, journal = {Clinical trials (London, England)}, volume = {}, number = {}, pages = {17407745241309056}, doi = {10.1177/17407745241309056}, pmid = {39862109}, issn = {1740-7753}, abstract = {INTRODUCTION: The sequential parallel comparison design has emerged as a valuable tool in clinical trials with high placebo response rates. To further enhance its efficiency and effectiveness, adaptive strategies, such as sample size adjustment and allocation ratio modification can be employed.

METHODS: We compared the performance of Jennison and Turnbull's method and the Promising Zone approach for sample size adjustment in a two-phase sequential parallel comparison design study. We also evaluated the impact of allocation ratio adjustments using Neyman and Optimal allocation strategies. Various scenarios were simulated to assess the effects of different design parameters, including weight in the test statistic, initial randomization ratio, and interim analysis timing.

RESULTS: The Promising Zone approach demonstrated superior or comparable power to Jennison and Turnbull's method at equivalent expected sample sizes while maintaining the intuitive property that more promising interim results lead to smaller required follow-up sample sizes. However, the Promising Zone approach may require a larger maximum possible sample size in some cases. The addition of allocation ratio adjustments offered minimal improvements overall, but showed potential benefits when the variance in the treatment group was larger than that in the placebo group. We also applied our findings to a real-world example from the AVP-923 trial in patients with Alzheimer's disease-related agitation, demonstrating the practical implications of adaptive sequential parallel comparison designs in clinical research.

DISCUSSION: Adaptive strategies can significantly enhance the efficiency of sequential parallel comparison designs. The choice between sample size adjustment methods should consider trade-offs between power, expected sample size, and maximum adjusted sample size. Although allocation ratio adjustments showed limited overall impact, they may be beneficial in specific scenarios. Future research should explore the application of these adaptive strategies to binary and survival outcomes in sequential parallel comparison designs.}, } @article {pmid39862009, year = {2025}, author = {Lu, F and Ma, Q and Shi, C and Yue, W}, title = {Changes in the Parietal Lobe Subregion Volume at Various Stages of Alzheimer's Disease and the Role in Cognitively Normal and Mild Cognitive Impairment Conversion.}, journal = {Journal of integrative neuroscience}, volume = {24}, number = {1}, pages = {25991}, doi = {10.31083/JIN25991}, pmid = {39862009}, issn = {0219-6352}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/physiopathology ; *Cognitive Dysfunction/diagnostic imaging/physiopathology/pathology ; Male ; Female ; *Parietal Lobe/diagnostic imaging/pathology ; Aged ; *Disease Progression ; *Magnetic Resonance Imaging ; Aged, 80 and over ; }, abstract = {BACKGROUND: Volume alterations in the parietal subregion have received less attention in Alzheimer's disease (AD), and their role in predicting conversion of mild cognitive impairment (MCI) to AD and cognitively normal (CN) to MCI remains unclear. In this study, we aimed to assess the volumetric variation of the parietal subregion at different cognitive stages in AD and to determine the role of parietal subregions in CN and MCI conversion.

METHODS: We included 662 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 228 CN, 221 early MCI (EMCI), 112 late MCI (LMCI), and 101 AD participants. We measured the volume of the parietal subregion based on the Human Brainnetome Atlas (BNA-246) using voxel-based morphometry among individuals at various stages of AD and the progressive and stable individuals in CN and MCI. We then calculated the area under the curve (AUC) of the receiver operating characteristic (ROC) curve to test the ability of parietal subregions to discriminate between different cognitive groups. The Cox proportional hazard model was constructed to determine which specific parietal subregions, alone or in combination, could be used to predict progression from MCI to AD and CN to MCI. Finally, we examined the relationship between the cognitive scores and parietal subregion volume in the diagnostic groups.

RESULTS: The left inferior parietal lobule (IPL)_6_5 (rostroventral area 39) showed the best ability to discriminate between patients with AD and those with CN (AUC = 0.688). The model consisting of the left IPL_6_4 (caudal area 40) and bilateral IPL_6_5 showed the best combination for predicting the CN progression to MCI. The left IPL_6_1 (caudal area 39) showed the best predictive power in predicting the progression of MCI to AD. Certain subregions of the volume correlated with cognitive scales.

CONCLUSION: Subregions of the angular gyrus are essential in the early onset and subsequent development of AD, and early detection of the volume of these regions may be useful in identifying the tendency to develop the disease and its treatment.}, } @article {pmid39862001, year = {2025}, author = {Chen, D and Sun, Y}, title = {Current Status of Plant-Based Bioactive Compounds as Therapeutics in Alzheimer's Diseases.}, journal = {Journal of integrative neuroscience}, volume = {24}, number = {1}, pages = {23090}, doi = {10.31083/JIN23090}, pmid = {39862001}, issn = {0219-6352}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Plants, Medicinal/chemistry ; Animals ; Phytochemicals/pharmacology ; Phytotherapy ; }, abstract = {Alzheimer's disease (AD) is a common central neurodegenerative disease disorder characterized primarily by cognitive impairment and non-cognitive neuropsychiatric symptoms that significantly impact patients' daily lives and behavioral functioning. The pathogenesis of AD remains unclear and current Western medicines treatment are purely symptomatic, with a singular pathway, limited efficacy, and substantial toxicity and side effects. In recent years, as research into AD has deepened, there has been a gradual increase in the exploration and application of medicinal plants for the treatment of AD. Numerous studies have shown that medicinal plants and their active ingredients can potentially mitigate AD by regulating various molecular mechanisms, including the production and aggregation of pathological proteins, oxidative stress, neuroinflammation, apoptosis, mitochondrial dysfunction, neurogenesis, neurotransmission, and the brain-gut microbiota axis. In this review, we analyzed the pathogenesis of AD and comprehensively summarized recent advancements in research on medicinal plants for the treatment of AD, along with their underlying mechanisms and clinical evidence. Ultimately, we aimed to provide a reference for further investigation into the specific mechanisms through which medicinal plants prevent and treat AD, as well as for the identification of efficacious active ingredients derived from medicinal plants.}, } @article {pmid39861773, year = {2025}, author = {Ortiz-Islas, E and Montes, P and Rodríguez-Pérez, CE and Ruiz-Sánchez, E and Sánchez-Barbosa, T and Pichardo-Rojas, D and Zavala-Tecuapetla, C and Carvajal-Aguilera, K and Campos-Peña, V}, title = {Evolution of Alzheimer's Disease Therapeutics: From Conventional Drugs to Medicinal Plants, Immunotherapy, Microbiotherapy and Nanotherapy.}, journal = {Pharmaceutics}, volume = {17}, number = {1}, pages = {}, pmid = {39861773}, issn = {1999-4923}, support = {CF-2023-G-971 and CBF-2023-2024-1982//Ciencia de Frontera/ ; }, abstract = {Alzheimer's disease (AD) represents an escalating global health crisis, constituting the leading cause of dementia among the elderly and profoundly impairing their quality of life. Current FDA-approved drugs, such as rivastigmine, donepezil, galantamine, and memantine, offer only modest symptomatic relief and are frequently associated with significant adverse effects. Faced with this challenge and in line with advances in the understanding of the pathophysiology of this neurodegenerative condition, various innovative therapeutic strategies have been explored. Here, we review novel approaches inspired by advanced knowledge of the underlying pathophysiological mechanisms of the disease. Among the therapeutic alternatives, immunotherapy stands out, employing monoclonal antibodies to specifically target and eliminate toxic proteins implicated in AD. Additionally, the use of medicinal plants is examined, as their synergistic effects among components may confer neuroprotective properties. The modulation of the gut microbiota is also addressed as a peripheral strategy that could influence neuroinflammatory and degenerative processes in the brain. Furthermore, the therapeutic potential of emerging approaches, such as the use of microRNAs to regulate key cellular processes and nanotherapy, which enables precise drug delivery to the central nervous system, is analyzed. Despite promising advances in these strategies, the incidence of Alzheimer's disease continues to rise. Therefore, it is proposed that achieving effective treatment in the future may require the integration of combined approaches, maximizing the synergistic effects of different therapeutic interventions.}, } @article {pmid39861082, year = {2024}, author = {Chamberlin, SR and Zweig, JA and Neff, CJ and Marney, L and Choi, J and Yang, L and Maier, CS and Soumyanath, A and McWeeney, S and Gray, NE}, title = {Multi-Omics Analysis in Mouse Primary Cortical Neurons Reveals Complex Positive and Negative Biological Interactions Between Constituent Compounds of Centella asiatica.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {1}, pages = {}, pmid = {39861082}, issn = {1424-8247}, support = {U19 AT010829/AT/NCCIH NIH HHS/United States ; S10 OD026922/OD/NIH HHS/United States ; S10 RR027878/RR/NCRR NIH HHS/United States ; U19 AT010829, U19 AT010829-02S1/AT/NCCIH NIH HHS/United States ; K08 AT012477/AT/NCCIH NIH HHS/United States ; }, abstract = {Background: A water extract of the Ayurvedic plant Centella asiatica (L.) Urban, family Apiaceae (CAW), improves cognitive function in mouse models of aging and Alzheimer's disease and affects dendritic arborization, mitochondrial activity, and oxidative stress in mouse primary neurons. Triterpenes (TT) and caffeoylquinic acids (CQA) are constituents associated with these bioactivities of CAW, although little is known about how interactions between these compounds contribute to the plant's therapeutic benefit. Methods: Mouse primary cortical neurons were treated with CAW or equivalent concentrations of four TT combined, eight CQA combined, or these twelve compounds combined (TTCQA). Treatment effects on the cell transcriptome (18,491 genes) and metabolome (192 metabolites) relative to vehicle control were evaluated using RNAseq and metabolomic analyses, respectively. Results: Extensive differentially expressed genes (DEGs) were seen with all treatments, as well as evidence of interactions between compounds. Notably, many DEGs seen with TT treatment were not observed in the TTCQA condition, possibly suggesting CQA reduced the effects of TT. Moreover, additional gene activity seen with CAW as compared to TTCQA indicates the presence of additional compounds in CAW that further modulate TTCQA interactions. Weighted Gene Correlation Network Analysis (WGCNA) identified 4 gene co-expression modules altered by treatments that were associated with extracellular matrix organization, fatty acid metabolism, cellular response to stress and stimuli, and immune function. Compound interaction patterns were seen at the eigengene level in these modules. Interestingly, in metabolomics analysis, the TTCQA treatment saw the highest number of changes in individual metabolites (20), followed by CQA (15), then TT (8), and finally CAW (3). WGCNA analysis found two metabolomics modules with significant eigenmetabolite differences for TT and CQA and possible compound interactions at this level. Conclusions: Four gene expression modules and two metabolite modules were altered by the four treatment types applied. This methodology demonstrated the existence of both negative and positive interactions between TT, CQA, and additional compounds found in CAW on the transcriptome and metabolome of mouse primary cortical neurons.}, } @article {pmid39860337, year = {2025}, author = {Long, C and Fritts, A and Broadway, J and Brawman-Mintzer, O and Mintzer, J}, title = {Neuroinflammation: A Driving Force in the Onset and Progression of Alzheimer's Disease.}, journal = {Journal of clinical medicine}, volume = {14}, number = {2}, pages = {}, pmid = {39860337}, issn = {2077-0383}, abstract = {Background/Objectives: The goal of this commentary is to highlight several key components of the inflammatory process as it relates to amyloid toxicity in Alzheimer's disease (AD), including the role of neuroinflammatory factors and peripheral inflammatory events. Methods: Google Scholar and PubMed were used to find articles with the following keywords: Alzheimer's disease, amyloids, neuroinflammation, peripheral inflammation, microglia, cytokines, and treatments. Sources that were case reports, not peer-reviewed, or older than 30 years were excluded. Abstracts were reviewed first for their relevance before the full text was considered. Methods sections were reviewed to ensure the interventional papers included were randomized controlled trials, meta-analyses, or systematic reviews; however, several literature reviews were also included due to the relevance of their background information. Results: Based on the literature review, we chose to concentrate on microglia, cytokine signaling, and peripheral inflammation markers. We found that microglia activation and subsequent microglia-driven inflammation play a pivotal role in the pathomechanism of AD. Additionally, cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a) appear to contribute to amyloid accumulation and cell damage. Finally, the increased permeability of the blood-brain barrier (BBB) allows for the peripheral inflammatory process to contribute to the inflammation of the central nervous system (CNS) and amyloid-beta (Aβ) accumulation. Conclusions: Current evidence suggests that the immune system plays a pivotal role in the pathogenesis of AD, both in the CNS and the periphery.}, } @article {pmid39860128, year = {2025}, author = {Vaz, M and Soares Martins, T and Leandro, K and de Almeida, LP and da Cruz E Silva, OAB and Nunes, A and Henriques, AG}, title = {Fourier Transform Infrared Spectroscopy Analysis as a Tool to Address Aβ Impact on Extracellular Vesicles.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {2}, pages = {}, pmid = {39860128}, issn = {1420-3049}, mesh = {*Extracellular Vesicles/metabolism/chemistry ; Spectroscopy, Fourier Transform Infrared/methods ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/metabolism ; Animals ; Humans ; Mice ; Neurons/metabolism ; Least-Squares Analysis ; Cell Line, Tumor ; }, abstract = {Alzheimer's disease is a challenge in modern healthcare due to its complex etiology and increasing prevalence. Despite advances, further understanding of Alzheimer's disease pathophysiology is needed, particularly the role of Aβ neurotoxic peptide. Fourier transform infrared spectroscopy (FTIR) has shown potential as a screening tool for several pathologies, including Alzheimer's disease. Nonetheless, limited research has explored Aβ direct effects on neurons and extracellular vesicles metabolic profiles. Hence, this study aims to investigate Aβ impact on the spectroscopic profiles of neuronal-like cells (N2a) and N2a-derived extracellular vesicles, employing FTIR spectroscopy and focusing on the 1280-900 cm[-1] region. A comprehensive analysis of spectral data was carried out, including multivariate partial least squares (PLS) analysis and peak intensities analysis. PLS analysis revealed moderate to strong correlations within this spectral region for both N2a and N2a-derived extracellular vesicles. The peak intensity analysis revealed additional peaks with significant differences in EVs' spectra relative to N2a, following Aβ treatment. Specifically, Aβ seems to cause alterations in protein phosphorylation and in the nucleic acids content of extracellular vesicles. These findings support that Aβ's role in Alzheimer's disease pathology may be mediated by extracellular vesicles and highlight FTIR's potential for advancing Alzheimer's disease research and clinical applications.}, } @article {pmid39860011, year = {2025}, author = {Rubio, C and López-Landa, A and Romo-Parra, H and Rubio-Osornio, M}, title = {Impact of the Ketogenic Diet on Neurological Diseases: A Review.}, journal = {Life (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, pmid = {39860011}, issn = {2075-1729}, abstract = {BACKGROUND: The ketogenic diet (KD), high in fat and low in carbohydrates, was introduced in the 1920s as a non-pharmacological treatment for refractory epilepsy. Although its mechanism of action is not fully understood, beneficial effects have been observed in neurological diseases such as epilepsy, Alzheimer's disease, and Parkinson's disease.

OBJECTIVE: This review examines the impact of the ketogenic diet and its molecular and neuroglial effects as a complementary therapy for neurological diseases.

DISCUSSION: KD is associated with neuroprotective and antioxidant effects that improve mitochondrial function, regulate neurotransmitter flow, and reduce neuroinflammation and oxidative stress. Glial cells play an essential role in the utilization of ketone bodies (KBs) within the central nervous system's metabolism, particularly during ketosis induced by the KD. Thus, the KD represents a broad and promising strategy that involves both neurons and glial cells, with a molecular impact on brain metabolism and neuroinflammatory homeostasis.

CONCLUSION: Multiple molecular mechanisms have been identified to explain the benefits of the KD in neurological diseases; however, further experimental and clinical studies are needed to address various molecular pathways in order to achieve conclusive results.}, } @article {pmid39859234, year = {2025}, author = {Jia, C and Zhang, M and Wu, X and Zhang, X and Lv, Z and Zhao, K and Zhang, J and Su, Y and Zhu, F}, title = {HERV-W Env Induces Neuron Pyroptosis via the NLRP3-CASP1-GSDMD Pathway in Recent-Onset Schizophrenia.}, journal = {International journal of molecular sciences}, volume = {26}, number = {2}, pages = {}, pmid = {39859234}, issn = {1422-0067}, support = {Nos. 82272321//National Natural Science Foundation of China/ ; 2042023kf0230//Fundamental Research Funds for the Central Universities/ ; No.06R- 1366//Stanley Foundation from the Stanley Medical Research Institute (SMRI), United States/ ; }, mesh = {Humans ; *Pyroptosis ; *Schizophrenia/metabolism/virology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; *Endogenous Retroviruses/genetics/metabolism ; *Caspase 1/metabolism/genetics ; *Neurons/metabolism/virology/pathology ; *Signal Transduction ; *Phosphate-Binding Proteins/metabolism/genetics ; *Intracellular Signaling Peptides and Proteins/metabolism/genetics ; Gene Products, env/metabolism/genetics ; Female ; Male ; Adult ; Interleukin-1beta/metabolism ; Gasdermins ; }, abstract = {HERVs (Human endogenous retroviruses) are remnants of ancient exogenous retroviruses that have integrated into the human genome, particularly in germ-line cells. Among these, the envelope protein gene HERV-W env (Human endogenous retroviruses W family envelope protein), located on chromosome 7 and primarily expressed in the human placenta, has been closely linked to various neuropsychiatric disorders, including schizophrenia, as well as autoimmune diseases and cancer. Recent studies have highlighted the abnormal expression of cytokines as a key factor in the pathophysiology of schizophrenia. Notably, elevated serum levels of IL-1β (interleukin 1 beta) in schizophrenia, a cytokine associated with inflammation, are a characteristic feature of pyroptosis-a form of pro-inflammatory programmed cell death. Although previous research has observed significant upregulation of pyroptosis-related genes such as CASP1 (Caspase-1), NLRP3 (NLR family pyrin domain containing 3), and IL1B (interleukin 1 beta) in the serum of schizophrenia patients, and extensive neuron pyroptosis has been documented in various neuropsychiatric disorders, including Alzheimer's disease, epilepsy, and multiple sclerosis, the occurrence of neuron pyroptosis in schizophrenia remains uncertain. Furthermore, the mechanisms underlying pyroptosis in schizophrenia and its potential connection with HERV-W env have yet to be fully elucidated. In this study, we found that the expression levels of pyroptosis-related genes, specifically CASP1, GSDMD (Gasdermin D), and IL1B, were significantly elevated in patients with schizophrenia compared to healthy controls. Furthermore, our analysis revealed a strong positive correlation between HERV-W env expression and the levels of CASP1/GSDMD/IL1B in these patients. Experimental evidence further demonstrated that HERV-W env promoted the activation of Caspase-1 and the cleavage of Gasdermin D, leading to increased release of LDH (lactate dehydrogenase) and IL-1β. Importantly, inhibitors targeting NLRP3, CASP1, and GSDMD significantly reduced the releases of LDH and IL-1β induced by HERV-W env, whereas BID (BH3 interacting domain death agonist) inhibitors did not have a notable effect. This suggests that HERV-W env induces CASP1-GSDMD-dependent pyroptosis through the NLRP3-CASP1-GSDMD signaling pathway. As pyroptosis is increasingly recognized for its connection to neurodegenerative diseases, this study provides insights into the molecular mechanisms of neuronal pyroptosis mediated by the NLRP3 inflammasome in the context of HERV-W env. Additionally, it explores the potential facilitation of HERV-W env in the development of schizophrenia via pyroptosis, proposing that certain pyroptosis indicators could serve as potential biomarkers for schizophrenia. Based on our existing research results and the findings of previous researchers, we infer that HERV-W env acts as a bridge in the onset and progression of schizophrenia. Furthermore, HERV-W env may serve as a potential target for the clinical treatment of schizophrenia, suggesting that monoclonal antibody therapy targeting HERV-W env could represent a novel approach to managing this disease.}, } @article {pmid39859201, year = {2025}, author = {Barbalho, SM and Laurindo, LF and de Oliveira Zanuso, B and da Silva, RMS and Gallerani Caglioni, L and Nunes Junqueira de Moraes, VBF and Fornari Laurindo, L and Dogani Rodrigues, V and da Silva Camarinha Oliveira, J and Beluce, ME and Penteado Detregiachi, CR and Barbalho Lamas, C and Dos Santos Haber, JF and Cavallari Strozze Catharin, VM and Quesada, K and Tanaka, M and Valenti, VE}, title = {AdipoRon's Impact on Alzheimer's Disease-A Systematic Review and Meta-Analysis.}, journal = {International journal of molecular sciences}, volume = {26}, number = {2}, pages = {}, pmid = {39859201}, issn = {1422-0067}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Adiponectin/metabolism/therapeutic use ; tau Proteins/metabolism ; Receptors, Adiponectin/metabolism/agonists ; Indenes/therapeutic use ; Piperidines/therapeutic use/pharmacology ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) remains a leading cause of cognitive decline and mortality worldwide, characterized by neurodegeneration, synaptic deficiencies, and neuroinflammation. Despite advancements in early detection, diagnosis, and treatment, AD presents substantial challenges due to its complex pathology, heterogeneity, and the limited efficacy of current therapies. Consequently, there is a pressing need for novel therapeutic agents to target the multifaceted aspects of AD pathology, enhance current treatments, and minimize adverse effects. AdipoRon, an adiponectin receptor agonist, has garnered interest for its potential neuroprotective effects, including reducing neuroinflammation, improving mitochondrial function, and mitigating tau hyperphosphorylation. This review aimed to evaluate the effects of AdipoRon-based adiponectin replacement therapy against AD, using a comprehensive approach grounded in the PICO framework-Population, Intervention, Comparison, and Outcomes. A total of six studies were reviewed, including in vitro and in vivo investigations examining AdipoRon's impact on various AD models. These studies involved different cell lines and transgenic mouse models, assessing various outcomes such as cognitive function, neuroinflammation, tau phosphorylation, synaptic deficiencies, and relevant molecular pathways. By synthesizing data from these studies, our review thoroughly explains AdipoRon's neuroprotective effects, mechanisms of action, and potential as a therapeutic agent for AD. This analysis aims to highlight the current state of knowledge, identify gaps in the research, and suggest directions for future studies and clinical applications.}, } @article {pmid39858890, year = {2025}, author = {Kuziak, A and Heczko, P and Pietrzyk, A and Strus, M}, title = {Iron Homeostasis Dysregulation, Oro-Gastrointestinal Microbial Inflammatory Factors, and Alzheimer's Disease: A Narrative Review.}, journal = {Microorganisms}, volume = {13}, number = {1}, pages = {}, pmid = {39858890}, issn = {2076-2607}, abstract = {Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder that profoundly impacts cognitive function and the nervous system. Emerging evidence highlights the pivotal roles of iron homeostasis dysregulation and microbial inflammatory factors in the oral and gut microbiome as potential contributors to the pathogenesis of AD. Iron homeostasis disruption can result in excessive intracellular iron accumulation, promoting the generation of reactive oxygen species (ROS) and oxidative damage. Additionally, inflammatory agents produced by pathogenic bacteria may enter the body via two primary pathways: directly through the gut or indirectly via the oral cavity, entering the bloodstream and reaching the brain. This infiltration disrupts cellular homeostasis, induces neuroinflammation, and exacerbates AD-related pathology. Addressing these mechanisms through personalized treatment strategies that target the underlying causes of AD could play a critical role in preventing its onset and progression.}, } @article {pmid39858858, year = {2025}, author = {Onisiforou, A and Charalambous, EG and Zanos, P}, title = {Shattering the Amyloid Illusion: The Microbial Enigma of Alzheimer's Disease Pathogenesis-From Gut Microbiota and Viruses to Brain Biofilms.}, journal = {Microorganisms}, volume = {13}, number = {1}, pages = {}, pmid = {39858858}, issn = {2076-2607}, support = {#101031962//European Commission Marie Skłodowska-Curie fellowship/ ; EXCELLENCE/0421/0543//Research & Innovation Foundation of Cyprus - Excellence Hubs 2021/ ; NA//IDSA Foundation/ ; }, abstract = {For decades, Alzheimer's Disease (AD) research has focused on the amyloid cascade hypothesis, which identifies amyloid-beta (Aβ) as the primary driver of the disease. However, the consistent failure of Aβ-targeted therapies to demonstrate efficacy, coupled with significant safety concerns, underscores the need to rethink our approach to AD treatment. Emerging evidence points to microbial infections as environmental factors in AD pathoetiology. Although a definitive causal link remains unestablished, the collective evidence is compelling. This review explores unconventional perspectives and emerging paradigms regarding microbial involvement in AD pathogenesis, emphasizing the gut-brain axis, brain biofilms, the oral microbiome, and viral infections. Transgenic mouse models show that gut microbiota dysregulation precedes brain Aβ accumulation, emphasizing gut-brain signaling pathways. Viral infections like Herpes Simplex Virus Type 1 (HSV-1) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) may lead to AD by modulating host processes like the immune system. Aβ peptide's antimicrobial function as a response to microbial infection might inadvertently promote AD. We discuss potential microbiome-based therapies as promising strategies for managing and potentially preventing AD progression. Fecal microbiota transplantation (FMT) restores gut microbial balance, reduces Aβ accumulation, and improves cognition in preclinical models. Probiotics and prebiotics reduce neuroinflammation and Aβ plaques, while antiviral therapies targeting HSV-1 and vaccines like the shingles vaccine show potential to mitigate AD pathology. Developing effective treatments requires standardized methods to identify and measure microbial infections in AD patients, enabling personalized therapies that address individual microbial contributions to AD pathogenesis. Further research is needed to clarify the interactions between microbes and Aβ, explore bacterial and viral interplay, and understand their broader effects on host processes to translate these insights into clinical interventions.}, } @article {pmid39858522, year = {2025}, author = {Miliotou, AN and Kotsoni, A and Zacharia, LC}, title = {Deciphering the Role of Adrenergic Receptors in Alzheimer's Disease: Paving the Way for Innovative Therapies.}, journal = {Biomolecules}, volume = {15}, number = {1}, pages = {}, pmid = {39858522}, issn = {2218-273X}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Receptors, Adrenergic/metabolism ; Animals ; Adrenergic Antagonists/therapeutic use ; }, abstract = {Neurodegenerative diseases are currently among the most devastating diseases with no effective disease-modifying drugs in the market, with Alzheimer's disease (AD) being the most prevalent. AD is a complex multifactorial neurodegenerative disorder characterized by progressive and severe cognitive impairment and memory loss. It is the most common cause of progressive memory loss (dementia) in the elderly, and to date, there is no effective treatment to cure or slow disease progression substantially. The role of adrenergic receptors in the pathogenesis of Alzheimer's disease and other tauopathies is poorly understood or investigated. Recently, some studies indicated a potential benefit of drugs acting on the adrenergic receptors for AD and dementias, although due to the heterogeneity of the drug classes used, the results on the whole remain inconclusive. The scope of this review article is to comprehensively review the literature on the possible role of adrenergic receptors in neurodegenerative diseases, stemming from the use of agonists and antagonists including antihypertensive and asthma drugs acting on the adrenergic receptors, but also from animal models and in vitro models where these receptors have been studied. Ultimately, we hope to obtain a better understanding of the role of these receptors, identify the gaps in knowledge, and explore the possibility of repurposing such drugs for AD, given their long history of use and safety.}, } @article {pmid39857687, year = {2025}, author = {Kim, DU and Kweon, B and Oh, J and Lim, Y and Noh, G and Yu, J and Kang, HR and Kwon, T and Lee, KY and Bae, GS}, title = {A Network Pharmacology Study and Experimental Validation to Identify the Potential Mechanism of Heparan Sulfate on Alzheimer's Disease-Related Neuroinflammation.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, pmid = {39857687}, issn = {2227-9059}, support = {2023RIS-008//Ministry of Education/ ; }, abstract = {BACKGROUND/OBJECTIVES: Heparan sulfate (HS) is a polysaccharide that is found on the surface of cells and has various biological functions in the body.

METHODS: The purpose of this study was to predict the pharmacological effects and molecular mechanisms of HS on Alzheimer's disease (AD) and neuroinflammation (NI) through a network pharmacology analysis and to experimentally verify them.

RESULTS: We performed functional enrichment analysis of common genes between HS target genes and AD-NI gene sets and obtained items such as the "Cytokine-Mediated Signaling Pathway", "Positive Regulation Of MAPK Cascade", and "MAPK signaling pathway". To confirm the predicted results, the anti-inflammatory effect of HS was investigated using lipopolysaccharide (LPS)-stimulated BV2 microglia cells. HS inhibited the production of nittic oxide, interleukin (IL)-6, and tumor necrosis factor-α in LPS-stimulated BV2 cells, but not IL-1β. In addition, HS inactivated P38 in the MAPK signaling pathway.

CONCLUSIONS: These findings suggest the potential for HS to become a new treatment for AD and NI.}, } @article {pmid39855473, year = {2025}, author = {Hansen, N and Teegen, B and Hirschel, S and Fox, J and Fitzner, D and Wiltfang, J and Bartels, C}, title = {Longitudinally persisting KCNA2-autoantibodies in mild amnestic dementia with Alzheimer´s pathology - Report and literature review.}, journal = {Behavioural brain research}, volume = {482}, number = {}, pages = {115437}, doi = {10.1016/j.bbr.2025.115437}, pmid = {39855473}, issn = {1872-7549}, abstract = {BACKGROUND: Neural autoantibodies are being increasingly detected in conjunction with neurodegenerative dementias such as Alzheimer's disease dementia (AD), yet their significance is not well clarified. In this case report, we report the previously unreported long-lasting persistence of potassium voltage-gated channel subfamily A member 2 (KCNA2) antibodies in biomarker-supported AD.

METHODS: We report on a 77-year-old, male patient evaluated in our outpatient memory clinic of the Department of Psychiatry and Psychotherapy, University Medical Center Göttingen. Neuropsychological test results and autoantibody testing in serum over a period of 4-5 years is provided.

REPORT: Our patient exhibited mild dementia syndrome and was diagnosed with AD on the basis of a prototypical biomarker profile (reduced Aβ42/40 ratio and elevated p-tau181 protein in cerebrospinal fluid). Within a 5-year follow-up with regular visits to our memory clinic, we observed a nearly stable neuropsychological profile of mild, amnestic variant dementia that did not noticeably progress. KCNA2 autoantibodies were also detectable in serum over 4 years with increasing titers over time. Combined anti-dementia therapy with donepezil, multimodal therapy including non-pharmacological cognitive therapy, and immunotherapy with intravenous methylprednisolone was carried out as an individual treatment approach.

CONCLUSIONS: KCNA2 autoantibody persistence in biomarker-supported AD does not necessarily trigger a poor outcome in the long-term, as cognitive impairment did not progress subsequently. At the same time, mild immunotherapy did not result in less immunoreactivity in conjunction with the detection of KCNA2 autoantibodies. This detection of KCNA2 autoantibodies in AD could provide indices of a potentially benign long-term AD course that should be further evaluated in studies.}, } @article {pmid39855275, year = {2025}, author = {Zhang, W and Zhang, L and Fu, S and Yan, R and Zhang, X and Song, J and Lu, Y}, title = {Roles of NLRC4 inflammasome in neurological disorders: Mechanisms, implications, and therapeutic potential.}, journal = {Pharmacology & therapeutics}, volume = {267}, number = {}, pages = {108803}, doi = {10.1016/j.pharmthera.2025.108803}, pmid = {39855275}, issn = {1879-016X}, abstract = {The nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 4 (NLRC4) inflammasome, a vital component of the innate immune system, is known for defending against bacterial infections. However, recent insights have revealed its significant impact on neurological disorders. This comprehensive review discussed the mechanisms underlying the activation and regulation of the NLRC4 inflammasome, highlighting the complexity of its response to cellular stress and damage signals. The biological functions of NLRC4 were explored, particularly its influence on cytokine production and the induction of pyroptosis, a form of inflammatory cell death. This review further emphasized the role of the NLRC4 inflammasome in brain injuries and neurodegenerative disorders. In the realm of brain injuries such as stroke and traumatic brain injury, as well as in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, the NLRC4 inflammasome played a pivotal role in modulating neuroinflammatory responses, which was crucial for understanding the progression and potential therapeutic targeting of these conditions. The emerging role of NLRC4 in psychiatric disorders and its potential impact on glioma progression were also examined. Additionally, this review presented a thorough summary of the latest research on inhibitors that impeded the assembly and activation of the NLRC4 inflammasome, pointing to new therapeutic possibilities in neurological disorders. In conclusion, by integrating current knowledge on the activation and regulation of NLRC4 with its biological functions and clinical implications, this article underscored the importance of NLRC4 inflammasome in neurological pathologies, which opened new possibilities for the treatment of challenging neurological conditions.}, } @article {pmid39853846, year = {2025}, author = {Moradi, F and Mokhtari, T}, title = {Role of NLRP3 Inflammasome in Chronic Pain and Alzheimer's Disease-A Review.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {2}, pages = {e70071}, pmid = {39853846}, issn = {1099-0461}, support = {R35 ES030443/ES/NIEHS NIH HHS/United States ; //This study was funded by the Faculty Development Grants from Hubei University of Medicine (No. 2023QDJZR) and partially supported by a grant from the National Institute of Environmental Health Sciences (NIEHS, R35ES030443)./ ; }, mesh = {*Alzheimer Disease/metabolism ; Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Inflammasomes/metabolism ; *Chronic Pain/metabolism/physiopathology ; Animals ; Microglia/metabolism/pathology ; }, abstract = {The coexistence of Alzheimer's disease (AD) and chronic pain (CP) in the elderly population has been extensively documented, and a growing body of evidence supports the potential interconnections between these two conditions. This comprehensive review explores the mechanisms by which CP may contribute to the development and progression of AD, with a particular focus on neuroinflammatory pathways and the role of microglia, as well as the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome. The review proposes that prolonged pain processing in critical brain regions can dysregulate the activity of the NLRP3 inflammasome within microglia, leading to the overproduction of pro-inflammatory cytokines and excessive oxidative stress in these regions. This aberrant microglial response also results in localized neuroinflammation in brain areas crucial for cognitive function. Additionally, CP as a persistent physiological and psychological stressor may be associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, systemic inflammation, disruption of the blood-brain barrier (BBB), and neuroinflammation. These pathophysiological changes can cause morphological and functional impairments in brain regions responsible for cognition, memory, and neurotransmitter production, potentially contributing to the development and progression of CP-associated AD. Resultant neuroinflammation can further promote amyloid-beta (Aβ) plaque deposition, a hallmark of AD pathology. Potential therapeutic interventions targeting these neuroinflammatory pathways, particularly through the regulation of microglial NLRP3 activation, hold promise for improving outcomes in individuals with comorbid CP and AD. However, further research is required to fully elucidate the complex interplay between these conditions and develop effective treatment strategies.}, } @article {pmid39853561, year = {2025}, author = {Lee, HH and Chinnameyyappan, A and Feldman, OJ and Marotta, G and Survilla, K and Lanctôt, KL}, title = {Behavioral and Psychological Symptoms (BPSD) in Alzheimer's Disease (AD): Development and Treatment.}, journal = {Current topics in behavioral neurosciences}, volume = {}, number = {}, pages = {}, doi = {10.1007/7854_2024_566}, pmid = {39853561}, issn = {1866-3370}, abstract = {Behavioral and psychological symptoms of dementia (BPSD), such as agitation, apathy, and psychosis, are highly prevalent and have a significant impact on patients and their care partners. The neurobiology of BPSD involves a complex interplay of structural brain changes and alterations in the neurotransmitter system. Various genetic and plasma biomarkers have also been studied. Research in BPSD has been limited by heterogeneity in the diagnostic criteria and assessment tools. As such, there have been ongoing efforts to develop a gold-standard assessment tool and diagnostic criteria. Current practice guidelines recommend nonpharmacological therapies as first-line treatments. Pharmacological options are often used when there is an insufficient response to nonpharmacological strategies, but there can be serious adverse effects with existing pharmacological agents. This has resulted in growing efforts to develop novel therapeutics with more favorable tolerability profiles, with some showing promising results. Other biological therapies, such as neurostimulation, have also demonstrated positive results. As our understanding of BPSD evolves, ongoing research efforts in treatment of BPSD are warranted in order to enhance the quality of life for patients and their care partners.}, } @article {pmid39853424, year = {2025}, author = {Zavarella, M and Cecchetti, G and Rugarli, G and Ghirelli, A and Bottale, I and Orlandi, F and Spinelli, EG and Santangelo, R and Caso, F and Calloni, SF and Vezzulli, PQ and Falini, A and Magnani, G and Agosta, F and Filippi, M}, title = {Favorable long-term cognitive outcomes following recurrent ARIA linked to amyloid-lowering therapies: two cases.}, journal = {Journal of neurology}, volume = {272}, number = {2}, pages = {168}, pmid = {39853424}, issn = {1432-1459}, support = {Project Age-It: "Ageing Well in an Ageing Society"//Ministero dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Cognitive Dysfunction/etiology/drug therapy ; *Antibodies, Monoclonal, Humanized/administration & dosage/adverse effects ; *Alzheimer Disease/drug therapy ; Aged ; Male ; Female ; Recurrence ; Positron-Emission Tomography ; Aged, 80 and over ; Disease Progression ; Follow-Up Studies ; }, abstract = {INTRODUCTION: The large-scale approval of anti-amyloid monoclonal antibodies for treating Alzheimer's disease (AD) has raised concerns about their safety due to treatment-emergent amyloid-related imaging abnormalities (ARIA).

METHODS: We present two cases of patients diagnosed with mild cognitive impairment due to AD who were enrolled in the GRADUATE I clinical trial. They received subcutaneous gantenerumab every two weeks during the study period.

RESULTS: Both patients experienced recurrent ARIA-Effusion/Edema type (ARIA-E). One developed symptomatic and severe ARIA, leading to hospitalization and study withdrawal. We report a long follow-up post-randomization (65 and 54 months), during which the adverse events did not appear to have a negative impact on disease progression. Additionally, one patient had a negative amyloid-PET over a year after treatment cessation.

DISCUSSION: These cases suggest that recurrent ARIA-E do not inevitably lead to accelerated progression, instead, may relate to possible long-term benefits. The mechanisms underlying these findings warrant further real-life evidence.}, } @article {pmid39852770, year = {2025}, author = {Kala, S and Strutz, AG and Katt, ME}, title = {The Rise of Pluripotent Stem Cell-Derived Glia Models of Neuroinflammation.}, journal = {Neurology international}, volume = {17}, number = {1}, pages = {}, pmid = {39852770}, issn = {2035-8385}, support = {P20 GM109098/GM/NIGMS NIH HHS/United States ; T32 AG052375/AG/NIA NIH HHS/United States ; T32AG052375/GF/NIH HHS/United States ; 5P20GM109098-10/GF/NIH HHS/United States ; }, abstract = {Neuroinflammation is a blanket term that describes the body's complex inflammatory response in the central nervous system (CNS). It encompasses a phenotype shift to a proinflammatory state, the release of cytokines, the recruitment of peripheral immune cells, and a wide variety of other processes. Neuroinflammation has been implicated in nearly every major CNS disease ranging from Alzheimer's disease to brain cancer. Understanding and modeling neuroinflammation is critical for the identification of novel therapeutic targets in the treatment of CNS diseases. Unfortunately, the translation of findings from non-human models has left much to be desired. This review systematically discusses the role of human pluripotent stem cell (hPSC)-derived glia and supporting cells within the CNS, including astrocytes, microglia, oligodendrocyte precursor cells, pericytes, and endothelial cells, to describe the state of the field and hope for future discoveries. hPSC-derived cells offer an expanded potential to study the pathobiology of neuroinflammation and immunomodulatory cascades that impact disease progression. While much progress has been made in the development of models, there is much left to explore in the application of these models to understand the complex inflammatory response in the CNS.}, } @article {pmid39851568, year = {2025}, author = {Mooradian, AD and Haas, MJ}, title = {Role of Thyroid Hormone in Neurodegenerative Disorders of Older People.}, journal = {Cells}, volume = {14}, number = {2}, pages = {}, pmid = {39851568}, issn = {2073-4409}, mesh = {Humans ; *Thyroid Hormones/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Aged ; }, abstract = {Thyroid dysfunction is associated with a number of neuropsychiatric manifestations. Cognitive decline is a common feature of hypothyroidism and clinical or subclinical hyperthyroidism. In addition, there is a significant association between thyroid hormone (TH) levels and the degree of cognitive impairment in Parkinson's disease (PD). The pathophysiology of TH-related neurodegeneration include changes in the blood-brain barrier, increased cellular stress, altered processing of β-amyloid precursor protein and the effect of TH on neuronal cell viability. The neurotoxicity of TH is partially mediated by the thyroid hormone responsive protein (THRP). This protein is 83% homologous to mouse c-Abl-interacting protein-2 (Abi2), a c-Abl-modulating protein with tumor suppressor activity. In cell cultures, increasing THRP expression either with TH treatment or exogenously through transfecting neuronal or PC 12 cells causes cell necrosis. The expression of exogenous THRP in other cells such as the colonic epithelial cell line Caco-2 and the glial cell line U251 has no effect on cell viability. The effect of THRP on cell viability is not modulated by c-Abl tyrosine kinase. The causal relationship between specific biochemical perturbations in cerebral tissue and thyroid dysfunction remains to be elucidated.}, } @article {pmid39851526, year = {2025}, author = {Chen, W and Kim, S and Kim, SY and Beheshtian, C and Kim, N and Shin, KH and Kim, RH and Kim, S and Park, NH}, title = {GV1001, hTERT Peptide Fragment, Prevents Doxorubicin-Induced Endothelial-to-Mesenchymal Transition in Human Endothelial Cells and Atherosclerosis in Mice.}, journal = {Cells}, volume = {14}, number = {2}, pages = {}, pmid = {39851526}, issn = {2073-4409}, support = {R21 DE031074/DE/NIDCR NIH HHS/United States ; 441902-19900//University of California System/ ; }, mesh = {*Doxorubicin/pharmacology/adverse effects ; Animals ; *Atherosclerosis/pathology/drug therapy ; Humans ; Mice ; *Epithelial-Mesenchymal Transition/drug effects ; *Telomerase/metabolism ; Mitochondria/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Endothelial Cells/drug effects/metabolism/pathology ; Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; NF-kappa B/metabolism ; Mice, Inbred C57BL ; Male ; Disease Models, Animal ; Peptide Fragments/pharmacology ; }, abstract = {Doxorubicin is a highly effective anticancer agent, but its clinical use is restricted by severe side effects, including atherosclerosis and cardiomyopathy. These complications are partly attributed to doxorubicin's ability to induce endothelial-to-mesenchymal transition (EndMT) in vascular endothelial cells, a critical process in the initiation and progression of atherosclerosis and cardiomyopathy. GV1001, a multifunctional peptide with anti-inflammatory, anti-cancer, antioxidant, and anti-Alzheimer's properties, has demonstrated inhibition of EndMT. We investigated whether GV1001 could counteract doxorubicin-induced EndMT in endothelial cells and prevent atherosclerosis in a mouse model. The results revealed that GV1001 significantly suppressed EndMT induced by doxorubicin, likely through its protective effects on mitochondria. By mitigating mitochondrial damage, GV1001 reduced the accumulation of mitochondrial and cellular reactive oxygen species (ROS), repressed the activation of nuclear factor kappa B (NF-κB), and reduced the production of proinflammatory cytokines in endothelial cells. Additionally, GV1001 reduced systemic and vascular inflammation, lipid accumulation, and monocyte/macrophage infiltration within arterial walls in mice. In conclusion, GV1001 appears to prevent doxorubicin-induced atherosclerosis by safeguarding vascular endothelial cells from mitochondrial dysfunction, inflammation, and phenotypic changes. These findings suggest the potential of GV1001 as a therapeutic agent to mitigate the long-term cardiovascular side effects associated with doxorubicin treatment in humans.}, } @article {pmid39851389, year = {2024}, author = {Trinh, DQ and Mai, NH and Pham, TD}, title = {Insufficient Sleep and Alzheimer's Disease: Potential Approach for Therapeutic Treatment Methods.}, journal = {Brain sciences}, volume = {15}, number = {1}, pages = {}, pmid = {39851389}, issn = {2076-3425}, abstract = {The interaction between Alzheimer's disease (AD) and sleep deprivation has recently gained attention in the scientific literature, and recent advances suggest that AD epidemiology management should coincide with the management of sleeping disorders. This review focuses on the aspects of the mechanisms underlying the link between AD and insufficient sleep with progressing age. We also provide information which could serve as evidence for future treatments of AD from the early stages in connection with sleep disorder medication.}, } @article {pmid39851253, year = {2024}, author = {Sun, Y and Pang, X and Huang, X and Liu, D and Huang, J and Zheng, P and Wei, Y and Pang, C}, title = {Potential mechanisms of non-coding RNA regulation in Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-00696}, pmid = {39851253}, issn = {1673-5374}, abstract = {Alzheimer's disease, a progressively degenerative neurological disorder, is the most common cause of dementia in the elderly. While its precise etiology remains unclear, researchers have identified diverse pathological characteristics and molecular pathways associated with its progression. Advances in scientific research have increasingly highlighted the crucial role of non-coding RNAs in the progression of Alzheimer's disease. These non-coding RNAs regulate several biological processes critical to the advancement of the disease, offering promising potential as therapeutic targets and diagnostic biomarkers. Therefore, this review aims to investigate the underlying mechanisms of Alzheimer's disease onset, with a particular focus on microRNAs, long non-coding RNAs, and circular RNAs associated with the disease. The review elucidates the potential pathogenic processes of Alzheimer's disease and provides a detailed description of the synthesis mechanisms of the three aforementioned non-coding RNAs. It comprehensively summarizes the various non-coding RNAs that have been identified to play key regulatory roles in Alzheimer's disease, as well as how these non-coding RNAs influence the disease's progression by regulating gene expression and protein functions. For example, miR-9 targets the UBE4B gene, promoting autophagy-mediated degradation of Tau protein, thereby reducing Tau accumulation and delaying Alzheimer's disease progression. Conversely, the long non-coding RNA BACE1-AS stabilizes BACE1 mRNA, promoting the generation of amyloid-[2] and accelerating Alzheimer's disease development. Additionally, circular RNAs play significant roles in regulating neuroinflammatory responses. By integrating insights from these regulatory mechanisms, there is potential to discover new therapeutic targets and potential biomarkers for early detection and management of Alzheimer's disease. This review aims to enhance the understanding of the relationship between Alzheimer's disease and non-coding RNAs, potentially paving the way for early detection and novel treatment strategies.}, } @article {pmid39851113, year = {2025}, author = {Mishra, AS and Vasantham, M and Ghosh, B and Malliappan, SP}, title = {Transforming Alzheimer's Treatment: Unveiling New Potential with Drug Repurposing Strategies.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673341391241231054936}, pmid = {39851113}, issn = {1875-533X}, abstract = {Alzheimer's disease (AD) remains a significant challenge in neurology, marked by progressive cognitive decline and neurodegeneration. Despite extensive research efforts, effective treatments are still lacking. Traditional drug discovery is often slow and costly, frequently resulting in limited success. Drug repurposing, which identifies new therapeutic uses for existing medications, has emerged as a promising approach to expedite AD treatment development. This review examines the potential of drug repurposing to transform AD therapy by utilizing the established safety profiles and known mechanisms of current drugs. We explore various repurposed drugs under investigation for AD, originally intended for cardiovascular, metabolic, and psychiatric conditions. Detailed discussions include how these drugs provide neuroprotective benefits by inhibiting amyloid-beta aggregation, reducing tau phosphorylation, and modulating neuroinflammation. Additionally, we emphasize the benefits of drug repurposing, such as shortened development timelines, lower costs, and increased chances of clinical success. By integrating current research findings, this review offers a thorough overview of the most promising repurposed drug candidates and their potential impact on AD treatment strategies. It stresses the importance of innovative approaches in AD research and calls for greater investment in drug repurposing initiatives. Through these strategies, we aim to accelerate the availability of effective treatments, providing renewed hope and a brighter future for those affected by this devastating disease.}, } @article {pmid39849525, year = {2025}, author = {Lu, Y and Xu, Y and Zhou, L and Wang, S and Han, Y and Wang, K and Qin, C}, title = {Bone marrow mesenchymal stem cells derived cytokines associated with AKT/IAPs signaling ameliorate Alzheimer's disease development.}, journal = {Stem cell research & therapy}, volume = {16}, number = {1}, pages = {14}, pmid = {39849525}, issn = {1757-6512}, support = {2021-I2M-1-034, 2019-I2M-1-004//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 2022QNRC001//Young Elite Scientitsts Sponsorship Program by CAST/ ; 2023-PT180-01//the Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences/ ; }, mesh = {Animals ; *Alzheimer Disease/therapy/metabolism ; Mice ; *Mesenchymal Stem Cells/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Cytokines/metabolism ; Female ; Signal Transduction ; Disease Models, Animal ; Mesenchymal Stem Cell Transplantation/methods ; Mice, Transgenic ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative condition affecting around 50 million people worldwide. Bone marrow-derived mesenchymal stem cells (BMMSCs) have emerged as a promising source for cellular therapy due to their ability to differentiate into multiple cell types and their paracrine effects. However, the direct injection of BMMSCs can lead to potential unpredictable impairments, prompting a renewed interest in their paracrine effects for AD treatment. The specific mechanism and central role of cytokines in this process have not been fully elucidated.

METHODS: Mouse BMMSCs were isolated, validated, and then transplanted intracerebrally into APP/PS1 female mice. The behavioral tests, including open-field test, novel object recognition test, and Morris water maze were performed, followed by β-amyloidosis plaque and neuron apoptosis analyses. Then the tissue RNA sequencing and mBMMSC cytokine analysis were performed. A cytokine antibody array for BMMSCs and the brain slice models were performed with AD model tissues were used to elucidate the molecular mechanisms. Finally, APP/PS1 mice were administrated with cytokine mixture for cognitive recovery.

RESULTS: Our results demonstrated that BMMSCs significantly improved cognitive function, reduced beta-amyloid plaque deposition, and decreased apoptotic neurons through the activation of the AKT signaling pathway. Using a cytokine antibody array, we identified three highly expressed AKT pathway regulated neuroprotective factors in BMMSCs: IGF1, VEGF, and Periostin2. These cytokines were found to upregulate inhibitors of apoptosis family proteins (IAPs) and suppress Caspase-3 activity in brain slices induced with beta amyloidosis (Aβ), okadaic acid (OA), and lipopolysaccharide (LPS). When injection of this cytokine mixture to APP/PS1 mice also resulted in a mitigation of cognitive impairment.

CONCLUSIONS: These findings suggest that the secretory factors IGF1, VEGF, and Periostin2 derived from BMMSCs play a crucial role in neuroprotection by modulating the AKT/IAPs pathway to restore neuronal function. These cytokine sets could be a potential therapeutic strategy for AD and lay the groundwork for promising clinical applications.}, } @article {pmid39848035, year = {2025}, author = {Azam, U and Naseer, MM and Rochais, C}, title = {Analysis of skeletal diversity of multi-target directed ligands (MTDLs) targeting Alzheimer's disease.}, journal = {European journal of medicinal chemistry}, volume = {286}, number = {}, pages = {117277}, doi = {10.1016/j.ejmech.2025.117277}, pmid = {39848035}, issn = {1768-3254}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Ligands ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Molecular Structure ; Animals ; tau Proteins/metabolism/antagonists & inhibitors ; }, abstract = {Alzheimer's disease (AD) remains a significant healthcare challenge, necessitating innovative therapeutic approaches to address its complex and multifactorial nature. Traditional drug discovery strategies targeting single molecular targets are not sufficient for the effective treatment of AD. In recent years, MTDLs have emerged as promising candidates for AD therapy, aiming to simultaneously modulate multiple pathological targets. Among the various strategies employed in MTDL design, pharmacophore hybridization offers a versatile approach to integrate diverse pharmacophoric features within a single molecular scaffold. This strategy provides access to a wide array of chemical space for the design and development of novel therapeutic agents. This review, therefore, provides a comprehensive overview of skeletal diversity exhibited by MTDLs designed recently for AD therapy based on pharmacophore hybridization approach. A diverse range of pharmacophoric elements and core scaffolds hybridized to construct MTDLs that has the potential to target multiple pathological features of AD including amyloid-beta aggregation, tau protein hyperphosphorylation, cholinergic dysfunction, oxidative stress, and neuroinflammation are discussed. Through the comprehensive analysis and integration of structural insights of key biomolecular targets, this review aims to enhance optimization efforts in MTDL design, ultimately striving towards a comprehensive cure for the multifaceted pathophysiology of the disease.}, } @article {pmid39846361, year = {2025}, author = {Wang, SJ and Wei, LC and Chiu, HJ}, title = {Comment on "Delirium event and associated treatment modifications among older adults with Alzheimer's disease: An interrupted time-series analysis of Medicare data".}, journal = {Pharmacotherapy}, volume = {45}, number = {1}, pages = {70}, doi = {10.1002/phar.4636}, pmid = {39846361}, issn = {1875-9114}, } @article {pmid39846360, year = {2025}, author = {Aparasu, RR and Talwar, A}, title = {Response to comment on "Delirium event and associated treatment modifications among older adults with Alzheimer's disease: An interrupted time-series analysis of Medicare data".}, journal = {Pharmacotherapy}, volume = {45}, number = {1}, pages = {71}, doi = {10.1002/phar.4637}, pmid = {39846360}, issn = {1875-9114}, } @article {pmid39846055, year = {2025}, author = {Wei, S and Yang, W and Wang, E and Wang, S and Li, Y}, title = {A 3D decoupling Alzheimer's disease prediction network based on structural MRI.}, journal = {Health information science and systems}, volume = {13}, number = {1}, pages = {17}, pmid = {39846055}, issn = {2047-2501}, abstract = {PURPOSE: This paper aims to develop a three-dimensional (3D) Alzheimer's disease (AD) prediction method, thereby bettering current predictive methods, which struggle to fully harness the potential of structural magnetic resonance imaging (sMRI) data.

METHODS: Traditional convolutional neural networks encounter pressing difficulties in accurately focusing on the AD lesion structure. To address this issue, a 3D decoupling, self-attention network for AD prediction is proposed. Firstly, a multi-scale decoupling block is designed to enhance the network's ability to extract fine-grained features by segregating convolutional channels. Subsequently, a self-attention block is constructed to extract and adaptively fuse features from three directions (sagittal, coronal and axial), so that more attention is geared towards brain lesion areas. Finally, a clustering loss function is introduced and combined with the cross-entropy loss to form a joint loss function for enhancing the network's ability to discriminate between different sample types.

RESULTS: The accuracy of our model is 0.985 for the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset and 0.963 for the Australian Imaging, Biomarker & Lifestyle (AIBL) dataset, both of which are higher than the classification accuracy of similar tasks in this category. This demonstrates that our model can accurately distinguish between normal control (NC) and Alzheimer's Disease (AD), as well as between stable mild cognitive impairment (sMCI) and progressive mild cognitive impairment (pMCI).

CONCLUSION: The proposed AD prediction network exhibits competitive performance when compared with state-of-the-art methods. The proposed model successfully addresses the challenges of dealing with 3D sMRI image data and the limitations stemming from inadequate information in 2D sections, advancing the utility of predictive methods for AD diagnosis and treatment.}, } @article {pmid39845447, year = {2024}, author = {Zhao, Y and Qiu, C and Lin, P and Yang, M and Huang, L and Zhao, Z and Wu, X and Zhou, D}, title = {Decreased prefrontal activation during verbal fluency task after repetitive transcranial magnetic stimulation treatment for depression in Alzheimer's disease: a functional near-infrared spectroscopy study.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1460853}, pmid = {39845447}, issn = {1663-4365}, abstract = {BACKGROUND: Studies have shown the clinical effects of repetitive transcranial magnetic stimulation (rTMS) on depression in Alzheimer's disease (AD). However, the underlying mechanisms remain poorly understood. The measurement of brain activation links neurobiological and functional aspects but is challenging in patients with dementia. This study investigated the influence of rTMS on cortical activation in patients with AD and depressive symptoms, measured using functional near-infrared spectroscopy (fNIRS) during a verbal fluency task.

METHODS: In this randomized, double-blind study, patients with AD and depression received either active rTMS (n = 17) or sham-rTMS (n = 16). Patients received 4 weeks of bilateral standard rTMS (1 Hz rTMS delivered to the right dorsolateral prefrontal cortex (DLPFC) and 10-Hz rTMS delivered to the left DLPFC).

RESULTS: No significant changes were found in the Mini-Mental State Examination (MMSE) and Modified Barthel Index (MBI); however, significant changes were found for the 17-item Hamilton Depression Rating Scale (HAMD-17) and the depression score of the Neuropsychiatric Inventory (NPI-depression; p < 0.05). The results showed a decrease in the concentration of oxygenated hemoglobin, as measured with fNIRS, from baseline to week 4 in CH41 (in right DLPFC; p = 0.0047, FDR-corrected). There was a negative correlation between the improvement in HAMD-17 severity in these patients and reduced oxygenated hemodynamic response of CH41 (r = - 0.504, p = 0.039).

CONCLUSION: The results indicated a positive effect of rTMS on depression in patients with AD. The underlying cortical changes were imaged using fNIRS. Prefrontal activation measured by fNIRS is a potential biomarker for monitoring the response of patients with depression in AD to rTMS treatment.}, } @article {pmid39844773, year = {2025}, author = {Xie, Y and Liu, J and Hou, Z and Wang, H and Liu, K and Chen, X and Fan, Z and Li, D and Li, C and Pan, Y and Zhao, Y and Zhu, Y and Hu, B}, title = {CD4-Derived Double-Negative T Cells Ameliorate Alzheimer's Disease-Like Phenotypes in the 5×FAD Mouse Model.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {1}, pages = {e70187}, pmid = {39844773}, issn = {1755-5949}, support = {2021YFA1101400//National Key Research and Development Program of China/ ; ZDBS-LY-SM024//Basic Frontier Science Research Program of CAS/ ; XDA 046205//Strategic Priority Research Program of CAS/ ; }, mesh = {Animals ; *Alzheimer Disease/therapy ; Mice ; *Disease Models, Animal ; *Mice, Transgenic ; *CD4-Positive T-Lymphocytes ; Phenotype ; Mice, Inbred C57BL ; Male ; Maze Learning/physiology ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a debilitating neurodegenerative disorder that is difficult to predict and is typically diagnosed only after symptoms manifest. Recently, CD4[+] T cell-derived double-negative T (DNT) cells have shown strong immuno-regulatory properties in both in vitro and in vivo neuronal inflammation studies. However, the effectiveness of DNT cells in treating on AD are not yet fully understood.

OBJECTIVE: This study's aims were three-fold, to (1) evaluate the efficacy of CD4[+] T cell-derived DNT cells treatment on AD mice, (2) understand how DNT treatment make changes in different cell types of 5FAD mice, (3) identify the side effects of DNT treatment.

METHODS: We performed tail vein injection of transformed and amplified CD4[+] T cell-derived DNT cells into 5 × FAD mice, while using WT mice and saline injection 5FAD mice as controls. DNT suspensions or NaCl alone were administered to 5 × FAD mice at the 6 months of age. For intravenous injection (n = 10 for both DNT and control injections), 5 × FAD mice were injected with a total of 5 × 10[6] DNT cells suspended in 200 μL of 0.9% NaCl or 0.9% NaCl alone via the lateral tail vein. Behavioral tests and pathology tests were carried out 30 days after cell transplantation.

RESULTS: Through qualitative analysis, we identified 6 main themes. DNT from young wild-type mice enhance the capability of spatial learning and memory in AD mice. DNT cell treatment rejuvenates the microglial function. DNT cell treatment improves the state of oligodendrocytes. DNT cell treatment finetunes the activation of the immune system. DNT cell treatment improves the synaptic plasticity and increases the complexity of neurons. DNT cell treatment reduces the density of amyloid Beta plaques deposition in the cortex and hippocampus of 5 × FAD mice.

DISCUSSION: The findings from this study reveal that DNT treatment improved spatial memory and learning abilities, reduced Aβ deposition, and enhanced synaptic plasticity, contrasting with previous reports on thymus-derived DNT cells. Additionally, CD4[+] T cell-derived DNT therapy exhibited anti-inflammatory effects and modulated microglial function, promoting a neuroprotective environment. Notably, DNT treatment also reduced tau pathology by decreasing levels of abnormally phosphorylated tau. These findings suggest that CD4[+] T cell-derived DNT cells hold therapeutic potential for AD, effectively targeting both Aβ and tau pathologies.}, } @article {pmid39843406, year = {2025}, author = {Islam, MR and Al-Imran, MIK and Zehravi, M and Sweilam, SH and Mortuza, MR and Gupta, JK and Shanmugarajan, TS and Devi, K and Tummala, T and Alshehri, MA and Rajagopal, K and Asiri, M and Ahmad, I and Emran, TB}, title = {Targeting signaling pathways in neurodegenerative diseases: Quercetin's cellular and molecular mechanisms for neuroprotection.}, journal = {Animal models and experimental medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/ame2.12551}, pmid = {39843406}, issn = {2576-2095}, abstract = {BACKGROUND: Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, and Huntington's disease, are complex and challenging due to their intricate pathophysiology and limited treatment options.

METHODS: This review systematically sourced articles related to neurodegenerative diseases, neurodegeneration, quercetin, and clinical studies from primary medical databases, including Scopus, PubMed, and Web of Science.

RESULTS: Recent studies have included quercetin to impact the cellular and molecular pathways involved in neurodegeneration. Quercetin, a flavonoid abundant in vegetables and fruits, is gaining attention for its antioxidant, anti-inflammatory, and antiapoptotic properties. It regulates signaling pathways such as nuclear factor-κB (NF-κB), sirtuins, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt). These pathways are essential for cellular survival, inflammation regulation, and apoptosis. Preclinical and clinical studies have shown that quercetin improves symptoms and pathology in neurodegenerative models, indicating promising outcomes.

CONCLUSIONS: The study explores the potential of incorporating laboratory research into practical medical treatment, focusing on quercetin's neuroprotective effects on NDs and its optimal dosage.}, } @article {pmid39842814, year = {2025}, author = {Ma, YN and Xia, Y and Karako, K and Song, P and Tang, W and Hu, X}, title = {Serum proteomics reveals early biomarkers of Alzheimer's disease: The dual role of APOE-ε4.}, journal = {Bioscience trends}, volume = {}, number = {}, pages = {}, doi = {10.5582/bst.2024.01365}, pmid = {39842814}, issn = {1881-7823}, abstract = {Alzheimer's disease (AD), the leading cause of dementia, significantly impacts global public health, with cases expected to exceed 150 million by 2050. Late-onset Alzheimer's disease (LOAD), predominantly influenced by the APOE-ε4 allele, exhibits complex pathogenesis involving amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), neuroinflammation, and blood-brain barrier (BBB) disruption. Proteomics has emerged as a pivotal technology in uncovering molecular mechanisms and identifying biomarkers for early diagnosis and intervention in AD. This paper reviews the genetic and molecular roles of APOE-ε4 in the pathology of AD, including its effects on Aβ aggregation, tau phosphorylation, neuroinflammation, and BBB integrity. Additionally, it highlights recent advances in serum proteomics, revealing APOE-ε4-dependent and independent protein signatures with potential as early biomarkers for AD. Despite technological progress, challenges such as population diversity, standardization, and distinguishing AD-specific biomarkers remain. Directions for future research emphasize multicenter longitudinal studies, multi-omics integration, and the clinical translation of proteomic findings to enable early detection of AD and personalized treatment strategies. Proteomics advances in AD research hold the promise of improving patient outcomes and reducing the global disease burden.}, } @article {pmid39842570, year = {2025}, author = {Raj, V and Raorane, CJ and Shastri, D and Kim, JH and Lee, S}, title = {Sulfonic acid functionalized β-amyloid peptide aggregation inhibitors and antioxidant agents for the treatment of Alzheimer's disease: Combining machine learning, computational, in vitro and in vivo approaches.}, journal = {International journal of biological macromolecules}, volume = {299}, number = {}, pages = {140142}, doi = {10.1016/j.ijbiomac.2025.140142}, pmid = {39842570}, issn = {1879-0003}, abstract = {Alzheimer's disease (AD) is characterized as a neurodegenerative disorder that is caused by plaque formation by accumulating β-amyloid (Aβ), leading to neurocognitive function and impaired mental development. Thus, targeting Aβ represents a promising target for the development of therapeutics in AD management. Several functionalized sulfonic acid molecules have been reported, including tramiprosate prodrug, which is currently in clinical trial III and exhibits a good response in mild to moderate AD patients. Therefore, expanding upon this approach, we hypothesized that the sulfonic acid functionalized aromatic class molecule might demonstrate a good inhibitory effect against β-amyloid aggregation, leading to a decrease in the progression burden of AD. We used computational and in vitro approaches to establish effective compounds. As a result, three potent hit molecules were selected based on binding score as well as availability. In the case of safety profile of compounds, in vitro using human neuroblastoma SH-SY5Y cells and in vivo using C. elegans was performed at doses up to 500 μM; no difference in viability was exhibited between control and treatment groups. However, H2O2-induced ROS stress was significantly reduced in neuroblastoma cells after treatment. The AFM and ThT-embedded β-amyloid1-42 kinetic studies confirmed B-PEA-MBSA and H-HPA-NSA potency. H-HPA-NSA arrested elongation phase of Aβ aggregation in kinetic study at a lower concentration (10 μM), while B-PEA-MBSA reduced the intensity of stationary phase at a dose of 100 μM. Thus, based on the outcomes, it can be suggested that B-PEA-MBSA and H-HPA-NSA can prevent β-amyloid aggregation with mild to moderate AD.}, } @article {pmid39841316, year = {2025}, author = {Hussain, A and Jairajpuri, DS and Anwar, S and Choudhury, A and Hawwal, MF and Firdous, A and Alajmi, MF and Hassan, MI}, title = {Apigenin-mediated MARK4 inhibition: a novel approach in advancing Alzheimer's disease therapeutics.}, journal = {Molecular diversity}, volume = {}, number = {}, pages = {}, pmid = {39841316}, issn = {1573-501X}, support = {RSPD2023R980//King Saud University/ ; Grant No. 3-69/2020-CCRUM/Tech//Central Council for Research in Unani Medicine/ ; }, abstract = {Apigenin, a dietary flavonoid with notable anti-cancer properties, has emerged as a promising candidate for the treatment of neurodegenerative disorders, particularly Alzheimer's disease (AD). While extensively studied for its ability to modulate key molecular pathways in cancers, apigenin also exerts neuroprotective effects by reducing neuroinflammation, protecting neurons from oxidative stress, and enhancing neuronal survival and synaptic plasticity. This dual functionality makes apigenin an intriguing therapeutic option for diseases like AD, where kinase dysregulation plays a central role. In this study, we focus on Microtubule Affinity-Regulating Kinase 4 (MARK4), a key enzyme implicated in tauopathies associated with AD, as well as in cancer progression. Through in silico analysis, we explore the interaction between apigenin and MARK4, revealing significant structural changes within the kinase domain upon ligand binding. These computational findings were confirmed via experimental assays using purified recombinant MARK4, where apigenin demonstrated potent inhibition with an IC50 value of 2.39 µM. Fluorescence binding assays further confirmed a strong binding affinity (Ka = 10[8] M[-1]), indicating that apigenin efficiently occupies the MARK4 active site, thereby suppressing its enzymatic activity. These results position apigenin as a potent inhibitor of MARK4, offering a dual therapeutic advantage-both as an anti-cancer agent and as a neuroprotective compound for the potential treatment of AD. This study opens new avenues for the development of apigenin-based therapeutics targeting kinase dysregulation in cancer and neurodegeneration.}, } @article {pmid39840612, year = {2025}, author = {Saks, DG and Sachdev, PS}, title = {Monogenic causes of cerebral small vessel disease- models for vascular cognitive impairment and dementia?.}, journal = {Current opinion in psychiatry}, volume = {38}, number = {2}, pages = {112-118}, pmid = {39840612}, issn = {1473-6578}, mesh = {Humans ; *Cerebral Small Vessel Diseases/genetics ; *Dementia, Vascular/genetics ; *Cognitive Dysfunction/genetics ; }, abstract = {PURPOSE OF REVIEW: Recent advancements in molecular biomarkers and therapeutic options for Alzheimer's disease have brought into focus the need for greater progress in the second most common cause of dementia, vascular cognitive impairment and dementia (VCID). We examine how the study of monogenic causes of VCID has contributed to the understanding of its pathophysiology and potential biomarker and treatment research.

RECENT FINDINGS: It is widely accepted that conditions which disrupt the cerebral small vessels contribute to vascular pathologies including stroke and cerebral microbleeds, ultimately leading to vascular cognitive impairment and dementia. Among these conditions are a range of monogenic small vessel diseases (SVDs) such as CADASIL, CARASIL, Fabry disease and COL4A-related disorders.

SUMMARY: This review indicates the importance of furthering research into monogenic SVDs in order to gain insight into the pathomechanisms of VCID more broadly. Monogenic conditions are easier to model than sporadic VCID and can serve as a guide for identifying biomarkers for diagnosis, monitoring and intervention outcomes.}, } @article {pmid39840140, year = {2024}, author = {Ashraf, F and Rasool, FK and Uddin, MMN and Siddiq, MA and Mustafa, MS}, title = {Targeting Beta-Amyloid Protein with Monoclonal Antibodies: A New Hope for Alzheimer's Treatment.}, journal = {Annals of neurosciences}, volume = {31}, number = {4}, pages = {243-245}, pmid = {39840140}, issn = {0972-7531}, } @article {pmid39839307, year = {2024}, author = {He, J and Xu, P and Xu, T and Yu, H and Wang, L and Chen, R and Zhang, K and Yao, Y and Xie, Y and Yang, Q and Wu, W and Sun, D and Wu, D}, title = {Therapeutic potential of hydrogen-rich water in zebrafish model of Alzheimer's disease: targeting oxidative stress, inflammation, and the gut-brain axis.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1515092}, pmid = {39839307}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder, with amyloid-beta (Aβ) aggregation playing a key role in its pathogenesis. Aβ-induced oxidative stress leads to neuronal damage, mitochondrial dysfunction, and apoptosis, making antioxidative strategies promising for AD treatment. This study investigates the effects of hydrogen-rich water (HRW) in a zebrafish AD model. Zebrafish were exposed to aluminum chloride to induce AD-like pathology and then treated with HRW using a nanobubble device. Behavioral assays, ELISA, Hematoxylin-eosin (H&E) staining, and reactive oxygen species (ROS) and neutrophil fluorescence labeling were employed to assess HRW's impact. Additionally, 16S rRNA sequencing analyzed HRW's effect on gut microbiota. HRW can significantly improve cognitive impairment and depression-like behavior in zebrafish AD model, reduce Aβ deposition (p < 0.0001), regulate liver Soluble epoxide hydrolase (sEH) levels (p < 0.05), reduce neuroinflammation, and reduce oxidative stress. Furthermore, HRW reduced the number of harmful bacteria linked to AD pathology by restoring the balance of microbiota in the gut. These findings suggest that HRW has potential as a therapeutic strategy for AD by targeting oxidative stress, inflammation, and gut-brain axis modulation.}, } @article {pmid39839126, year = {2024}, author = {Liu, B and Sun, H and Zhao, Q and Li, L and Tian, R and Lui, S and Zhu, H}, title = {Plastic but not progressive changes in cognitive function and hippocampal volume in an adolescent with bipolar disorder: a case report.}, journal = {Frontiers in psychiatry}, volume = {15}, number = {}, pages = {1507333}, pmid = {39839126}, issn = {1664-0640}, abstract = {Bipolar disorder (BD) is a prevalent mood disorder characterized by alternating episodes of depression and mania, often accompanied by varying degrees of cognitive impairment. Cognitive impairments often serve as indicators of a bleak prognosis or the likelihood of progressing to dementia. Additionally, some studies suggest that individuals diagnosed with BD may undergo a decline in hippocampal volume. However, the potential for reversibility of these changes, particularly in adolescents, remains unclear. We present an intriguing case involving an 18-year-old male student who experiences concurrent occurrences of both BD and mild cognitive impairment (MCI), accompanied by a subtle reduction in hippocampal volume. Initially, the individual exhibited impaired general cognitive function, as indicated by an IQ score of 80 on the Standard Raven's Progressive Matrices test, and demonstrated slightly reduced bilateral hippocampal volume compared to the normative reference, as determined through quantitative structural magnetic resonance imaging (qsMRI). The deposition profiles of amyloid beta (Aβ) peptide in the brain were not identified with 18F-AV45 PET/MRI. Following six months of combined psychopharmacological treatment and cognitive behavioral therapy, the individual's psychopathological symptoms improved significantly, leading to a restoration of his IQ score to 116 and normalization of hippocampal volume. This case suggests that the hippocampal volume reduction and cognitive impairment seen in some adolescents with BD may demonstrate greater plasticity compared to neurodegenerative conditions such as Alzheimer's disease (AD). These findings highlight the potential importance of early intervention in young BD patients with cognitive impairments.}, } @article {pmid39839078, year = {2025}, author = {Underwood, BR and Lourida, I and Gong, J and Tamburin, S and Tang, EYH and Sidhom, E and Tai, XY and Betts, MJ and Ranson, JM and Zachariou, M and Olaleye, OE and Das, S and Oxtoby, NP and Chen, S and Llewellyn, DJ and , }, title = {Data-driven discovery of associations between prescribed drugs and dementia risk: A systematic review.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70037}, pmid = {39839078}, issn = {2352-8737}, support = {R01 AG017644/AG/NIA NIH HHS/United States ; }, abstract = {ABSTRACT: Recent clinical trials on slowing dementia progression have led to renewed focus on finding safer, more effective treatments. One approach to identify plausible candidates is to assess whether existing medications for other conditions may affect dementia risk. We conducted a systematic review to identify studies adopting a data-driven approach to investigate the association between a wide range of prescribed medications and dementia risk. We included 14 studies using administrative or medical records data for more than 130 million individuals and 1 million dementia cases. Despite inconsistencies in identifying specific drugs that may modify Alzheimer's or dementia risk, some themes emerged for drug classes with biological plausibility. Antimicrobials, vaccinations, and anti-inflammatories were associated with reduced risk, while diabetes drugs, vitamins and supplements, and antipsychotics were associated with increased risk. We found conflicting evidence for antihypertensives and antidepressants. Drug repurposing for use in dementia is an urgent priority. Our findings offer a basis for prioritizing candidates and exploring underlying mechanisms.

HIGHLIGHTS: ·We present a systematic review of studies reporting association between drugs prescribed for other conditions and risk of dementia including 139 million people and 1 million cases of dementia.·Our work supports some previously reported associations, for example, showing decreased risk of dementia with drugs to treat inflammatory disease and increased risk with antipsychotic treatment.·Antimicrobial treatment was perhaps more surprisingly associated with decreased risk, supportive of recent increased interest in this potential therapeutic avenue.·Our work should help prioritize drugs for entry into adaptive platform trials in Alzheimer's disease and will serve as a useful resource for those investigating drugs or classes of drugs and risk of dementia.}, } @article {pmid39838927, year = {2025}, author = {Wang, Z and Sun, Y and Bai, Z and Li, M and Kong, D and Wu, G}, title = {Mitochondria-Related Genome-Wide Mendelian Randomization Identifies Putatively Causal Genes for Neurodegenerative Diseases.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {}, number = {}, pages = {}, doi = {10.1002/mds.30123}, pmid = {39838927}, issn = {1531-8257}, support = {SDQLQN2021-01//Qilu Young Scholars Program of Shandong University/ ; 202306352//Taishan Scholar Foundation of Shandong Province/ ; }, abstract = {BACKGROUND: Mitochondrial dysfunction is increasingly recognized as a key factor in neurodegenerative diseases (NDDs), underscoring the therapeutic potential of targeting mitochondria-related genes. This study aimed to identify novel biomarkers and drug targets for these diseases through a comprehensive analysis that integrated genome-wide Mendelian randomization (MR) with genes associated with mitochondrial function.

METHODS: Using existing publicly available genome-wide association studies (GWAS) summary statistics and comprehensive data on 1136 mitochondria-related genes, we initially identified a subset of genes related to mitochondrial function that exhibited significant associations with NDDs. We then conducted colocalization and summary-data-based Mendelian randomization (SMR) analyses using expression quantitative trait loci (eQTL) to validate the causal role of these candidate genes. Additionally, we assessed the druggability of the encoded proteins to prioritize potential therapeutic targets for further exploration.

RESULTS: Genetically predicted levels of 10 genes were found to be significantly associated with the risk of NDDs. Elevated DMPK and LACTB2 levels were associated with increased Alzheimer's disease risk. Higher expression of NDUFAF2, BCKDK, and MALSU1, along with lower TTC19, raised Parkinson's disease risk. Higher ACLY levels were associated with both amyotrophic lateral sclerosis and multiple sclerosis (MS) risks, while decreased MCL1, TOP3A, and VWA8 levels raised MS risk. These genes primarily impact mitochondrial function and energy metabolism. Notably, several druggable protein targets identified are being explored for potential NDDs treatment.

CONCLUSIONS: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in NDDs. Additionally, this study identified candidate genes that could serve as potential pharmacological targets for the prevention and treatment of NDDs. © 2025 International Parkinson and Movement Disorder Society.}, } @article {pmid39838674, year = {2025}, author = {Cheng, M and Gao, Y and Wu, Y and Zhang, L and Xu, B and Lu, X}, title = {Plasmalogens Activate AKT/mTOR Signaling to Attenuate Reactive Oxygen Species Production in Spinal Cord Injury.}, journal = {Current gene therapy}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115665232330349241225074627}, pmid = {39838674}, issn = {1875-5631}, abstract = {BACKGROUND: Plasmalogens, the primary phospholipids in the brain, possess intrinsic antioxidant properties and are crucial components of the myelin sheath surrounding neuronal axons. While their neuroprotective effects have been demonstrated in Alzheimer's disease, their potential benefits in spinal cord injury remain unexplored. This study investigates the reparative effects of plasmalogens on spinal cord injury and the underlying mechanisms.

METHODS: In vitro, we developed dorsal root ganglion (DRG) and RAW 264.7 cell models under high-reactive oxygen species (ROS) conditions to assess ROS levels, neuronal damage, and inflammatory microenvironment changes before and after plasmalogen application. In vivo, we used a complete mouse spinal cord transection model to evaluate changes in ROS levels, neuronal demyelination, and apoptosis following plasmalogen treatment. Additionally, we assessed sensory and motor function recovery and investigated the regulatory effects of plasmalogens on the AKT/mTOR signaling pathway.

RESULTS: In high-ROS cell models, plasmalogens protected DRG neurons (TUJ-1) from axonal damage and modulated the proinflammatory/anti-inflammatory balance in RAW 264.7 cells. In vivo, plasmalogens significantly reduced ROS levels, improved the immune microenvironment, decreased the proinflammatory (iNOS)/anti-inflammatory (ARG-1) ratio, lowered neuronal (TUJ-1) apoptosis (Caspase-3, BAX), and reduced axonal degeneration while promoting myelin (MBP) regeneration, indicating a neuroprotective effect. These findings are linked to the activation of the AKT/mTOR signaling pathway.

CONCLUSION: Plasmalogens reduce ROS levels and regulate inflammation-induced damage, contributing to neuroprotection. This study reveals that plasmalogens promote remyelination, reduce axonal degeneration and neuronal apoptosis, and-used here for the first time in spinal cord injury repair- may protect neurons by reducing ROS levels and activating the AKT/mTOR signaling pathway.}, } @article {pmid39838656, year = {2025}, author = {Xie, D and Cai, Z and Mao, J and Qu, X and Cao, L and Zhou, J}, title = {High-prediction QSAR Modeling Study Based on the Efficacy of a Novel 6-hydroxybenzothiazole-2-carboxamide Targeted Monoamine Oxidase B in the Treatment of Neurodegenerative Diseases.}, journal = {Medicinal chemistry (Shariqah (United Arab Emirates))}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115734064364749250102024805}, pmid = {39838656}, issn = {1875-6638}, abstract = {BACKGROUND: Neurodegenerative diseases are a group of disorders characterized by progressive neuronal degeneration and death, of which Alzheimer's disease and Parkinson's disease are the most common. These diseases are closely associated with increased expression of monoamine oxidase B (MAO-B), an important enzyme that regulates neurotransmitter concentration, and its overactivity leads to oxidative stress and neurotoxicity, accelerating the progression of neurodegenerative diseases. Therefore, the development of effective MAO-B inhibitors is important for the treatment of neurodegenerative diseases.

OBJECTIVE: This study aims to improve the prediction of the efficacy of novel 6-hydroxybenzothiazole- 2-carboxamide compounds in inhibiting MAO-B by improving the quantitative constitutive effect relationship (QSAR) modeling and to provide a theoretical basis for the discovery of novel neuroprotective drugs.

METHODS: The study first optimized the structures of 36 compounds using the heuristic method (HM) in CODESSA software to construct linear QSAR models. Subsequently, key descriptors were screened by using the gene expression programming (GEP) technique to generate nonlinear QSAR models and validate them.

RESULTS: The R², F-value, and R²cv of the linear model were 0.5724, 10.3752, and 0.4557, respectively, whereas the nonlinear model constructed by the GEP algorithm showed higher prediction accuracies by achieving R² values of 0.89 and 0.82, and mean squared errors (MSE) of 0.0799 and 0.1215 for the training and test sets, respectively. In addition, molecular docking experiments confirmed that the novel compound 31 was tightly bound to the MAO-B active site with significant inhibitory activity.

CONCLUSION: In this study, we successfully improved the prediction ability of the efficacy of novel 6-hydroxybenzothiazole-2-carboxamide compounds to inhibit MAO-B by improving the QSAR model. This not only provides new drug candidates for the treatment of neurodegenerative diseases, but also provides important theoretical guidance for subsequent drug design and development, which can help accelerate the process of new drug discovery and reduce the disease burden of patients.}, } @article {pmid39838483, year = {2025}, author = {Clemmensen, FK and Gramkow, MH and Simonsen, AH and Ashton, NJ and Huber, H and Blennow, K and Zetterberg, H and Waldemar, G and Hasselbalch, SG and Frederiksen, KS}, title = {Short-term variability of Alzheimer's disease plasma biomarkers in a mixed memory clinic cohort.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {26}, pmid = {39838483}, issn = {1758-9193}, mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; Female ; Male ; Aged ; *Amyloid beta-Peptides/blood ; *tau Proteins/blood ; Cohort Studies ; Middle Aged ; Peptide Fragments/blood ; Aged, 80 and over ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; }, abstract = {BACKGROUND: For clinical implementation of Alzheimer's disease (AD) blood-based biomarkers (BBMs), knowledge of short-term variability, is crucial to ensure safe and correct biomarker interpretation, i.e., to capture changes or treatment effects that lie beyond that of expected short-term variability and considered clinically relevant. In this study we investigated short-term intra- and inter-individual variability of AD biomarkers in the intended use population, memory clinic patients.

METHODS: In a consecutive sample of memory clinic patients (AD n = 27, non-AD n = 20), blood samples were collected on three separate days within a period of 36 days and analysed for plasma Aβ40, Aβ42, p-tau181, p-tau217, p-tau231, T-tau, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). We measured intra- and inter-individual variability and explored if the variability could be affected by confounding factors. Secondly, we established the minimum change required to detect a difference between two given blood samples that exceeds intra-individual variability and analytical variation (reference change value, RCV). Finally, we tested if classification accuracy varied across the three visits.

RESULTS: Intra-individual variability ranged from ~ 3% (Aβ42/40) to ~ 12% (T-tau). Inter-individual variability ranged from ~ 7% (Aβ40) to ~ 39% (NfL). Adjusting the models for time, eGFR, Hba1c, and BMI did not affect the variation. RCV was lowest for Aβ42/Aβ40 (- ~ 15%/ + ~ 17%) and highest in p-tau181 (- ~ 30/ + ~ 42%). No variation in classification accuracies was found across visits.

CONCLUSION: We found low intra-individual variability, robust to various factors, appropriate to capture individual changes in AD BBMs, while moderate inter-individual variability may give rise to caution in diagnostic contexts. High RCVs may pose challenges for AD BBMs with low fold changes and consequently, short-term variability is important to take into consideration when, e.g., estimating intervention effect and longitudinal changes of AD BBM levels.

TRIAL REGISTRATION: Clinicaltrials.gov (NCT05175664), date of registration 2021-12-01.}, } @article {pmid39838434, year = {2025}, author = {Kimura, N and Sasaki, K and Masuda, T and Ataka, T and Matsumoto, M and Kitamura, M and Nakamura, Y and Matsubara, E}, title = {Machine learning models for dementia screening to classify brain amyloid positivity on positron emission tomography using blood markers and demographic characteristics: a retrospective observational study.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {25}, pmid = {39838434}, issn = {1758-9193}, mesh = {Humans ; Male ; Female ; Retrospective Studies ; Aged ; *Machine Learning ; *Positron-Emission Tomography/methods ; *Brain/diagnostic imaging/metabolism ; Biomarkers/blood ; Amyloid beta-Peptides/blood/metabolism ; Cognitive Dysfunction/blood/diagnostic imaging/diagnosis ; Aged, 80 and over ; Alzheimer Disease/blood/diagnostic imaging ; Dementia/blood/diagnostic imaging/diagnosis ; Middle Aged ; }, abstract = {BACKGROUND: Intracerebral amyloid β (Aβ) accumulation is considered the initial observable event in the pathological process of Alzheimer's disease (AD). Efficient screening for amyloid pathology is critical for identifying patients for early treatment. This study developed machine learning models to classify positron emission tomography (PET) Aβ-positivity in participants with preclinical and prodromal AD using data accessible to primary care physicians.

METHODS: This retrospective observational study assessed the classification performance of combinations of demographic characteristics, routine blood test results, and cognitive test scores to classify PET Aβ-positivity using machine learning. Participants with mild cognitive impairment (MCI) or normal cognitive function who visited Oita University Hospital or had participated in the USUKI study and met the study eligibility criteria were included. The primary endpoint was assessment of the classification performance of the presence or absence of intracerebral Aβ accumulation using five machine learning models (i.e., five combinations of variables), each constructed with three classification algorithms, resulting in a total of 15 patterns. L2-regularized logistic regression, and kernel Support Vector Machine (SVM) and Elastic Net algorithms were used to construct the classification models using 34 pre-selected variables (12 demographic characteristics, 11 blood test results, 11 cognitive test results).

RESULTS: Data from 262 records (260 unique participants) were analyzed. The mean (standard deviation [SD]) participant age was 73.8 (7.8) years. Using L2-regularized logistic regression, the mean receiver operating characteristic (ROC) area under the curve (AUC) (SD) in Model 0 (basic demographic characteristics) was 0.67 (0.01). Classification performance was similar in Model 1 (basic demographic characteristics and Mini Mental State Examination [MMSE] subscores) and Model 2 (demographic characteristics and blood test results) with a cross-validated mean ROC AUC (SD) of 0.70 (0.01) for both. Model 3 (demographic characteristics, blood test results, MMSE subscores) and Model 4 (Model 3 and ApoE4 phenotype) showed improved performance with a mean ROC AUC (SD) of 0.73 (0.01) and 0.76 (0.01), respectively. In models using blood test results, thyroid-stimulating hormone and mean corpuscular volume tended to be the largest contributors to classification. Classification performances were similar using the SVM and Elastic Net algorithms.

CONCLUSIONS: The machine learning models used in this study were useful for classifying PET Aβ-positivity using data from routine physician visits.

TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000051776, registered on 31/08/2023).}, } @article {pmid39838228, year = {2025}, author = {Hou, Q and Li, Y}, title = {Dual inhibition of AChE and MAO-B in Alzheimer's disease: machine learning approaches and model interpretations.}, journal = {Molecular diversity}, volume = {}, number = {}, pages = {}, pmid = {39838228}, issn = {1573-501X}, support = {2021YFA1500300//National Key Research and Development Program of China/ ; 22275027//National Natural Science Foundation of China/ ; }, abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases. Given the multifactorial pathophysiology of AD, monotargeted agents can only alleviate symptoms but not cure AD. Acetylcholinesterase (AChE) and Monoamine oxidase B (MAO-B) are two key targets in the treatment of AD, molecules that inhibiting both targets are considered promising avenue to develop more effective AD therapies. In the present work, a dual inhibition dataset containing 449 molecules was established, based on which five machine learning algorithms (KNN, SVM, RF, GBDT, and LGBM) four fingerprints (MACCS, ECFP4, RDKitFP, PubChemFP) and DRAGON descriptors were combined to develop 25 classification models in which GBDT paired with ECFP4 and RF paired with PubchemFP achieved the same best performance across multiple metrics (Accuracy = 0.92, F1 Score = 0.94, MCC = 0.81). Moreover, based on the curated bioactivity datasets of AChE and MAO-B, regression models were developed to predict pIC50 values. For the AChE inhibition task, GBDT demonstrated the best performance (RMSE = 0.683, MAE = 0.500, R[2] = 0.721). The SVM algorithm emerged as the most effective for MAO-B inhibition (RMSE = 0.668, MAE = 0.507, R[2] = 0.675). The SHAP algorithm was used to interpret the optimal models, identifying and analyzing the key substructures and properties for both dual-target and single-target inhibitors. Moreover, molecules docking process provided potential mechanism and Structure-Activity Relationships (SAR) of dual-target inhibition further.}, } @article {pmid39837459, year = {2025}, author = {Yang, MX and Wang, ZR and Zhang, YL and Zhang, ZN and Li, YL and Wang, R and Su, Q and Guo, JH}, title = {Albumin antagonizes Alzheimer's disease-related Tau pathology and enhances cognitive performance by inhibiting aberrant Tau aggregation.}, journal = {Experimental neurology}, volume = {386}, number = {}, pages = {115155}, doi = {10.1016/j.expneurol.2025.115155}, pmid = {39837459}, issn = {1090-2430}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive impairment, for which effective treatments remain lacking. Albumin (ALB) is an essential carrier protein found in various body fluids, playing crucial roles in anti-inflammatory processes, antioxidation, and signal transduction. Recent research indicates that ALB may play a significant role in the development and progression of AD, though its specific function is not yet fully understood. In this study, we observed a link between serum ALB levels and cognitive performance in the elderly. Administration of ALB intranasally was shown to enhance learning and memory in MAPT/P301S transgenic mice, markedly decreasing hyperphosphorylation of Tau protein and reducing neuronal apoptosis. In a neuronal cell model overexpressing Tau, ALB administration in vitro attenuated Tau-induced toxicity and reduced the production of phosphorylated Tau. Additionally, co-incubation of Tau with ALB significantly reduced the formation of neurofibrillary tangles. These results suggest that ALB improves AD-related cognitive function by preventing the pathological aggregation of Tau and reducing its abnormal phosphorylation. Furthermore, ALB's neuroprotective effect helps prevent neuronal apoptosis in the cortex and hippocampus, providing potential targets for AD prevention and treatment.}, } @article {pmid39835706, year = {2025}, author = {Cacabelos, R and Martínez-Iglesias, O and Cacabelos, N and Carrera, J and Rodríguez, D and Naidoo, V}, title = {The impact of genetic variability on Alzheimer's therapies: obstacles for pharmacogenetic progress.}, journal = {Expert opinion on drug metabolism & toxicology}, volume = {}, number = {}, pages = {1-28}, doi = {10.1080/17425255.2024.2433626}, pmid = {39835706}, issn = {1744-7607}, abstract = {INTRODUCTION: Genetic load influences the therapeutic response to conventional drugs in Alzheimer's disease (AD). Pharmacogenetics (PGx) is the best option to reduce drug-drug interactions and adverse drug reactions in patients undergoing polypharmacy regimens. However, there are important limitations that make it difficult to incorporate pharmacogenetics into routine clinical practice.

AREAS COVERED: This article analyzes the pharmacogenetic apparatus made up of pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes responsible for the efficacy and safety of pharmacological treatment, the impact of genetic load on the outcome of multifactorial treatments, and practical aspects for the effective use of PGx.

EXPERT OPINION: Over 120 genes are closely associated with AD. There is an accumulation of cerebrovascular (CVn) and neurodegenerative (ADn) genes in AD. APOE-4 carriers accumulate more deleterious genetic load related to other CVn and ADn genes, develop the disease earlier, and are at a biological disadvantage compared to APOE-4 non-carriers. CYP2D6-PMs and APOE-4 carriers are the worst responders to anti-dementia drugs. Some limitations hinder the implementation of PGx in clinical practice, including lack of pharmacogenetic information for many drugs, low number of genes in PGx screening protocols, and educational deficiencies in the medical community regarding PGx and genomic medicine.}, } @article {pmid39835563, year = {2025}, author = {Kushwaha, SK and Ashawat, MS and Arora, R and Baldi, A}, title = {Auranofin-loaded PLGA Nanoparticles for Neuroprotection against Aluminium-induced Alzheimer's Disease.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128336703241202182209}, pmid = {39835563}, issn = {1873-4286}, abstract = {AIM: The aim of the current study was to explore nano-formulation for effective neuroprotection by auranofin.

BACKGROUND: Currently, the treatment options for various CNS disorders, particularly neurodegenerative disorders, are greatly constrained. A significant obstacle in this pursuit is the blood-brain barrier, a shielding covering that hinders the route of numerous biochemical treatments into the brain. To overcome this problem, nanoformulation- based approaches are gaining interest, increasing the compound's BBB penetrability.

OBJECTIVE: The objective of this study was to evaluate whether nanoparticles fabricated from poly(lactic-co-glycolic acid) encapsulated with auranofin could oppose aluminium chloride-induced Alzheimer's disease.

METHOD: Auranofin-encapsulated PLGA nanoparticles were prepared, and their particle size, Entrapment Efficiency (EE), distribution of particles, morphological surface charge, and structural characteristics were characterized. During the in vivo study, rats were orally administered AlCl3 at 100 mg/kg for 21 days. Meanwhile, auranofin and auranofin nanoparticles were orally administered at doses of 5 and 10 mg/kg and 2.5 and 5 mg/kg, respectively, within 2 weeks. After the course therapy, the rats were decapitated, and the hippocampus was collected for the estimated biochemical and neuroinflammatory markers.

RESULTS: The auranofin nanoparticles were characterized, revealing % entrapment efficiency (98%) and % loading dose (76%). The nanoparticles exhibited a morphological surface charge of 27.5 ± 5.10 mV, a polydispersity index of 0.438 ± 0.12, and a mean particle size of 101.5 ± 10.3 nm. In the in vivo study, administering a gold compound (auranofin) and formulation (auranofin nanoparticles) resulted in a significant improvement in cognitive deficits, changes in biochemical parameters, and markers of neuroinflammation triggered with aluminium chloride.

CONCLUSION: The results have suggested that auranofin nanoparticles demonstrate abilities to protect neurons compared to auranofin alone. The noticed therapeutic benefits of the auranofin-encapsulated PLGA nanoparticles can be attributed to modulation in particle size with antioxidative and anti-inflammatory impacts of auranofin. Consequently, the outcome of the research has revealed that gold compound nanoparticles hold the potential to be a promising option for altering the therapeutic course of Alzheimer's disease.}, } @article {pmid39834810, year = {2024}, author = {Yang, C and Zhao, E and Zhang, H and Duan, L and Han, X and Ding, H and Cheng, Y and Wang, D and Lei, X and Diwu, Y}, title = {Xixin Decoction's novel mechanism for alleviating Alzheimer's disease cognitive dysfunction by modulating amyloid-β transport across the blood-brain barrier to reduce neuroinflammation.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1508726}, pmid = {39834810}, issn = {1663-9812}, abstract = {PURPOSE: Xixin Decoction (XXD) is a classical formula that has been used to effectively treat dementia for over 300 years. Modern clinical studies have demonstrated its significant therapeutic effects in treating Alzheimer's disease (AD) without notable adverse reactions. Nevertheless, the specific mechanisms underlying its efficacy remain to be elucidated. This investigation sought to elucidate XXD's impact on various aspects of AD pathology, including blood-brain barrier (BBB) impairment, neuroinflammatory processes, and amyloid-β (Aβ) deposition, as well as the molecular pathways involved in these effects.

METHODS: In vitro experiments were conducted using hCMEC/D3 and HBVP cell coculture to establish an in vitro blood-brain barrier (BBB) model. BBB damage was induced in this model by 24-h exposure to 1 μg/mL lipopolysaccharide (LPS). After 24, 48, and 72 h of treatment with 10% XXD-medicated serum, the effects of XXD were assessed through Western blotting, RT-PCR, and immunofluorescence techniques. In vivo, SAMP8 mice were administered various doses of XXD via gavage for 8 weeks, including high-dose XXD group (H-XXD) at 5.07 g kg[-1]·d[-1], medium-dose XXD group (M-XXD) at 2.535 g kg[-1]·d[-1], and low-dose XXD group (L-XXD) at 1.2675 g kg[-1]·d[-1]. Cognitive function was subsequently evaluated using the Morris water maze test. BBB integrity was evaluated using Evans blue staining, and protein expression levels were analyzed via ELISA, Western blotting, and immunofluorescence.

RESULTS: In vitro experiments revealed that XXD-containing serum, when cultured for 24, 48, and 72 h, could upregulate the expression of P-gp mRNA and protein, downregulate CB1 protein expression, and upregulate CB2 and Mfsd2a protein expression. In vivo studies demonstrated that XXD improved spatial learning and memory abilities in SAMP8 mice, reduced the amount of Evans blue extravasation in brain tissues, modulated the BBB-associated P-gp/ECS axis, RAGE/LRP1 receptor system, as well as MRP2 and Mfsd2a proteins, and decreased the accumulation of Aβ in the brains of SAMP8 mice. Additionally, XXD upregulated the expression of TREM2, downregulated IBA1, TLR1, TLR2, and CMPK2 expression, and reduced the levels of pro-inflammatory factors NLRP3, NF-κB p65, COX-2, TNF-α, and IL-1β in the hippocampal tissues.

CONCLUSION: XXD may exert its effects by regulating the P-gp/ECS axis, the RAGE/LRP1 receptor system, and the expression of MRP2 and Mfsd2a proteins, thereby modulating the transport function of the BBB to expedite the clearance of Aβ, reduce cerebral Aβ accumulation, and consequently inhibit the activation of microglia induced by Aβ aggregation. This process may suppress the activation of the CMPK2/NLRP3 and TLRs/NF-κB pathways, diminish the production of inflammatory cytokines and chemokines, alleviate neuroinflammation associated with microglia in the brain of AD, and ultimately improve AD pathology.}, } @article {pmid39834440, year = {2025}, author = {Alkhatabi, HA and Pushparaj, PN}, title = {Untangling the complex mechanisms associated with Alzheimer's disease in elderly patients using high-throughput RNA sequencing data and next-generation knowledge discovery methods: Focus on potential gene signatures and drugs for dementia.}, journal = {Heliyon}, volume = {11}, number = {1}, pages = {e41266}, pmid = {39834440}, issn = {2405-8440}, abstract = {OBJECTIVES: Alzheimer's disease (AD) is a complex neurodegenerative disorder that primarily affects elderly individuals. This study aimed to elucidate the intricate mechanisms underlying AD in elderly patients compared with healthy aged individuals using high-throughput RNA sequencing (RNA-seq) data and next-generation knowledge discovery methods (NGKD), with a focus on identifying potential therapeutic agents.

METHODS: High-throughput RNA-seq data were obtained from the Gene Expression Omnibus (GEO) database (accession number: GSE104704). These data were derived from healthy and diseased human brains (eight young healthy brains [young], 10 aged healthy brains [Old], and 12 aged diseased brains [AD]). We used NGKD tools such as GEO RNA-seq Experiments Interactive Navigator (GREIN) to obtain differentially expressed genes (DEGs) by comparing the AD versus Old RNA-seq data and further filtered and normalized to obtain differentially regulated Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome and Panther pathways using ExpressAnalyst tool. Besides, WebGestalt was used to identify differentially regulated Gene Ontologies (GO) and the pre-ranked Gene Set Enrichment Analysis (GSEA) was performed using GSEA software. The X2K web tool was used to infer upstream regulator networks and X2K Appyter tool for obtaining transcription factors (TFs) and kinase network information. LFW1000 and L1000CDS[2] tools were used to identify specific drugs that reverse AD-associated gene signatures in elderly patients.

RESULTS: Our study revealed significant downregulation of pathways related to neuroactive receptor-ligand interaction, synaptic vesicle cycle, and neuronal system in elderly individuals with AD. GO analysis showed negative enrichment of functions related to cognition, potassium ion transport, receptor-ligand activity, SNARE binding, and primary lysosomes. The transcription factors SUZ12 and REST, along with increased MAPK signaling, were identified as key regulators of downregulated genes. Several drugs and natural products, including dihydroergocristine, mepacrine, gedunin, amlodipine, and disulfiram have been identified as potential therapeutic agents for reversing AD-associated gene signatures.

CONCLUSIONS: This comprehensive analysis of AD in elderly individuals using RNA-seq data and NGKD tools revealed multiple differentially regulated pathways, gene signatures, and potential drugs for dementia treatment. These findings highlight the complex molecular mechanisms underlying AD and provide insights into potential therapeutic strategies. Further research is needed to validate these findings and to develop personalized treatment approaches for AD in elderly patients.}, } @article {pmid39834035, year = {2025}, author = {Asken, BM and Brett, BL and Barr, WB and Banks, S and Wethe, JV and Dams-O'Connor, K and Stern, RA and Alosco, ML}, title = {Chronic traumatic encephalopathy: State-of-the-science update and narrative review.}, journal = {The Clinical neuropsychologist}, volume = {}, number = {}, pages = {1-25}, doi = {10.1080/13854046.2025.2454047}, pmid = {39834035}, issn = {1744-4144}, support = {R01 AG061028/AG/NIA NIH HHS/United States ; RF1 NS122854/NS/NINDS NIH HHS/United States ; RF1 NS132290/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVE: The long-recognized association of brain injury with increased risk of dementia has undergone significant refinement and more detailed study in recent decades. Chronic traumatic encephalopathy (CTE) is a specific neurodegenerative tauopathy related to prior exposure to repetitive head impacts (RHI). We aim to contextualize CTE within a historical perspective and among emerging data which highlights the scientific and conceptual evolution of CTE-related research in parallel with the broader field of neurodegenerative disease and dementia.

METHODS: We provide a narrative state-of-the-science update on CTE neuropathology, clinical manifestations, biomarkers, different types and patterns of head impact exposure relevant for CTE, and the complicated influence of neurodegenerative co-pathology on symptoms.

CONCLUSIONS: Now almost 20 years since the initial case report of CTE in a former American football player, the field of CTE continues evolving with increasing clarity but also several ongoing controversies. Our understanding of CTE neuropathology outpaces that of disease-specific clinical correlates or the development of in-vivo biomarkers. Diagnostic criteria for symptoms attributable to CTE are still being validated, but leveraging increasingly available biomarkers for other conditions like Alzheimer's disease may be helpful for informing the CTE differential diagnosis. As diagnostic refinement efforts advance, clinicians should provide care and/or referrals to providers best suited to treat an individual patient's clinical symptoms, many of which have evidence-based behavioral treatment options that are etiologically agnostic. Several ongoing research initiatives and the gradual accrual of gold standard clinico-pathological data will pay dividends for advancing the many existing gaps in the field of CTE.}, } @article {pmid39833961, year = {2025}, author = {Lin, Y and Luo, X and Wang, F and Cai, H and Lin, Y and Kang, D and Fang, W}, title = {Sex differences in cognition, anxiety-phenotype and therapeutic effect of metformin in the aged apoE-TR mice.}, journal = {Biology of sex differences}, volume = {16}, number = {1}, pages = {3}, pmid = {39833961}, issn = {2042-6410}, support = {2023J05136//Natural Science Foundation of Fujian Province/ ; 2022QNA036//Fujian Provincial Health Technology Project/ ; 2023YSJYX-YL-1//Neurosurgery Department, Fujian Neurological Disease Medical Center construction project/ ; }, mesh = {Animals ; *Metformin/pharmacology/therapeutic use ; Female ; Male ; *Anxiety/drug therapy ; *Sex Characteristics ; *Cognition/drug effects ; *Mice, Transgenic ; Hypoglycemic Agents/pharmacology/therapeutic use ; Apolipoprotein E4/genetics ; Aging/drug effects ; Mice ; Phenotype ; Cognitive Dysfunction/drug therapy ; Depression/drug therapy ; Mice, Inbred C57BL ; Blood Glucose ; Apolipoprotein E3/genetics ; }, abstract = {BACKGROUND: Apolipoprotein E4 (ApoE4) is associated with an increased risk of Alzheimer's disease (AD), depression, and anxiety, which were reported to improve after the administration of metformin. However, sex influence on the effect of ApoE4 and metformin on cognition and mental health is poorly understood.

METHODS: ApoE3-TR and apoE4-TR mice of both sexes were randomly assigned to the normal saline and metformin groups from 13 months to 18 months of age. Behavior tests (MWM, EPM, OFT, TST, FST) were conducted to assess cognition, anxiety, and depression-like behaviors. The mice's blood glucose was also recorded.

RESULTS: Male aged apoE4-TR mice are more vulnerable to cognitive decline than females. Metformin improves the spatial memory of female, but not male apoE3-TR mice and female apoE4-TR mice while aggravating the cognitive impairment of male apoE4-TR mice. The anxiety-like phenotypes in male apoE4-TR mice are more severe than in male apoE3-TR mice, while metformin ameliorates the anxiety-like behaviors in the male apoE4-TR mice but not in male apoE3-TR mice. In addition, metformin alleviates depression-like behaviors in male and female apoE4-TR mice. The hypoglycemic effect of metformin is insignificant in both male and female apoE4-TR mice.

CONCLUSIONS: Male sex exacerbates APOE4-related cognitive impairment and anxiety in aged mice and is insensitive to the cognition improvement effect of metformin in the aged apoE3 mice. Male sex with APOE4 may experience more severe cognitive impairment after treatment with metformin while sensitive to the anti-anxiety effects of metformin. These findings identify sex-specific effects on ApoE4-based dementia, anxiety prevention, and therapy, emphasizing the importance of further sex dimension analyses in vivo and clinical studies.}, } @article {pmid39833898, year = {2025}, author = {Wang, Z and Wang, C and Yuan, B and Liu, L and Zhang, H and Zhu, M and Chai, H and Peng, J and Huang, Y and Zhou, S and Liu, J and Wu, L and Wang, W}, title = {Akkermansia muciniphila and its metabolite propionic acid maintains neuronal mitochondrial division and autophagy homeostasis during Alzheimer's disease pathologic process via GPR41 and GPR43.}, journal = {Microbiome}, volume = {13}, number = {1}, pages = {16}, pmid = {39833898}, issn = {2049-2618}, mesh = {*Propionates/metabolism/pharmacology ; Animals ; *Alzheimer Disease/metabolism/microbiology ; Mice ; *Receptors, G-Protein-Coupled/metabolism ; Humans ; *Gastrointestinal Microbiome ; *Homeostasis ; *Akkermansia ; *Mitochondria/metabolism ; *Autophagy ; *Neurons/metabolism ; Disease Models, Animal ; Male ; Female ; Fatty Acids, Volatile/metabolism ; Aged ; Mitochondrial Dynamics ; Feces/microbiology ; Mitophagy ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disease (ND). In recent years, multiple clinical and animal studies have shown that mitochondrial dysfunction may be involved in the pathogenesis of AD. In addition, short-chain fatty acids (SCFA) produced by intestinal microbiota metabolism have been considered to be important factors affecting central nervous system (CNS) homeostasis. Among the main mediators of host-microbe interactions, volatile fatty acids play a crucial role. Nevertheless, the influence and pathways of microorganisms and their metabolites on Alzheimer's disease (AD) remain uncertain.

RESULTS: In this study, we present distinctions in blood and fecal SCFA levels and microbiota composition between healthy individuals and those diagnosed with AD. We found that AD patients showed a decrease in the abundance of Akkermansia muciniphila and a decrease in propionic acid both in fecal and in blood. In order to further reveal the effects and the mechanisms of propionic acid on AD prevention, we systematically explored the effects of propionic acid administration on AD model mice and cultured hippocampal neuronal cells. Results showed that oral propionate supplementation ameliorated cognitive impairment in AD mice. Propionate downregulated mitochondrial fission protein (DRP1) via G-protein coupled receptor 41 (GPR41) and enhanced PINK1/PARKIN-mediated mitophagy via G-protein coupled receptor 43 (GPR43) in AD pathophysiology which contribute to maintaining mitochondrial homeostasis both in vivo and in vitro. Administered A. muciniphila to AD mice before disease onset showed improved cognition, mitochondrial division and mitophagy in AD mice.

CONCLUSIONS: Taken together, our results demonstrate that A. muciniphila and its metabolite propionate protect against AD-like pathological events in AD mouse models by targeting mitochondrial homeostasis, making them promising therapeutic candidates for the prevention and treatment of AD. Video Abstract.}, } @article {pmid39832406, year = {2025}, author = {Lee, S and Hahn, C and Seong, E and Choi, HS}, title = {Reactive EEG Biomarkers for Diagnosis and Prognosis of Alzheimer's Disease and Mild Cognitive Impairment.}, journal = {Biosensors & bioelectronics}, volume = {273}, number = {}, pages = {117181}, doi = {10.1016/j.bios.2025.117181}, pmid = {39832406}, issn = {1873-4235}, mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; Aged ; *Electroencephalography ; *Biomarkers ; Female ; Male ; Prognosis ; Aged, 80 and over ; Biosensing Techniques/methods ; }, abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative condition characterized by progressive cognitive decline with currently no effective treatment available. One of the most critical areas in AD research is the identification of reliable biomarkers, which are essential for accurate diagnosis, prognostic assessment, and the development of targeted therapies. In this study, we introduce two novel reactive EEG (rEEG) biomarkers aimed at enhancing the diagnosis of AD and mild cognitive impairment (MCI). These biomarkers, previously unexplored in the literature, offer new insights into differentiating between various cognitive states. The first biomarker demonstrates a significant ability to distinguish between AD patients and normal controls (NC), while also effectively distinguishing MCI patients from NC. The second biomarker is designed to identify a subset of AD patients exhibiting hyperconductivity or hyperactivity, characterized by distinctive neural electrical patterns. A cohort of 90 elderly participants (mean age 76.63 ± 6.08 years) was recruited, including 30 AD patients, 30 individuals with MCI, and 30 NC subjects. Psychiatric diagnoses of participants were made by qualified professionals at Daejeon St. Mary's Hospital, The Catholic University of Korea, utilizing comprehensive neuropsychological assessments. Notably, the rEEG biomarkers achieved accuracies of 95%, 95%, and 98% in distinguishing between AD and NC, AD and MCI, and MCI and NC groups, respectively. These results underscore the potential of rEEG as a highly accurate and reliable diagnostic tool for cognitive impairments, including AD and MCI.}, } @article {pmid39832109, year = {2025}, author = {Pelczarski, M and Wolaniuk, S and Zaborska, M and Sadowski, J and Sztangreciak-Lehun, A and Bułdak, RJ}, title = {The role of α-tocopherol in the prevention and treatment of Alzheimer's disease.}, journal = {Molecular and cellular biochemistry}, volume = {}, number = {}, pages = {}, pmid = {39832109}, issn = {1573-4919}, abstract = {Scientific reports from various areas of the world indicate the potential role of tocopherols (vitamin E) in particular α-tocopherol in the prevention and therapy of Alzheimer's disease. The current phenomenon is related to the growing global awareness of eating habits and is also determined by the need to develop the prevention, management and therapy of Alzheimer's disease. This article is a review of current research on the action of the active form of vitamin E-α-tocopherol and its impact on the development and course of Alzheimer's disease. Additionally, to contrast this information, selected primary research on this topic was included. The aim of this article is to analyze and summarize the available scientific information on the effects of the active form of vitamin E, α-tocopherol, on the development and course of Alzheimer's disease. In the structure of the review, particular attention was paid to the analysis of the pathophysiological processes of the disease and the biochemical features of the action of α-tocopherol. To discuss the relationship between the effect of α-tocopherol and the occurrence of Alzheimer's disease, a literature review was conducted using the following databases: PubMed, Google Scholar, and Elsevier. During the search process, the following keywords were used: "tocopherols", "vitamin E", "α-tocopherol", "Alzheimer's disease" in various combinations. The process was conducted in accordance with the adopted search strategy taking into account the inclusion and exclusion criteria. Alzheimer's disease (AD) is the most common, irreversible neurodegenerative disease, so many scientists are actively looking for substances and/or strategies to prevent its development and to slow down its course in patients. Alpha-tocopherols (ATF) are a factor that inhibits the pathophysiological processes associated with the development of AD by reducing the formation of atherogenic amyloid B (AB). Additionally, this type of tocopherols has antioxidant and anti-inflammatory properties and has a positive effect on the metabolic functioning of mitochondria. It has been shown that a higher intake of α-tocopherol (ATF) was associated with a reduced risk of developing dementia and the occurrence of mild types of cognitive impairment (MCI). Various sources indicate an insufficient supply of ATF in the diet. ATF supplementation may potentially help to slow down the course of Alzheimer's disease, which is why this substance may be popularized in the treatment of this disease in the future. However, there is a need for further research on this issue.}, } @article {pmid39832031, year = {2025}, author = {Padti, AC and Bhavi, SM and Thokchom, B and Singh, SR and Bhat, SS and Harini, BP and Sillanpää, M and Yarajarla, RB}, title = {Nanoparticle Interactions with the Blood Brain Barrier: Insights from Drosophila and Implications for Human Astrocyte Targeted Therapies.}, journal = {Neurochemical research}, volume = {50}, number = {1}, pages = {80}, pmid = {39832031}, issn = {1573-6903}, mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; *Nanoparticles ; *Astrocytes/metabolism ; *Drosophila ; Drug Delivery Systems/methods ; Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {This review explores the intricate connections between Drosophila models and the human blood-brain barrier (BBB) with nanoparticle-based approaches for neurological treatment. Drosophila serves as a powerful model organism due to its evolutionary conservation of key biological processes, particularly in the context of the BBB, which is formed by glial cells that share structural and functional similarities with mammalian endothelial cells. Recent advancements in nanoparticle technology have highlighted their potential for effective drug delivery across the BBB, utilizing mechanisms such as passive diffusion, receptor-mediated transcytosis, and carrier-mediated transport. The ability to engineer nanoparticles with specific physicochemical properties-such as size, surface charge, and functionalization-enhances their targeting capabilities, particularly towards astrocytes, which play a crucial role in maintaining BBB integrity and responding to neuroinflammation. Insights gained from Drosophila studies have informed the design of personalized nanomedicine strategies aimed at treating neurodegenerative diseases, including Alzheimer's, Parkinson's disease etc. As research progresses, the integration of findings from Drosophila models with emerging humanized BBB systems will pave the way for innovative therapeutic approaches that improve drug delivery and patient outcomes in neurological disorders.}, } @article {pmid39831743, year = {2025}, author = {Maupin, EA and Adams, KL}, title = {Cellular Senescence in Glial Cells: Implications for Multiple Sclerosis.}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16301}, pmid = {39831743}, issn = {1471-4159}, support = {TA-2305-41311//National Multiple Sclerosis Society/ ; }, mesh = {Humans ; *Cellular Senescence/physiology ; *Multiple Sclerosis/pathology/metabolism ; *Neuroglia/pathology/metabolism ; Animals ; }, abstract = {Aging is the most common risk factor for Multiple Sclerosis (MS) disease progression. Cellular senescence, the irreversible state of cell cycle arrest, is the main driver of aging and has been found to accumulate prematurely in neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Cellular senescence in the central nervous system of MS patients has recently gained attention, with several studies providing evidence that demyelination induces cellular senescence, with common hallmarks of p16INK4A and p21 expression, oxidative stress, and senescence-associated secreted factors. Here we discuss the current evidence of cellular senescence in animal models of MS and different glial populations in the central nervous system, highlighting the major gaps in the field that still remain. As premature senescence in MS may exacerbate demyelination and inflammation, resulting in inhibition of myelin repair, it is critical to increase understanding of cellular senescence in vivo, the functional effects of senescence on glial cells, and the impact of removing senescent cells on remyelination and MS. This emerging field holds promise for opening new avenues of treatment for MS patients.}, } @article {pmid39831085, year = {2024}, author = {Kollarik, S and Bimbiryte, D and Sethi, A and Dias, I and Moreira, CG and Noain, D}, title = {Pharmacological enhancement of slow-wave activity at an early disease stage improves cognition and reduces amyloid pathology in a mouse model of Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1519225}, pmid = {39831085}, issn = {1663-4365}, abstract = {INTRODUCTION: Improving sleep in murine Alzheimer's disease (AD) is associated with reduced brain amyloidosis. However, the window of opportunity for successful sleep-targeted interventions, regarding the reduction in pathological hallmarks and related cognitive performance, remains poorly characterized.

METHODS: Here, we enhanced slow-wave activity (SWA) during sleep via sodium oxybate (SO) oral administration for 2 weeks at early (6 months old) or moderately late (11 months old) disease stages in Tg2576 mice and evaluated resulting neuropathology and behavioral performance.

RESULTS: We observed that the cognitive performance of 6-month-old Tg2576 mice significantly improved upon SO treatment, whereas no change was observed in 11-month-old mice. Histochemical assessment of amyloid plaques demonstrated that SO-treated 11-month-old Tg2576 mice had significantly less plaque burden than placebo-treated ones, whereas ELISA of insoluble protein fractions from brains of 6-month-old Tg2576 mice indicated lower Aβ-42/Aβ-40 ratio in SO-treated group vs. placebo-treated controls.

DISCUSSION: Altogether, our results suggest that SWA-dependent reduction in brain amyloidosis leads to alleviated behavioral impairment in Tg2576 mice only if administered early in the disease course, potentially highlighting the key importance of early sleep-based interventions in clinical cohorts.}, } @article {pmid39831016, year = {2025}, author = {Liao, H and Liao, S and Gao, YJ and Wang, X and Guo, LH and Zheng, S and Yang, W and Dai, YN}, title = {Near-infrared brain functional characteristics of mild cognitive impairment with sleep disorders.}, journal = {World journal of psychiatry}, volume = {15}, number = {1}, pages = {97945}, pmid = {39831016}, issn = {2220-3206}, abstract = {BACKGROUND: Mild cognitive impairment (MCI) has a high risk of progression to Alzheimer's disease. The disease is often accompanied by sleep disorders, and whether sleep disorders have an effect on brain function in patients with MCI is unclear.

AIM: To explore the near-infrared brain function characteristics of MCI with sleep disorders.

METHODS: A total of 120 patients with MCI (MCI group) and 50 healthy subjects (control group) were selected. All subjects underwent the functional near-infrared spectroscopy test. Collect baseline data, Mini-Mental State Examination, Montreal Cognitive Assessment scale, fatigue severity scale (FSS) score, sleep parameter, and oxyhemoglobin (Oxy-Hb) concentration and peak time of functional near-infrared spectroscopy test during the task period. The relationship between Oxy-Hb concentration and related indexes was analyzed by Pearson or Spearmen correlation.

RESULTS: Compared with the control group, the FSS score of the MCI group was higher (t = 11.310), and the scores of Pittsburgh sleep quality index, sleep time, sleep efficiency, nocturnal sleep disturbance, and daytime dysfunction were higher (Z = -10.518, -10.368, -9.035, -10.661, -10.088). Subjective sleep quality and total sleep time scores were lower (Z = -11.592, -9.924). The sleep efficiency of the MCI group was lower, and the awakening frequency, rem sleep latency period, total sleep time, and oxygen desaturation index were higher (t = 5.969, 5.829, 2.887, 3.003, 5.937). The Oxy-Hb concentration at T0, T1, and T2 in the MCI group was lower (t = 14.940, 11.280, 5.721), and the peak time was higher (t = 18.800, 13.350, 9.827). In MCI patients, the concentration of Oxy-Hb during T0 was negatively correlated with the scores of Pittsburgh sleep quality index, sleep time, total sleep time, and sleep efficiency (r = -0.611, -0.388, -0.563, -0.356). It was positively correlated with sleep efficiency and total sleep time (r = 0.754, 0.650), and negatively correlated with oxygen desaturation index (r = -0.561) and FSS score (r = -0.526). All comparisons were P < 0.05.

CONCLUSION: Patients with MCI and sleep disorders have lower near-infrared brain function than normal people, which is related to sleep quality. Clinically, a comprehensive assessment of the near-infrared brain function of patients should be carried out to guide targeted treatment and improve curative effect.}, } @article {pmid39830657, year = {2024}, author = {Nikray, N and Abharian, N and Jafari Ashtiani, S and Kobarfard, F and Faizi, M}, title = {Comparative Evaluation of Aminoguanidine, Semicarbazide and Thiosemicarbazide Treatment for Methylglyoxal-Induced Neurological Toxicity in Experimental Models.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {23}, number = {1}, pages = {e153322}, pmid = {39830657}, issn = {1726-6890}, abstract = {BACKGROUND: Advanced glycation end products (AGEs) are complex compounds that play a critical role in neurological disorders, including the pathogenesis of Alzheimer's disease. Methylglyoxal (MG) is recognized as the primary precursor of AGEs. Methylglyoxal is produced endogenously and also introduced through dietary exposures.

OBJECTIVES: This study aimed to investigate and compare the effects of aminoguanidine (AG), semicarbazide (SC), and thiosemicarbazide (TSC) on MG-induced neurological toxicity in rats.

METHODS: Male Wistar rats were exposed orally to MG, MG + AG, MG + SC, and MG + TSC for 70 days. Neurobehavioral, biochemical, and histopathological changes were evaluated.

RESULTS: The findings indicated that oral administration of MG for 70 days resulted in memory impairment and increased anxiety in neurobehavioral tests. Additionally, MG elevated protein carbonylation in brain tissues. Semicarbazide was found to prevent MG-induced memory problems, while both SC and AG reduced carbonyl content in brain tissues. Aminoguanidine and TSC were effective in alleviating anxiety induced by MG exposure. Histopathological analysis revealed that MG caused cell damage and neuronal necrosis in the hippocampus, particularly in the cornu ammonis 1 and 3 (CA1 and CA3) and AG, SC, and TSC improved neuronal survival specifically in the CA1 and DG areas.

CONCLUSIONS: The data suggest that SC, AG, and TSC may offer neuroprotective effects against MG-induced neurobehavioral toxicity. Further studies are required to explore the mechanisms of action of these compounds.}, } @article {pmid39830554, year = {2024}, author = {Medel Sánchez, A and Ortiz Hernández, A and Moreno Moreno, RA and Salas López, D and Madrigal Gómez, LE and Dominguez Ibarra, AK and Gutiérrez Rojas, BA and Garcia Navarro, CO and Moreno Becerril, GT and Montelongo Quevedo, M and Flores Valdés, JR}, title = {Aducanumab in Alzheimer's Disease: A Comparative Study of Its Effects on Dementia and Mild Cognitive Impairment.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e75907}, pmid = {39830554}, issn = {2168-8184}, abstract = {Alzheimer's disease (AD) is the leading cause of dementia, characterized by progressive cognitive decline. Cholinesterase inhibitors are commonly used to manage symptoms but have limited efficacy as the disease progresses. Aducanumab, a monoclonal antibody targeting amyloid-β (Aβ) plaques, has emerged as a novel therapeutic approach. Despite its Food and Drug Administration (FDA) approval, its efficacy and safety remain contentious, particularly following the European Medicines Agency's (EMA's) rejection. This systematic review aims to evaluate the efficacy, safety, and clinical outcomes of aducanumab in treating mild AD. Adhering to Preferred Reporting Items for Systematic Reviews (PRISMA) 2020 guidelines, we conducted a comprehensive search of PubMed and Science Direct databases, including randomized controlled trials (RCTs), cohort studies, and case-control studies focusing on aducanumab versus placebo in mild AD. Studies were screened based on predefined inclusion and exclusion criteria, and data were extracted on clinical outcomes, biomarkers, and neuroimaging markers. The risk of bias was assessed using the Cochrane Handbook and Newcastle-Ottawa Scale. Out of 967 identified records, seven studies met the inclusion criteria. Findings indicated a dose-dependent reduction in Aβ plaques with aducanumab, but clinical outcomes varied. High-dose aducanumab (10 mg/kg) demonstrated significant improvements in some studies but not others. Adverse events, notably amyloid-related imaging abnormalities (ARIA), were frequent, especially at higher doses. The studies exhibited heterogeneous treatment effects and underscored the potential of cerebrospinal fluid biomarkers as an alternative to amyloid positron emission tomography (PET) scans. Aducanumab shows promise in reducing Aβ plaques and has potential clinical benefits at high doses; however, its safety profile, particularly concerning ARIA, remains a significant concern. The variability in clinical efficacy highlights the need for further research to optimize dosing regimens and identify patient populations most likely to benefit from treatment. Future studies should focus on refining treatment protocols and exploring alternative biomarkers to improve therapeutic outcomes for AD.}, } @article {pmid39830039, year = {2024}, author = {Chen, R and Lu, X and Xiao, A and Ma, J}, title = {Role of insulin-like growth factor-2 in Alzheimer's disease induced memory impairment and underlying mechanisms.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1520253}, pmid = {39830039}, issn = {1662-5102}, abstract = {Alzheimer's disease (AD) is the most prevalent type of dementia. Treatments for AD do not reverse the loss of brain function; rather, they decrease the rate of cognitive deterioration. Current treatments are ineffective in part because they do not address neurotrophic mechanisms, which are believed to be critical for functional recovery. Given that structural losses are assumed to be the root cause of cognitive impairment in AD, strengthening neurotrophic pathways may be a useful preventative therapeutic approach. Insulin-like growth factor-2 (IGF2), which is widely expressed in the central nervous system (CNS), has emerged as a crucial mechanism of synaptic plasticity and learning and memory, and many studies have indicated that this neurotrophic peptide is a viable candidate for treating and preventing AD-induced cognitive decline. An increase in IGF2 levels improves memory in healthy animals and alleviates several symptoms associated with neurodegenerative disorders. These effects are primarily caused by the IGF2 receptor, which is widely expressed in neurons and controls protein trafficking, synthesis, and degradation. However, the use of IGF2 as a potential target for the development of novel pharmaceuticals to treat AD-induced memory impairment needs further investigation. We compiled recent studies on the role of IGF2 in AD-associated memory issues and summarized the current knowledge regarding IGF2 expression and function in the brain, specifically in AD-induced memory impairment.}, } @article {pmid39829171, year = {2025}, author = {Wang, M and Guo, S and Yi, L and Li, Z and Shi, X and Fan, Y and Luo, M and He, Y and Song, W and Du, Y and Dong, Z}, title = {KIF9 Ameliorates Neuropathology and Cognitive Dysfunction by Promoting Macroautophagy in a Mouse Model of Alzheimer's Disease.}, journal = {Aging cell}, volume = {}, number = {}, pages = {e14490}, doi = {10.1111/acel.14490}, pmid = {39829171}, issn = {1474-9726}, support = {CSTB2022NSCQ-LZX0010//Natural Science Foundation of Chongqing Municipality/ ; CSTB2024NSCQ-LZX0008//Natural Science Foundation of Chongqing Municipality/ ; 32371030//National Natural Science Foundation of China/ ; 82071395//National Natural Science Foundation of China/ ; 82371194//National Natural Science Foundation of China/ ; W0044//CQMU Program for Youth Innovation in Future Medicine/ ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting the elderly. The imbalance of protein production and degradation processes leads to the accumulation of misfolded and abnormally aggregated amyloid-beta (Aβ) in the extracellular space and forms senile plaques, which constitute one of the most critical pathological hallmarks of AD. KIF9, a member of the kinesin protein superfamily, mediates the anterograde transport of intracellular cargo along microtubules. However, the exact role of KIF9 in AD pathogenesis remains largely elusive. In this study, we reported that the expression of kinesin family member 9 (KIF9) in the hippocampus of APP23/PS45 double-transgenic AD model mice declined in an age-dependent manner, concurrent with macroautophagy dysfunction. Furthermore, we found that KIF9 mediated the transport of lysosomes through kinesin light chain 1 (KLC1), thereby participating in the degradation of amyloidogenic pathway-related proteins of Aβ precursor protein (APP) in AD model cells through promoting the macroautophagy pathway. Importantly, genetic upregulation of KIF9 via adeno-associated virus (AAV) diminished Aβ deposition and alleviated cognitive impairments in AD model mice by enhancing macroautophagy function. Collectively, our findings underscore the ability of KIF9 to promote macroautophagy through KLC1-mediated anterograde transport of lysosomes, effectively ameliorating cognitive dysfunction in AD model mice. These discoveries suggest that KIF9 may represent a novel therapeutic target for the treatment of AD.}, } @article {pmid39828895, year = {2025}, author = {Wang, Z and Liang, Q and Lin, Z and Li, H and Chen, X and Zou, Z and Mo, J}, title = {Potential role of formononetin as a novel natural agent in Alzheimer's disease and osteoporosis comorbidity.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {2}, pages = {361-371}, doi = {10.1177/13872877241299104}, pmid = {39828895}, issn = {1875-8908}, mesh = {*Alzheimer Disease/drug therapy/genetics ; *Isoflavones/pharmacology/therapeutic use ; Humans ; *Osteoporosis/drug therapy/genetics ; *Molecular Docking Simulation ; Animals ; Comorbidity ; Mice ; Gene Regulatory Networks/drug effects ; Biological Products/therapeutic use ; Calcium Channels, L-Type/genetics/metabolism ; }, abstract = {BACKGROUND: The growing aging population has led to an increase in the prevalence of Alzheimer's disease (AD) and osteoporosis (OP), both of which significantly impair quality of life. The comorbid nature of these conditions suggests a shared genetic etiology, the understanding of which is crucial for developing targeted therapies.

OBJECTIVE: This study aims to explore the shared genetic etiology underlying AD and OP, using a system biology approach to identify potential therapeutic targets and natural compounds for treatment.

METHODS: We employed Weighted Gene Co-Expression Network Analysis (WGCNA) with molecular docking strategies to uncover the genetic links between AD and OP. MT2A and CACNA1C were identified as key pleiotropic hub genes potentially linking AD and OP. Molecular docking was utilized to screen for compounds with therapeutic potential, leading to the identification of formononetin as a compound with significant binding affinity to these hub genes. Quantitative real-time PCR (qRT-PCR) validation was conducted to confirm the gene expression changes in disease models.

RESULTS: Our study indicate that formononetin exhibits strong binding affinity to the identified hub genes, MT2A and CACNA1C. qRT-PCR validation confirmed the upregulation of these genes in disease models, which was mitigated upon treatment with formononetin, suggesting a reversal of disease markers.

CONCLUSIONS: This study advances our understanding of the genetic intersections between AD and OP and positions formononetin as a promising natural agent for further translational research. Formononetin's multi-target potential makes it a valuable candidate for managing these comorbid conditions, meriting further investigation and development as a therapeutic strategy.}, } @article {pmid39828502, year = {2025}, author = {Wang, J and Li, X and Pang, H and Bu, S and Zhao, M and Liu, Y and Yu, H and Jiang, Y and Fan, G}, title = {Differential Connectivity Patterns of Mild Cognitive Impairment in Alzheimer's and Parkinson's Disease: A Large-scale Brain Network Study.}, journal = {Academic radiology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.acra.2024.09.017}, pmid = {39828502}, issn = {1878-4046}, abstract = {RATIONALE AND OBJECTIVES: Cognitive disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), significantly impact the quality of life in older adults. Mild cognitive impairment (MCI) is a critical stage for intervention and can predict the development of dementia. The causes of these two diseases are not fully understood, but there is an overlap in their neuropathology. There is a lack of direct comparison regarding the changes in functional connectivity within and between different brain networks during cognitive impairment in these two diseases.

OBJECTIVE: This study aims to investigate changes in brain network connectivity of AD and PD with mild cognitive impairment, shedding light on the underlying neuropathological mechanisms and potential treatment options.

METHODS: A total of 33 AD-MCI patients, 55 PD-MCI patients, and 34 healthy controls (HCs) underwent resting-state functional MRI and cognitive function assessment using Independent Components Analysis (ICA). We compared intra- and inter-network functional connectivity among the three groups and analyzed the correlation between changes in functional connectivity and cognitive domain performance.

RESULTS: Using ICA, we identified eight functional networks. In the AD-MCI group, reductions in internetwork functional connectivity were mainly around the default mode network (DMN). Intra-network functional connectivity was widely reduced, especially in the DMN, while intra-network functional connectivity in the Salience Network (SN) increased. In contrast, in the PD-MCI group, reductions in internetwork functional connectivity were mainly around the SN. Intra-network functional connectivity in the SN decreased, while intra-network functional connectivity in other networks increased.

CONCLUSION: This study highlights distinct yet overlapping changes in brain network connectivity in AD and PD, providing new insights into the underlying mechanisms of cognitive impairment disorders.}, } @article {pmid39828086, year = {2025}, author = {Kara, S and Polat, S and Akillioglu, K and Saker, D and Evli Ce, AT and Sencar, L and Aydın, UF and Polat, S}, title = {Effects of TGF-β1 on Aβ-40 and α- β- γ secretase expression in hippocampus and prefrontal cortex in experimental Alzheimer's disease.}, journal = {Behavioural brain research}, volume = {482}, number = {}, pages = {115432}, doi = {10.1016/j.bbr.2025.115432}, pmid = {39828086}, issn = {1872-7549}, abstract = {Alzheimer's disease is a chronic complex neurodegenerative disease characterized with amyloid plaques and loss of neurons. TGF-β1 is important growth factor, plays critical roles in cell metabolism, tissue homeostasis, neuronal development, and synaptic plasticity. In this study, we aimed to examine the effect of TGF-β1 on the regulation of α, β, and γ-secretase enzymes, Aβ-40 accumulation, apoptosis, and neuronal damage in an experimental Scopolamine-induced AD-like model. The subjects were divided into 5 groups such as control, sham, TGF-β1 control, Scopolamin group, TGF-β1 treatment groups.Then all groups were divided into 2 subgroups according to 28th-56th days. Except for Morris water maze (MWM) test, hippocampus and prefrontal cortex tissues were taken for light-electron microscopic, immunohistochemical, and biochemical examinations. It was observed that learning and memory abilities, which decreased in the MWM test of the Scopolamine group, increased in the treatment groups. In addition, α-secretase expression decreased in the Scopolamin group, while it increased in the TGF-β1 treatment group. It was determined that Aβ-40 and caspase-3 immunoreactivity, β and γ-secretase enzyme levels increased in the Scopolamin group and decreased in TGF-β1 treatment group. Cellular degenerations were relatively decreased in TGF-β1 treatment group. It was thought that TGF-β1 might have a therapeutic effect on Alzheimer's disease by increasing memory performance and preventing Aβ-40 accumulation in the AD-like model induced by Scopolamine and also, may be effective preventing neuronal damage by down-regulating caspase-3 expression. When all the findings evaluated together, it was concluded that TGF-β1 could be evaluated as a therapeutic agent in Alzheimer's disease.}, } @article {pmid39828018, year = {2025}, author = {Sharma, D and Singh, V and Kumar, A and Singh, TG}, title = {Genistein: A promising ally in combating neurodegenerative disorders.}, journal = {European journal of pharmacology}, volume = {991}, number = {}, pages = {177273}, doi = {10.1016/j.ejphar.2025.177273}, pmid = {39828018}, issn = {1879-0712}, abstract = {Neurodegenerative disorders arise when nerve cells in the brain or peripheral nervous system gradually lose functions and eventually die. Although certain therapies may alleviate some of the physical and mental symptoms associated with neurodegenerative disorders, hence slowing their progression, but no sure-shot treatment is currently available. It was shown that the rise in life expectancy and the number of elderly people in the community led to an increasing trend in the incidence and prevalence of neurodegenerative disease. Phytomolecules are demonstrating their effectiveness in combating, regression, and delaying various diseases. Genistein is one of soy isoflavone with antioxidant, anti-inflammatory, and estrogenic effects. Researchers demonstrated that Genistein treatment significantly reduced hyperglycemia, improved cognitive performance by modulating acetylcholinesterase activity and oxidative stress, and alleviated neuroinflammatory conditions in mice. This paper evaluates (in vivo and in vitro) various molecular targets of isoflavones and their ability to effectively counter several neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases and amyotrophic lateral sclerosis. In this review, we aim to provide an overview of the role that genistein plays in delaying the development of neurodegenerative disorders.}, } @article {pmid39827439, year = {2025}, author = {Fasth, LM and Kelley, CJ and Colón-Emeric, C and Green, AR and Thorpe, CT and Gilliam, M and Lund, JL and Hanson, LC and Niznik, JD}, title = {How Should Clinicians Discuss Deprescribing with Caregivers of Older Adults Living with Dementia? A Qualitative Study.}, journal = {Drugs & aging}, volume = {42}, number = {2}, pages = {155-164}, pmid = {39827439}, issn = {1179-1969}, support = {K08 AG071794/AG/NIA NIH HHS/United States ; K08AG071794/AG/NIA NIH HHS/United States ; K08AG071794/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Deprescriptions ; *Caregivers/psychology ; Female ; Male ; *Dementia/drug therapy ; *Qualitative Research ; Aged ; Middle Aged ; Physicians/psychology ; Communication ; Diphosphonates/therapeutic use/adverse effects ; Aged, 80 and over ; }, abstract = {BACKGROUND: Preventive medications are potential targets for deprescribing in older adults with dementia as goals of care change from preventive to palliative. Yet, prescribers lack communication guidance to address deprescribing.

OBJECTIVE: Using bisphosphonates as a case example, we sought to characterize and compare communication preferences of prescribers and family/informal caregivers regarding deprescribing.

METHODS: We conducted 23 semi-structured interviews with prescribers (12) and caregivers (11) of older adults with Alzheimer's disease or related dementias (ADRD). Prescribers and caregivers were asked to provide their impressions of seven conversation starters for discussing deprescribing, focusing on a case example using bisphosphonates. These phrases focused on topics including life expectancy, treatment burden, adverse effects, and costs. We used a qualitative framework analysis to identify relevant themes as prescribers and caregivers discussed their general perceptions of the potential benefits and harms of bisphosphonates and experiences with deprescribing.

RESULTS: Among prescribers, there were ten physicians and two nurse practitioners; most (nine) female and white. Among caregivers, eight were female, seven were white, and five were Latino/a. For both prescribers and caregivers, preferred conversation starters initiated a risk versus benefit discussion, emphasizing medication adverse effects and patient-specific factors, such as functional status and indication for treatment. While prescribers emphasized discussing common medication adverse effects, caregivers noted the importance of knowing a medication's potential impact on ADRD. The least preferred conversation starter for deprescribing among both groups focused on the extra effort and cost of continuing bisphosphonates. Discordance between caregivers and prescribers were identified in several phrases; notably, caregivers disliked statements that introduced discussions of prognosis and life expectancy.

CONCLUSIONS: Deprescribing conversations may be best perceived by caregivers when introduced with a discussion of a medication's adverse effects and potential impact on cognition. In addition, deprescribing conversations should be tailored to patient-specific factors, including functional status, goals of care, and the role of their caregiver in medical decision-making. Avoiding discussions of medication cost, pill burden, and life expectancy may help reassure the caregiver that deprescribing is a form of medication optimization and not a withdrawal of care.}, } @article {pmid39826816, year = {2025}, author = {Chen, L and Zhao, X and Sheng, R and Lazarovici, P and Zheng, W}, title = {Artemisinin alleviates astrocyte overactivation and neuroinflammation by modulating the IRE1/NF-κB signaling pathway in in vitro and in vivo Alzheimer's disease models.}, journal = {Free radical biology & medicine}, volume = {229}, number = {}, pages = {96-110}, doi = {10.1016/j.freeradbiomed.2025.01.027}, pmid = {39826816}, issn = {1873-4596}, abstract = {Recent studies have shown that neuroinflammation and heightened glial activity, particularly astrocyte overactivation, are associated with Alzheimer's disease (AD). Abnormal accumulation of amyloid-beta (Aβ) induces endoplasmic reticulum (ER) stress and activates astrocytes. Artemisinin (ART), a frontline anti-malarial drug, has been found to have neuroprotective properties. However, its impact on astrocytes remains unclear. In this study, we used Aβ1-42 induced astrocyte cultures and 3 × Tg-AD mice as in vitro and in vivo models, respectively, to investigate the effects of ART on AD related astrocyte overactivation and its underlying mechanisms. ART attenuated Aβ1-42-induced astrocyte activation, ER stress, and inflammatory responses in astrocyte cultures by inhibiting IRE1 phosphorylation and the NF-κB pathway, as evidenced by the overexpression of IRE1 WT and IRE1-K599A (kinase activity invalidated), along with application of activators and inhibitors related to ER stress. Furthermore, ART alleviated the detrimental effects and restored neurotrophic function of astrocytes on co-cultured neurons, preventing neuronal apoptosis during Aβ1-42 treatment. In 3 × Tg-AD mice, ART treatment improved cognitive function and reduced astrocyte overactivation, neuroinflammation, ER stress, and neuronal apoptosis. Moreover, ART attenuated the upregulation of IRE1/NF-κB pathway activity in AD mice. Astrocyte-specific overexpression of IRE1 via adeno-associated virus in AD mice reversed the ameliorating effects of ART. Our findings suggest that ART inhibits astrocyte overactivation and neuroinflammation in both in vitro and in vivo AD models by modulating the IRE1/NF-κB signaling pathway, thereby enhancing neuronal functions. This study underscores the therapeutic potential of ART in AD and highlights the significance of modulating the ER stress-inflammatory cycle and normalizing astrocyte-neuron communication.}, } @article {pmid39826482, year = {2025}, author = {Zulhafiz, NA and Teoh, TC and Chin, AV and Chang, SW}, title = {Drug repurposing using artificial intelligence, molecular docking, and hybrid approaches: A comprehensive review in general diseases vs Alzheimer's disease.}, journal = {Computer methods and programs in biomedicine}, volume = {261}, number = {}, pages = {108604}, doi = {10.1016/j.cmpb.2025.108604}, pmid = {39826482}, issn = {1872-7565}, abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent form of dementia, remains enigmatic in its origins despite the widely accepted "amyloid hypothesis," which implicates amyloid-beta peptide aggregates in its pathogenesis and progression. Despite advancements in technology and healthcare, the incidence of AD continues to rise. The traditional drug development process remains time-consuming, often taking years to bring an AD treatment to market. Drug repurposing has emerged as a promising strategy for developing cost-effective and efficient therapeutic options by identifying new uses for existing approved drugs, thus accelerating drug development.

OBJECTIVES: This study aimed to examine two key drug repurposing methodologies in general diseases and specifically in AD, which are artificial intelligent (AI) approach and molecular docking approach. In addition, the hybrid approach that integrates AI with molecular docking techniques will be explored too.

METHODOLOGY: This study systematically compiled a comprehensive collection of relevant academic articles, scientific papers, and research studies which were published up until November 2024 (as of the writing of this review paper). The final selection of papers was filtered to include studies related to Alzheimer's disease and general diseases, and then categorized into three groups: AI articles, molecular docking articles, and hybrid articles.

RESULTS: As a result, 331 papers were identified that employed AI for drug repurposing in general diseases, and 58 papers focused specifically in AD. For molecular docking in drug repurposing, 588 papers addressed general diseases, while 46 papers were dedicated to AD. The hybrid approach combining AI and molecular docking in drug repurposing has 52 papers for general diseases and 9 for AD. A comparative review was done across the methods, results, strengths, and limitations in those studies. Challenges of drug repurposing in AD are explored and future prospects are proposed.

DISCUSSION AND CONCLUSION: Drug repurposing emerges as a compelling and effective strategy within AD research. Both AI and molecular docking methods exhibit significant potential in this domain. AI algorithms yield more precise predictions, thus facilitating the exploration of new therapeutic avenues for existing drugs. Similarly, molecular docking techniques revolutionize drug-target interaction modelling, employing refined algorithms to screen extensive drug databases against specific target proteins. This review offers valuable insights for guiding the utilization of AI, molecular docking, or their hybrid in AD drug repurposing endeavors. The hope is to speed up the timeline of drug discovery which could improve the therapeutic approach to AD.}, } @article {pmid39826392, year = {2025}, author = {Mei, Z and Zhang, Y and Zhao, W and Lam, C and Luo, S and Wang, S and Luo, S}, title = {Music-based interventions for anxiety and depression in older adults with dementia: A systematic review of randomized controlled trials.}, journal = {Complementary therapies in clinical practice}, volume = {59}, number = {}, pages = {101951}, doi = {10.1016/j.ctcp.2025.101951}, pmid = {39826392}, issn = {1873-6947}, abstract = {OBJECTIVE: The objective of this systematic review was to synthesize evidence from randomized controlled trials (RCTs) regarding the efficacy of music-based interventions (MBIs) in improving anxiety and depression in older adults with dementia.

METHODS: Relevant RCTs were identified through searches in electronic databases, including PubMed, Embase, EBSCOhost, Scopus, Web of Science, APA PsycINFO, and Google. The Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) was used to evaluate the risk of bias in the included trials. A narrative synthesis of the included trials was conducted.

RESULTS: Nine RCTs involving 496 patients met the inclusion criteria; five trials evaluated the efficacy of MBIs for anxiety, and six trials evaluated their efficacy for depression in older adults with dementia. Of the nine trials, two reported significant improvements in anxiety in older adults with dementia following MBIs (Cohen's d = -1.71 to -2.48), while one trial reported significant improvements in depression (Cohen's d = -0.66).

CONCLUSIONS: Only a few trials support the efficacy of MBIs in alleviating negative emotions in older adults with dementia, as evidenced by three out of the nine trials. However, due to the small sample sizes and heterogeneity in dementia types, stages, and interventions, quantitative results were not pooled, making it challenging to draw reliable conclusions. Further validation and examination of the findings presented in this study are warranted to strengthen the evidence base for integrating MBIs into dementia care and treatment protocols.}, } @article {pmid39824583, year = {2025}, author = {Mishra, S and Banerjee, S and Tiwari, BS and Tiwari, AK}, title = {Recent progress in CRISPR-Cas-system for neurological disorders.}, journal = {Progress in molecular biology and translational science}, volume = {210}, number = {}, pages = {231-261}, doi = {10.1016/bs.pmbts.2024.07.017}, pmid = {39824583}, issn = {1878-0814}, mesh = {Humans ; *CRISPR-Cas Systems/genetics ; *Nervous System Diseases/genetics/therapy ; Animals ; Gene Editing ; Genetic Therapy/methods ; }, abstract = {Different neurological diseases including, Parkinson's, Alzheimer's, and Huntington's diseases extant momentous global disease burdens, affecting millions of lives for imposing a heavy disease burden on the healthcare systems. Despite various treatment strategies aimed at alleviating symptoms, treatments remain elusive and ineffective due to the disease's complexity. However, recent advancements in gene therapy via the CRISPR-Cas system offer ground-breaking and targeted treatment options. Based on a bacterial immune mechanism, the CRISPR-Cas system enables precise genome editing, allowing for the alteration of different genetic mutations and the possible cure of genetic diseases. In the context of neurological disorders, the CRISPR-Cas system shows a promising avenue by allowing researchers to conduct genome-editing which is implicated in neurodegenerative disease therapeutics. This book chapter provides an updated overview of the application of the CRISPR-Cas system for addressing target-specific therapeutic approaches for neurodegenerative disorders. Furthermore, we discuss the principles of the CRISPR-Cas mechanism, its role in modeling neurological disorders, identifying molecular targets, and developing gene-based therapies. Additionally, the chapter explores the recent clinical trials and CRISPR-Cas-mediated treatments for neurological conditions. By leveraging the accuracy and versatility of the CRISPR-Cas system, scientists can more effectively handle the genetic underpinnings of neurodegenerative diseases. Furthermore, the chapter extends the critical viewpoints on ethical considerations and technical limitations related to the clinical deployment of this revolutionizing technique.}, } @article {pmid39824445, year = {2025}, author = {Cardaci, V and Di Pietro, L and Zupan, MC and Sibbitts, J and Privitera, A and Lunte, SM and Caraci, F and Hartley, MD and Caruso, G}, title = {Characterizing oxidative stress induced by Aβ oligomers and the protective role of carnosine in primary mixed glia cultures.}, journal = {Free radical biology & medicine}, volume = {229}, number = {}, pages = {213-224}, doi = {10.1016/j.freeradbiomed.2025.01.030}, pmid = {39824445}, issn = {1873-4596}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. A critical aspect of AD pathology is represented by oxidative stress, which significantly contributes to neuronal damage and death. Microglia and astrocytes, the primary glial cells in the brain, are crucial for managing oxidative stress and supporting neuronal function. Carnosine is an endogenous dipeptide possessing a multimodal mechanism of action that includes antioxidant, anti-inflammatory, and anti-aggregant activities. The present study investigated the effects of Aβ1-42 oligomers (oAβ), small aggregates associated with the neurodegeneration observed in AD, on primary rat mixed glia cultures composed of both microglia and astrocytes, focusing on the ability of these detrimental species to induce oxidative stress. We assessed intracellular reactive oxygen species (ROS) and nitric oxide (NO) levels as markers of oxidative stress. Exposure to oAβ significantly elevated both ROS and NO intracellular levels compared to control cells. However, this effect was completely inhibited by the pre-treatment of mixed cultures with carnosine, resulting in ROS and NO levels similar to those observed in untreated (control) cells. Single-cell analysis of cellular responses to oAβ revealed heterogeneous ROS production, resulting in two distinct clusters of cells, one of which was very responsive to the treatment. The presence of carnosine counteracted the overproduction of ROS, also leading to a single, homogeneous cluster, similar to that observed in the case of control cells. Interestingly, unlike ROS response, single-cell analysis of NO production did not show any distinct clusters. Overall, our findings demonstrated the ability of carnosine to mitigate Aβ-induced oxidative stress in mixed glia cells, by rescuing ROS and NO intracellular levels, as well as to normalize the heterogeneous response to the treatment measured in terms of clusters' formation. The present study suggests a therapeutic potential of carnosine in pathologies characterized by oxidative stress including AD.}, } @article {pmid39823370, year = {2025}, author = {Bell, MB and Kane, MS and Ouyang, X and Young, ME and Jegga, AG and Chatham, JC and Darley-Usmar, V and Zhang, J}, title = {Brain Transcriptome Changes Associated With an Acute Increase of Protein O-GlcNAcylation and Implications for Neurodegenerative Disease.}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16302}, pmid = {39823370}, issn = {1471-4159}, support = {R01 HL142216/HL/NHLBI NIH HHS/United States ; R56AG060959/NH/NIH HHS/United States ; T32 HL007457/HL/NHLBI NIH HHS/United States ; I01 BX-004251-01//VA merit award/ ; R56 AG060959/AG/NIA NIH HHS/United States ; P30 AG050886/AG/NIA NIH HHS/United States ; NHLBI HL142216/NH/NIH HHS/United States ; T32 HL007457/NH/NIH HHS/United States ; P30 AG050886/NH/NIH HHS/United States ; }, mesh = {*Brain/metabolism/pathology ; *Transcriptome/drug effects/genetics ; Glycosylation ; *Neurodegenerative Diseases/genetics/metabolism ; *Proteins/metabolism ; Mice, Inbred C57BL ; Animals ; Gene Expression Profiling ; Up-Regulation/drug effects ; Down-Regulation/drug effects ; Metabolic Networks and Pathways/genetics ; Thiazoles/pharmacology ; }, abstract = {Enhancing protein O-GlcNAcylation by pharmacological inhibition of the enzyme O-GlcNAcase (OGA) has been considered as a strategy to decrease tau and amyloid-beta phosphorylation, aggregation, and pathology in Alzheimer's disease (AD). There is still more to be learned about the impact of enhancing global protein O-GlcNAcylation, which is important for understanding the potential of using OGA inhibition to treat neurodegenerative diseases. In this study, we investigated the acute effect of pharmacologically increasing O-GlcNAc levels, using the OGA inhibitor Thiamet G (TG), in normal mouse brains. We hypothesized that the transcriptome signature in response to a 3 h TG treatment (50 mg/kg) provides a comprehensive view of the effect of OGA inhibition. We then performed mRNA sequencing of the brain using NovaSeq PE 150 (n = 5 each group). We identified 1234 significant differentially expressed genes with TG versus saline treatment. Functional enrichment analysis of the upregulated genes identified several upregulated pathways, including genes normally down in AD. Among the downregulated pathways were the cell adhesion pathway as well as genes normally up in AD and aging. When comparing acute to chronic TG treatment, protein autophosphorylation and kinase activity pathways were upregulated, whereas cell adhesion and astrocyte markers were downregulated in both datasets. AMPK subunit Prkab2 was one gene in the kinase activity pathway, and the increase after acute and chronic treatment was confirmed using qPCR. Interestingly, mitochondrial genes and genes normally down in AD were up in acute treatment and down in chronic treatment. Data from this analysis will enable the evaluation of the mechanisms underlying the impact of OGA inhibition in the treatment of AD. In particular, OGA inhibitors appear to have downstream effects related to bioenergetics which may limit their therapeutic benefits.}, } @article {pmid39822440, year = {2024}, author = {Barnett, C and Morris, K and Shah, Y}, title = {Clinical Diagnoses and Characterization of Patients With Amyloid-Negative Amyloid-Beta, p-Tau, and Neurofilament Light Chain (ATN) Profiles.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e75874}, pmid = {39822440}, issn = {2168-8184}, abstract = {The novel amyloid-beta, p-Tau, and neurofilament light chain (ATN) classification scheme has become a promising system for clinically detecting and diagnosing Alzheimer's disease (AD). In addition to its utility in Alzheimer's diagnosis and treatment, the ATN framework may also have clinical relevance in identifying non-Alzheimer's pathologies. In this study conducted at Broadlawns Geriatric and Memory Center, 92 amyloid-negative profiles out of 182 patients with an ATN framework were categorized into subjective cognitive impairment (SCI), non-amnestic mild cognitive impairment (non-amnestic MCI), amnestic MCI, Alzheimer's dementia, vascular dementia, mixed dementia, unspecified dementia, or other memory changes based on diagnoses written in the chart. Additionally, other secondary diagnoses were found in the differential, including sleep disorders, anxiety, depressive disorders and grief, and cerebrovascular disease. The results are concordant with our expectations that amyloid-negative ATN profiles are associated with mostly non-Alzheimer's cognitive decline. We were also able to demonstrate that amyloid-negative patients have other secondary neurologic or psychiatric diagnoses related to memory or cognitive changes. However, certain enigmatic patient presentations warrant further scrutiny in the medical chart. It is possible that ATN may pose a risk of misclassification in both Alzheimer and non-Alzheimer pathologies, particularly at early stages. Future work may be required to corroborate findings using other new plasma biomarkers, such as p-Tau217. Overall, we hope that this study will provide options for early detection and future treatment of AD and other neurocognitive disorders. We also anticipate that this work will lead to the recognition of other non-neurocognitive conditions comorbid with such neurocognitive disorders.}, } @article {pmid39822295, year = {2025}, author = {Gleerup, HS and Simonsen, AH and Grötschel, L and Gramkow, MH and Høgh, P and Blennow, K and Zetterberg, H and Ashton, N and Hasselbalch, SG}, title = {Plasma biomarkers of amyloid, tau, astrogliosis, and axonal injury in a mixed memory clinic cohort.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {1}, pages = {e70073}, pmid = {39822295}, issn = {2352-8729}, abstract = {INTRODUCTION: Studies have shown that blood biomarkers can differentiate dementia disorders. However, the diagnosis of dementia still relies primarily on cerebrospinal fluid and imaging modalities. The new disease-modifying treatments call for more widely applicable biomarkers.

METHODS: Plasma samples (n = 250) from two mixed memory clinic were included. Participants were divided into amyloid beta positives (Aβ+) and Aβ negatives (Aβ-). Plasma phosphorylated tau (p-tau) 181, p-tau231, Aβ1-42 (Aβ42), Aβ40, Aβ42/Aβ40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were measured by single molecule array.

RESULTS: Significant differences were found among cognitively unimpaired, mild cognitive impairment, Alzheimer's disease (AD), and non-AD, and nearly all of the biomarkers were able to predict amyloid status. When combining p-tau181 and p-tau231 they predicted Aβ positivity with an area under the curve (AUC) of 0.75, and when combining all biomarkers an AUC of 0.86 was found.

DISCUSSION: This study supports previous findings on plasma biomarkers, even when investigated in a typical clinical setting in a consecutive, heterogeneous, mixed memory clinic.

HIGHLIGHTS: This study investigated seven plasma biomarkers in a mixed memory clinic, regardless of amyloid co-pathology or atypical phenotypes.These findings support previous promising results on plasma biomarkers, even when investigated in a heterogeneous population.The combination of phosphorylated tau (p-tau)181 and p-231 performed only slightly worse than a panel of multiple biomarkers, aligning with previous studies.Plasma biomarkers show potential for future applications in primary care, treatment monitoring, and trial selection.}, } @article {pmid39821693, year = {2025}, author = {Caruso, A and Tommonaro, G and Vassallo, A and Paris, D and Monné, M and Catalano, A and Sinicropi, MS and Saturnino, C}, title = {Imino and Thioureidic Derivatives as New Tools for Alzheimer's Disease: Preliminary Studies.}, journal = {Chemical biology & drug design}, volume = {105}, number = {1}, pages = {e70049}, doi = {10.1111/cbdd.70049}, pmid = {39821693}, issn = {1747-0285}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Acetylcholinesterase/metabolism/chemistry ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis/metabolism ; *Molecular Docking Simulation ; Humans ; *Antioxidants/pharmacology/chemistry ; Structure-Activity Relationship ; }, abstract = {Alzheimer's disease is a neurodegenerative chronic disease with a severe social and economic impact in the societies, which still lacks an efficient therapy. Several pathophysiological events (β-amyloid [Aβ] deposits, τ-protein aggregation, loss of cholinergic activity, and oxidative stress) occurs in the progression of the disease. Therefore, the search for efficient multi-targeted agents for the treatment of Alzheimer's disease becomes indispensable. In this paper we evaluated the AChE inhibition by Ellman's method and antioxidant activity by DPPH assay of nine synthetic compounds: two hydroxy-benzene derivatives (1 and 2), three bis-thioureidic derivatives (3-5), two imidazole derivatives (6 and 7), and two phenylacetamide derivatives (8 and 9). The compound 2, (3s,5s,7s)-adamantan-1-yl 4-(((E)-2,5-dihydroxybenzylidene)amino)benzoate, exhibited the best antioxidant activity (30.00 ± 1.05 μM eq Trolox) and compound 4 showed the highest AChE inhibition value (IC50 [μM] 8.40 ± 0.32). In the search for a compound showing combined activities (antioxidant and AChE inhibition), the compound 4, octane-1,8-diyl-bis-S-amidinothiourea dihydrobromide, (19.02 ± 1.52 μM eq Trolox; IC50 [μM] 8.40 ± 0.32) was chosen to carry out a molecular docking study. The results showed that compound 4 has the ability to bind the active site of acetylcholinesterase with considerable affinity (estimated binding energies of -8.5 kcal/mol). All data indicate that compound 4 has the potential to be further investigated as a possible candidate in the Alzheimer's disease treatment.}, } @article {pmid39820731, year = {2025}, author = {Xiong, R and Liu, H and Zhang, S and Wang, L and Liu, L and Pan, S and Zhang, Y and Zhu, F and Liu, Y and Lai, X}, title = {Integrating network pharmacology and experimental verification to reveal the ferroptosis-associated mechanism of Changpu-Yizhi-Wan in the treatment of Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {106}, pmid = {39820731}, issn = {1573-7365}, support = {2022XQN28//Army Military Medical University/ ; }, mesh = {*Ferroptosis/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Network Pharmacology ; Animals ; Mice ; NF-E2-Related Factor 2/metabolism ; Protein Interaction Maps/drug effects ; }, abstract = {To explore the pharmacological mechanism of Changpu-Yizhi-Wan (CYW) in the treatment of Alzheimer's disease (AD) from the perspective of ferroptosis based on network pharmacology and experimental verification. The Encyclopedia of Traditional Chinese Medicine 2.0 (ETCM2.0) database was used to collect the active components of CYW, and the putative targets were predicted in ETCM2.0 and SwissTargetPrediction database. The AD related targets were collected from GeneCards, comparative toxicogenomics database (CTD), Online Mendelian Inheritance in Man (OMIM), DisGeNET and Therapeutic Target Database (TTD), the ferroptosis related targets were collected from FerrDb V2 database, and the common targets of CYW, AD and ferroptosis were calculated by Venny2.1 platform. Protein-protein interaction (PPI) analysis was performed by STRING database, and the active compounds-target network and the PPI network were constructed using Cytoscape software. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway enrichment analysis were performed through DAVID database. RSL3 was used to induce HT22 cells to establish a neuronal ferroptosis cell model, and the inhibitory effect of CYW on neuronal ferroptosis was evaluated by cell viability assay, intracellular iron assay and lipid peroxidation staining. The ferroptosis-associated key protein expressions of Nrf2, SLC7A11, GPX4 and FTH1 were detected by Western blot. A total of 100 candidate compounds were identified from CYW, and 1129 putative targets were obtained. 3924 AD-related targets and 564 ferroptosis-related targets were collected, respectively. There were 78 common targets between them and CYW targets, which were potential targets for CYW to regulate ferroptosis in the treatment of AD. PPI network analysis identified 10 key targets, including TP53, IL6, STAT3, HIF1A, NFE2L2, and others. GO, KEGG and Reactome enrichment analysis showed that 78 potential targets were involved in the regulation of ferroptosis and Nrf2-mediated gene transcription. Molecular docking showed that some active components of CYW had good affinity with Nrf2. In RSL3-induced HT22 cells, CYW significantly improved cell viability, reduced intracellular iron levels and inhibited lipid peroxidation, and improved the protein expression of Nrf2, SLC7A11, GPX4 and FTH1. The pharmacological mechanism of CYW in the treatment of AD may be related to the regulation of Nrf2/SLC7A11/GPX4/FTH1 axis to inhibit neuronal ferroptosis.}, } @article {pmid39820594, year = {2025}, author = {Guerguer, FZ and Bouribab, A and Karim, EM and Khedraoui, M and Amegrissi, F and Raouf, YS and Samadi, A and Chtita, S}, title = {Moroccan natural products for multitarget-based treatment of Alzheimer's disease: A computational study.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0313411}, pmid = {39820594}, issn = {1932-6203}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Hesperidin/chemistry/pharmacology/therapeutic use ; Biological Products/chemistry/therapeutic use/pharmacology ; Molecular Dynamics Simulation ; Flavanones/chemistry/therapeutic use/pharmacology ; Morocco ; Molecular Docking Simulation ; Acetylcholinesterase/metabolism/chemistry ; Plants, Medicinal/chemistry ; }, abstract = {Alzheimer's disease is a neurodegenerative disorder that impairs neurocognitive functions. Acetylcholinesterase, Butyrylcholinesterase, Monoamine Oxidase B, Beta-Secretase, and Glycogen Synthase Kinase Beta play central roles in its pathogenesis. Current medications primarily inhibit AChE but fail to halt or reverse disease progression due to the multifactorial nature of Alzheimer's. This underscores the necessity of developing multi-target ligands for effective treatment. This study investigates the potential of phytochemical compounds from Moroccan medicinal plants as multi-target agents against Alzheimer's disease, employing computational approaches. A virtual screening of 386 phytochemical compounds, followed by an assessment of pharmacokinetic properties and ADMET profiles, led to the identification of two promising compounds, naringenin (C23) and hesperetin (C24), derived from Anabasis aretioides. These compounds exhibit favourable pharmacokinetic profiles and strong binding affinities for the five key targets associated with the disease. Density functional theory, molecular dynamics simulations, and MM-GBSA calculations further confirmed their structural stability, with a slight preference for C24, exhibiting superior intermolecular interactions and overall stability. These findings provide a strong basis for further experimental research, including in vitro and in vivo studies, to substantiate their potential efficacy in Alzheimer's disease.}, } @article {pmid39820472, year = {2025}, author = {Liu, Y and Ding, X and Jia, S and Gu, X}, title = {Current understanding and prospects for targeting neurogenesis in the treatment of cognitive impairment.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-00802}, pmid = {39820472}, issn = {1673-5374}, abstract = {Adult hippocampal neurogenesis is linked to memory formation In the adult brain, with new neurons in the hippocampus exhibiting greater plasticity during their immature stages compared to mature neurons. Abnormal adult hippocampal neurogenesis is closely associated with cognitive impairment in central nervous system diseases. Targeting and regulating adult hippocampal neurogenesis have been shown to improve cognitive deficits. This review aims to expand the current understanding and prospects of targeting neurogenesis in the treatment of cognitive impairment. Recent research indicates the presence of abnormalities in AHN in several diseases associated with cognitive impairment, including cerebrovascular diseases, Alzheimer's disease, aging-related conditions, and issues related to anesthesia and surgery. The role of these abnormalities in the cognitive deficits caused by these diseases has been widely recognized, and targeting AHN is considered a promising approach for treating cognitive impairment. However, the underlying mechanisms of this role are not yet fully understood, and the effectiveness of targeting abnormal adult hippocampal neurogenesis for treatment remains limited, with a need for further development of treatment methods and detection techniques.By reviewing recent studies, we classify the potential mechanisms of adult hippocampal neurogenesis abnormalities into four categories: immunity, energy metabolism, aging, and pathological states. In immunity-related mechanisms, abnormalities in meningeal, brain, and peripheral immunity can disrupt normal adult hippocampal neurogenesis.Lipid metabolism and mitochondrial function disorders are significant energy metabolism factors that lead to abnormal adult hippocampal neurogenesis. During aging, the inflammatory state of the neurogenic niche and the expression of aging-related microRNAs contribute to reduced adult hippocampal neurogenesis and cognitive impairment in older adult patients. Pathological states of the body and emotional disorders may also result in abnormal adult hippocampal neurogenesis. Among the current strategies used to enhance this form of neurogenesis, physical therapies such as exercise, transcutaneous electrical nerve stimulation, and enriched environments have proven effective. Dietary interventions, including energy intake restriction and nutrient optimization, have shown efficacy in both basic research and clinical trials. However, drug treatments, such as antidepressants and stem cell therapy, are primarily reported in basic research, with limited clinical application. The relationship between abnormal adult hippocampal neurogenesis and cognitive impairment has garnered widespread attention, and targeting the former may be an important strategy for treating the latter. However, the mechanisms underlying abnormal adult hippocampal neurogenesis remain unclear, and treatments are lacking. This highlights the need for greater focus on translating research findings into clinical practice.}, } @article {pmid39820046, year = {2025}, author = {Guo, T and Hayat, MA and Hu, J}, title = {Ferritin nanoparticles: new strategies for the diagnosis and treatment of central nervous system diseases.}, journal = {Biomedical materials (Bristol, England)}, volume = {20}, number = {2}, pages = {}, doi = {10.1088/1748-605X/adab5a}, pmid = {39820046}, issn = {1748-605X}, mesh = {Humans ; *Ferritins/chemistry/metabolism ; *Blood-Brain Barrier/metabolism ; *Nanoparticles/chemistry ; *Central Nervous System Diseases/diagnosis/drug therapy ; Animals ; *Drug Delivery Systems ; Receptors, Transferrin/metabolism ; Drug Carriers/chemistry ; }, abstract = {Ferritin nanoparticles, which can penetrate the blood-brain barrier (BBB), have gained significant research interest for the diagnosis and treatment of central nervous system (CNS) diseases, including gliomas, Alzheimer's disease, and brain metastases. In recent years, ferritin has been proved as a candidate to cross the BBB using receptor-mediated transport (RMT) mechanism through transferrin receptor 1 (TfR1) which is overexpressed in the cells of the BBB. Various types of cargo molecules, including therapeutics, imaging agents, nucleic acids, and metal nanoparticles, have been incorporated into ferritin nanocages for the diagnosis and treatment of CNS diseases. In particular, low immunogenicity of ferritin implies safety for its usage in clinical practices, and high biocompatibility add to the perspectives of its applications. Furthermore, contemporary strides in molecular biology have enabled some alteration in the configuration of the ferritin outer layers and surface characters so as to enhance the drug encapsulation capacity and conjugation affinity. Such modifications not only enhance the property of ferritin in crossing the BBB, but also enhance its efficacy when applied to CNS diseases. In summary, ferritin, as a drug delivery system, shows great potential for the treatment and diagnosis of CNS diseases.}, } @article {pmid39819742, year = {2025}, author = {Xu, B and Lei, X and Yang, Y and Yu, J and Chen, J and Xu, Z and Ye, K and Zhang, J}, title = {Peripheral proteinopathy in neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {2}, pmid = {39819742}, issn = {2047-9158}, support = {82020108012//National Natural Science Foundation of China/ ; 82371250//National Natural Science Foundation of China/ ; LY24H090006//Natural Science Foundation of Zhejiang Province/ ; LZ23H090002//Natural Science Foundation of Zhejiang Province/ ; 2024C03098//Key Research and Development Program of Zhejiang Province/ ; 2024SSYS0018//Key Research and Development Program of Zhejiang Province/ ; ZR2022QH177//Natural Science Foundation of Shandong Province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; alpha-Synuclein/metabolism ; }, abstract = {Proteinopathies in neurology typically refer to pathological changes in proteins associated with neurological diseases, such as the aggregation of amyloid β and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease and multiple system atrophy, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal dementia. Interestingly, these proteins are also commonly found in peripheral tissues, raising important questions about their roles in neurological disorders. Multiple studies have shown that peripherally derived pathological proteins not only travel to the brain through various routes, aggravating brain pathology, but also contribute significantly to peripheral dysfunction, highlighting their crucial impact on neurological diseases. Investigating how these peripherally derived proteins influence the progression of neurological disorders could open new horizons for achieving early diagnosis and treatment. This review summarizes the distribution, transportation pathways, and pathogenic mechanisms of several neurodegenerative disease-related pathological proteins in the periphery, proposing that targeting these peripheral pathological proteins could be a promising strategy for preventing and managing neurological diseases.}, } @article {pmid39819531, year = {2025}, author = {Li, C and Chen, Y and Yao, Y and Shang, Y}, title = {Establishment and Validation of the Diagnostic Value of Oligodendrocyte-related Genes in Alzheimer's Disease.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273339310241205055554}, pmid = {39819531}, issn = {1996-3181}, abstract = {BACKGROUND: AD is a demyelinating disease. Myelin damage initiates the pathological process of AD, resulting in abnormal synaptic function and cognitive decline. The myelin sheath formed by oligodendrocytes (OL) is a crucial component of white matter. Investigating AD from the perspective of OL may offer novel diagnostic and therapeutic perspectives.

OBJECTIVES: This study aimed to analyze the association between OL-related genes and Alzheimer's disease (AD) using bioinformatics and verify this association via molecular biology experiments.

METHODS: The AD datasets were acquired from the Gene Expression Omnibus (GEO) database of NCBI. Consensus clustering was employed to determine the subtypes of AD, followed by evaluating the clinical characteristics of these subtypes. Subsequently, immune infiltration analysis of relevant genes and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identify modules and hub genes associated with AD progression. The intersection of genes obtained was analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. To narrow down the scope and identify OL-related genes with diagnostic potential, three machine learning algorithms were utilized. In addition, the eXtreme Sum (XSum) algorithm was used to screen small molecule drug candidates based on the connectivity map (CMAP) database. Finally, these identified genes were validated using Real-time fluorescence quantitative PCR (RT-qPCR).

RESULTS: Among the three subtypes of AD, Cluster A and Cluster C exhibited increased levels of Braak and neurofibrillary tangles compared to Cluster B. The proportion of females was greater than that of males among the three subclasses of AD. There were no significant differences in age among the three subclasses, but significant differences in gene expression existed. Through WGCNA analysis, 108 genes were identified. Among these, 16 genes were identified as shared genes by the least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machines (SVM) algorithms, and logistic regression further determined 11 genes. The establishment of a nomogram demonstrated the significance of these 11 genes in AD. The "XSum" algorithm revealed five drugs with therapeutic potential for AD. qPCR analysis revealed the upregulation and downregulation of the highlighted genes. According to this study, 11 genes related to OL were also found to be associated with immune cell infiltration in AD patients. These genes demonstrated potential diagnostic value for AD. Additionally, we screened five small molecular drugs that exhibit potential therapeutic effects on AD.

CONCLUSION: This research provides a new perspective for personalized clinical management and treatment of AD.}, } @article {pmid39819417, year = {2025}, author = {Khan, SA and Qamar, Z and Rohilla, A and Singh, PP and Parvez, S and Baboota, S and Ali, J}, title = {Prospective Utilization of Nanocarriers Loaded with Drug Combination for Treating Alzheimer's Disease.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128348877241202053633}, pmid = {39819417}, issn = {1873-4286}, abstract = {Alzheimer's disease (AD) is a debilitating condition that significantly affects the elderly. Early diagnosis is not only critical for improving patient outcomes but also directly influences the success of emerging therapeutic interventions. A therapeutic strategy targeting only one pathogenic mechanism is unlikely to be very effective, as there is increasing evidence that AD does not have a single pathogenic cause. Therefore, combining medications or developing therapies that address multiple pathways may be beneficial. Most clinical trials can be classified under added therapy rather than combination therapy. Effective treatment of AD likely requires targeting multiple mechanisms, such as amyloid-beta (Aβ) and tau pathology. However, many medications face challenges, including poor solubility, low permeability, and the inability to cross the blood- -brain barrier (BBB). This is where nanocarriers come into play, as they can be loaded with these medications to facilitate targeted drug delivery. This approach enhances the pharmacokinetic profile of drugs in both the blood and the brain. Therefore, this paper provides a concise overview of the use of various nanocarriers loaded with drug combinations for treating AD.}, } @article {pmid39818939, year = {2025}, author = {Bagán, A and López-Ruiz, A and Abás, S and Ruiz-Cantero, MC and Vasilopoulou, F and Taboada-Jara, T and Griñán-Ferré, C and Pallàs, M and Muguruza, C and Diez-Alarcia, R and Callado, LF and Entrena, JM and Cobos, EJ and Pérez, B and Morales-García, JA and Molins, E and De Jonghe, S and Daelemans, D and Brea, J and Val, C and Loza, MI and Hernández-Hernández, E and García-Sevilla, JA and García-Fuster, MJ and Díaz, C and Fernández-Godino, R and Genilloud, O and Beljkaš, M and Oljačić, S and Nikolic, K and Escolano, C}, title = {Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties.}, journal = {Journal of medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jmedchem.4c01644}, pmid = {39818939}, issn = {1520-4804}, abstract = {Imidazoline I2 receptors (I2-IRs) are altered in Alzheimer's disease (AD) patients and are associated with analgesia. I2-IRs are not structurally described, and their pharmacological characterization relies on their modulation by highly affine ligands. Herein, we describe the synthesis of (3-phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates endowed with relevant affinities for I2-IRs in human brain tissues. The optimal ADME and pharmacokinetic profile of a selected compound, 12d, secured its in vivo exploration in a senescence accelerated prone 8 mice revealing improvement in the cognitive impairment and unveiling the mechanism of action by analyzing specific AD biomarkers. The treatment of a capsaicin-induced mechanical hypersensitivity murine model with 12d revealed analgesic properties devoid of motor coordination issues. The target engagement of 12d was demonstrated by suppression of the analgesic effect by pretreatment with idazoxan. Overall, 12d is a putative candidate for advancing preclinical phases and supports the modulation of I2-IRs as an innovative approach for therapeutics.}, } @article {pmid39818099, year = {2025}, author = {Esandi, J and Renault, P and Capilla-López, MD and Blanch, R and Edo, Á and Ramirez-Gómez, D and Bosch, A and Almolda, B and Saura, CA and Giraldo, J and Chillón, M}, title = {HEBE: A novel chimeric chronokine for ameliorating memory deficits in Alzheimer's disease.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {183}, number = {}, pages = {117815}, doi = {10.1016/j.biopha.2025.117815}, pmid = {39818099}, issn = {1950-6007}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Memory Disorders/drug therapy ; *tau Proteins/metabolism ; Mice ; *Mice, Transgenic ; Humans ; *Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Male ; Recombinant Fusion Proteins ; Amyloid beta-Protein Precursor/genetics/metabolism ; Phosphorylation ; Memory/drug effects ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-β and Tau protein depositions, with treatments focusing on single proteins have shown limited success due to the complexity of pathways involved. This study explored the potential of chronokines -proteins that modulate aging-related processes- as an alternative therapeutic approach. Specifically, we focused on a novel pleiotropic chimeric protein named HEBE, combining s-KL, sTREM2 and TIMP2, guided by bioinformatic analyses to ensure the preservation of each protein's conformation, crucial for their functions. In vitro studies confirmed HEBE's stability and enzymatic activities, even suggesting it has different activities compared to the individual chronokines. In vivo experiments on APP/Tau mice revealed improved learning and memory functions with HEBE treatment, along with decreased levels of phosphorylated Tau and minor effects on amyloid-β levels. These findings suggest that HEBE is as a promising therapeutic candidate for ameliorating memory deficits and reducing pTau in an AD mouse model.}, } @article {pmid39818021, year = {2025}, author = {Dawa, Y and Hua, YC and Hu, FD and Chen, J}, title = {Cellulose filter paper immobilized acetylcholinesterase for rapid screening of enzyme inhibitors in Phyllanthus emblica L.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {256}, number = {}, pages = {116669}, doi = {10.1016/j.jpba.2025.116669}, pmid = {39818021}, issn = {1873-264X}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/analysis ; *Acetylcholinesterase/metabolism ; *Plant Extracts/chemistry/pharmacology ; *Phyllanthus emblica/chemistry ; *Molecular Docking Simulation ; *Tandem Mass Spectrometry/methods ; Chromatography, High Pressure Liquid/methods ; *Cellulose/chemistry ; Enzymes, Immobilized/chemistry/antagonists & inhibitors ; Paper ; Fruit/chemistry ; Reproducibility of Results ; Alkaloids ; Sesquiterpenes ; }, abstract = {Acetylcholinesterase (AChE) is widely recognized as a promising therapeutic target enzyme for Alzheimer's disease (AD). The screening of AChE inhibitors (AChEIs) holds great significance for the treatment of AD. In this study, cellulose filter paper (CFP) -immobilized AChE was prepared and firstly applied to screening AChEIs from 30 % ethanol extract of Phyllanthus emblica L. fruits combined with ultra-high performance liquid chromatography quadrupole time-of-fight mass spectrometry (UHPLC-Q-TOF-MS/MS). Using CFP-immobilized AChE as the bait, AChEIs were harvested and the instantaneous separation characteristics of CFP were utilized to further facilitate the separation of the complex from the inactive components. Ultimately, 27 compounds specifically bound with AChE were screened and identified using UHPLC-Q-TOF-MS/MS. Additionally, molecular docking was employed to explore the binding mechanisms between screened potential inhibitors and AChE. The results show that, most of the screened compounds were found to exhibit higher affinity that of the positive control (huperzine A), and all the compounds expect mucic acid to be well embedded into the active pocket of AChE. To verify the reliability of the screening method and molecular docking, two commercial standards geraniin and ellagic acid were experimented with an AChE inhibition assay in vitro. The results showed that both compounds were found to effectively inhibit AChE with IC50 values of 42.42 ± 7.10 μM, 172.43 ± 9.22 μM. The developed method exhibits the advantages of rapidness and effectiveness in screening of AChEIs from complex herbal extracts.}, } @article {pmid39817315, year = {2025}, author = {Goodwin, GJ and Briley, DA and Singsank, K and Tanner, D and Maloy-Robertson, M and John, SE}, title = {Neuropsychiatric symptoms predict rate of change in executive function in Alzheimer's disease and related dementias.}, journal = {Journal of the International Neuropsychological Society : JINS}, volume = {}, number = {}, pages = {1-10}, doi = {10.1017/S1355617724000730}, pmid = {39817315}, issn = {1469-7661}, support = {U24 AG072122/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVE: Neuropsychiatric symptoms (NPS) are considered diagnostic and prognostic indicators of dementia and are attributable to neurodegenerative processes. Little is known about the prognostic value of early NPS on executive functioning (EF) decline in Alzheimer's disease and related dementias (ADRD). We examined whether baseline NPS predicted the rate of executive function (EF) decline among older adults with ADRD.

METHOD: Older adults (n = 1625) with cognitive impairment were selected from the National Alzheimer's Coordinating Center database. EF was estimated with a latent factor indicated by scores on Number Span Backward, Letter Fluency, and Trail Making-Part B. A curve of factors (CUFF) latent growth curve model was estimated to examine rate of change over four years. Baseline NPS severity was entered as a predictor in the model to examine its influence on the rate of change in EF over time.

RESULTS: The CUFF models exhibited good fit. EF significantly declined over four waves (slope = -.16, p < .001). Initial visit NPS severity predicted decline in EF (slope = .013, p < .001), such that those with greater baseline NPS severity demonstrated a more rapid decline in EF performance over time. Presence of 2 NPS significantly predicted EF decline, and those with medium total NPS severity (NPS score of 2-4) at baseline exhibited a sharper decline in EF.

CONCLUSIONS: Findings underscore the importance of targeting NPS early across ADRD syndromes to minimize EF decline, offering novel insights into how early NPS treatment may alter cognitive trajectories. We provide an innovative, user-friendly web-based application that may be helpful for personalized treatment planning.}, } @article {pmid39817194, year = {2025}, author = {Wu, CY and Kupferschmid, AC and Chen, L and McManus, AJ and Kivisäkk, P and Galler, JA and Schwab, NA and DesRuisseaux, LA and Williams, VJ and Gerber, J and Riley, M and Young, C and Guzmán-Vélez, E and Dodge, HH and Tanzi, RE and Singer, CM and Arnold, SE}, title = {Cognitive and Alzheimer's disease biomarker effects of oral nicotinamide riboside (NR) supplementation in older adults with subjective cognitive decline and mild cognitive impairment.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70023}, pmid = {39817194}, issn = {2352-8737}, abstract = {INTRODUCTION: Age-associated depletion in nicotinamide adenine dinucleotide (NAD+) concentrations has been implicated in metabolic, cardiovascular, and neurodegenerative disorders. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), offers a potential therapeutic avenue against neurodegenerative pathologies in aging, Alzheimer's disease, and related dementias. A crossover, double-blind, randomized placebo (PBO) controlled trial was conducted to test the safety and efficacy of 8 weeks' active treatment with NR (1 g/day) on cognition and plasma AD biomarkers in older adults with subjective cognitive decline and mild cognitive impairment.

METHODS: The primary efficacy outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Secondary outcomes included plasma phosphorylated tau 217 (pTau[217]), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Exploratory outcomes included Lumosity gameplay (z-scores) for cognition and step counts from wearables. Mixed model for repeated measures was used for between-group comparisons; paired t-tests were used for within-individual comparisons.

RESULTS: Forty-six participants aged over 55 were randomized to NR-PBO or PBO-NR groups; 41 completed baseline visits, and 37 completed the trial. NR supplementation was safe and well tolerated with no differences in adverse events reported between NR and PBO treatment phases. For the between-group comparison, there was a 7% reduction in pTau[217] concentrations after taking NR, while an 18% increase with PBO (p = 0.02). No significant between-group differences were observed for RBANS, other plasma biomarkers(GFAP and NfL), Lumosity gameplay scores or step counts. For the within-individual comparison, pTau[217] concentrations significantly decreased during the NR phase compared to the PBO (p = 0.02), while step counts significantly increased during the NR phase than PBO (p = 0.04).

DISCUSSION: Eight weeks NR supplementation is safe and lowered pTau[217] concentrations but did not alter cognition as measured by conventional or novel digital assessments. Further research is warranted to validate NR's efficacy in altering pathological brain aging processes.

HIGHLIGHTS: The integrated study design combines a two-arm parallel trial with a crossover phase, offering the opportunity to enhance sample size for within-individual analysis and assess carryover effects.NR is safe but did not alter cognition as measured by multi-modal assessments in SCD/MCI.For between-group comparison, pTau[217] levels decreased with NR and increased with PBO at 8-week follow-up.For within-individual comparison, step counts increased after NR and decreased after PBO.A larger, longer study with pharmacodynamic and pathophysiological biomarkers is needed to assess NR's disease-modifying effects.}, } @article {pmid39816194, year = {2025}, author = {Yulug, B and Altay, O and Li, X and Hanoglu, L and Cankaya, S and Velioglu, HA and Lam, S and Yang, H and Coskun, E and Idil, E and Bayraktaroglu, Z and Nogaylar, R and Ozsimsek, A and Yildirim, S and Bolat, I and Kiliclioglu, M and Bayram, C and Yuksel, N and Tozlu, OO and Arif, M and Shoaie, S and Hacimuftuoglu, A and Zhang, C and Nielsen, J and Turkez, H and Borén, J and Uhlén, M and Mardinoglu, A}, title = {Multi-omics characterization of improved cognitive functions in Parkinson's disease patients after the combined metabolic activator treatment: a randomized, double-blinded, placebo-controlled phase II trial.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcae478}, pmid = {39816194}, issn = {2632-1297}, abstract = {Parkinson's disease is primarily marked by mitochondrial dysfunction and metabolic abnormalities. We recently reported that the combined metabolic activators improved the immunohistochemical parameters and behavioural functions in Parkinson's disease and Alzheimer's disease animal models and the cognitive functions in Alzheimer's disease patients. These metabolic activators serve as the precursors of nicotinamide adenine dinucleotide and glutathione, and they can be used to activate mitochondrial metabolism and eventually treat mitochondrial dysfunction. Here, we designed a randomized, double-blinded, placebo-controlled phase II study in Parkinson's disease patients with 84 days combined metabolic activator administration. A single dose of combined metabolic activator contains L-serine (12.35 g), N-acetyl-L-cysteine (2.55 g), nicotinamide riboside (1 g) and L-carnitine tartrate (3.73 g). Patients were administered either one dose of combined metabolic activator or a placebo daily for the initial 28 days, followed by twice-daily dosing for the next 56 days. The main goal of the study was to evaluate the clinical impact on motor functions using the Unified Parkinson's Disease Rating Scale and to determine the safety and tolerability of combined metabolic activator. A secondary objective was to assess cognitive functions utilizing the Montreal Cognitive Assessment and to analyse brain activity through functional MRI. We also performed comprehensive plasma metabolomics and proteomics analysis for detailed characterization of Parkinson's disease patients who participated in the study. Although no improvement in motor functions was observed, cognitive function was shown to be significantly improved (P < 0.0000) in Parkinson's disease patients treated with the combined metabolic activator group over 84 days, whereas no such improvement was noted in the placebo group (P > 0.05). Moreover, a significant reduction (P = 0.001) in Montreal Cognitive Assessment scores was observed in the combined metabolic activator group, with no decline (P > 0.05) in the placebo group among severe Parkinson's disease patients with lower baseline Montreal Cognitive Assessment scores. We showed that improvement in cognition was associated with critical brain network alterations based on functional MRI analysis, especially relevant to areas with cognitive functions in the brain. Finally, through a comprehensive multi-omics analysis, we elucidated the molecular mechanisms underlying cognitive improvements observed in Parkinson's disease patients. Our results show that combined metabolic activator administration leads to enhanced cognitive function and improved metabolic health in Parkinson's disease patients as recently shown in Alzheimer's disease patients. The trial was registered in ClinicalTrials.gov NCT04044131 (17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131).}, } @article {pmid39816083, year = {2024}, author = {Widaja, E and Pawitan, JA}, title = {Integrating epigenetic modification and stem cell therapy strategies: A novel approach for advancing Alzheimer's disease treatment - A literature review.}, journal = {Narra J}, volume = {4}, number = {3}, pages = {e935}, pmid = {39816083}, issn = {2807-2618}, mesh = {*Alzheimer Disease/therapy/genetics/metabolism ; Humans ; *Epigenesis, Genetic ; *Stem Cell Transplantation/methods ; DNA Methylation ; MicroRNAs/genetics/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most frequent form of dementia and represents an increasing global burden, particularly in countries like Indonesia, where the population has begun to age significantly. Current medications, including cholinesterase inhibitors and NMDA receptor antagonists, have modest effects on clinical symptoms in the early to middle stages, but there is no curative treatment available so far despite progress. Activating or repressing epigenetic modifications, including DNA methylation, histone modification and microRNA regulation, appears to play an important role in AD development. These alterations further enact transcriptional changes relevant to the signature AD pathologies of amyloid-β deposition, tau protein malfunctioning, neuroinflammation, and neuronal death. Here, we discuss the feasibility of targeting these epigenetic alterations as a new treatment strategy due to the reversibility of epigenetics and their ability to correct faulty gene expression. We also review the combined promise of stem cell therapies and epigenetic modulation in neurodegeneration, inflammation and cognitive decline. This combined approach may provide a multifaceted strategy to slow disease progression, replace lost neurons, and restore neural function. Despite challenges, including ethical, financial, and methodological barriers, ongoing research in epigenetic modulation and stem cell therapy holds promise for pioneering therapies in AD.}, } @article {pmid39815655, year = {2025}, author = {Bhattacharya, RS and Singh, R and Panghal, A and Thakur, A and Singh, L and Verma, RK and Singh, C and Goyal, M and Kumar, J}, title = {Multi-Targeting Phytochemicals for Alzheimer's Disease.}, journal = {Phytotherapy research : PTR}, volume = {}, number = {}, pages = {}, doi = {10.1002/ptr.8435}, pmid = {39815655}, issn = {1099-1573}, abstract = {Alzheimer's disease (AD) is a type of neurodegenerative illness in which β-amyloid (Aβ) and tau protein accumulate in neurons in the form of tangles. The pathophysiological pathway of AD consists of Aβ-amyloid peptides, tau proteins, and oxidative stress in neurons and increased neuro-inflammatory response. Food and Drug Administration in the United States has authorized various drugs for the effective treatment of AD, which include galantamine, rivastigmine, donepezil, memantine, sodium oligomannate, lecanemab, and aducanumab. The major disadvantage of these drugs is that they only provide "symptomatic" relief. They are most effective in the early stages or for mild to moderate cases of the disease, but are not suitable for long-term use. Besides conventional therapies, phytochemicals have the potential to stop the progression of AD. According to research, the use of potential phytochemicals against AD has gained attention due to their potent anti-inflammatory, antioxidant, anti-hyperphosphorylation of the tau protein, metal chelation, and anti-amyloid properties. This study seeks to provide an up-to-date compilation of the most current and promising breakthroughs in AD therapy using phytochemicals. It could be concluded that phytochemicals light serve as an effective therapy for AD. However, more mechanistic investigations are needed to determine the clinical implications of phytochemicals in AD treatment.}, } @article {pmid39815147, year = {2025}, author = {Gao, M and Kong, W and Liu, K and Wen, G and Yu, Y and Zhu, Y and Jiang, Z and Wei, K}, title = {Exploring Brain Imaging and Genetic Risk Factors in Different Progression States of Alzheimer's Disease Through OSnetNMF-Based Methods.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {1}, pages = {7}, pmid = {39815147}, issn = {1559-1166}, mesh = {*Alzheimer Disease/genetics/diagnostic imaging ; Humans ; *Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/metabolism ; Cognitive Dysfunction/diagnostic imaging/genetics ; Algorithms ; Female ; Aged ; Male ; Disease Progression ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with no effective treatment, often preceded by mild cognitive impairment (MCI). Multimodal imaging genetics integrates imaging and genetic data to gain a deeper understanding of disease progression and individual variations. This study focuses on exploring the mechanisms that drive the transition from normal cognition to MCI and ultimately to AD. As an effective joint feature extraction and dimensionality reduction method, non-negative matrix factorization (NMF) and its improved variants, particularly the network-based non-negative matrix factorization (netNMF), have been widely used in multimodal analysis to mine brain imaging and genetic data by considering the interactions between different features. However, many of these methods overlook the importance of the coefficient matrix and do not address issues related to data accuracy and feature redundancy. To address these limitations, we propose an orthogonal sparse network non-negative matrix factorization (OSnetNMF) algorithm, which introduces orthogonal and sparse constraints based on netNMF. By establishing linear relationships between structural magnetic resonance imaging (sMRI) and corresponding gene expression data, OSnetNMF reduces feature redundancy and decreases correlation between data, resulting in more accurate and reliable biomarker extraction. Experiments demonstrate that the OSnetNMF algorithm can accurately identify risk regions of interest (ROIs) and key genes that characterize AD progression, revealing significant trends in ROI pairs such as l4thVen-HIF1A, rBst-MPO, and rBst-PTK2B. Comparative experiments show that the improved algorithm outperforms traditional methods, identifying more disease-related biomarkers and achieving better reconstruction performance.}, } @article {pmid39814858, year = {2025}, author = {Li, G and Hsu, LM and Wu, Y and Bozoki, AC and Shih, YI and Yap, PT}, title = {Revealing excitation-inhibition imbalance in Alzheimer's disease using multiscale neural model inversion of resting-state functional MRI.}, journal = {Communications medicine}, volume = {5}, number = {1}, pages = {17}, pmid = {39814858}, issn = {2730-664X}, support = {R01 EB008374/EB/NIBIB NIH HHS/United States ; R01EB006733//U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (NIBIB)/ ; R01 EB006733/EB/NIBIB NIH HHS/United States ; R01EB008374//U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (NIBIB)/ ; R01 MH125479/MH/NIMH NIH HHS/United States ; R01MH125479//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R21 AG083589/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a serious neurodegenerative disorder without a clear understanding of pathophysiology. Recent experimental data have suggested neuronal excitation-inhibition (E-I) imbalance as an essential element of AD pathology, but E-I imbalance has not been systematically mapped out for either local or large-scale neuronal circuits in AD, precluding precise targeting of E-I imbalance in AD treatment.

METHOD: In this work, we apply a Multiscale Neural Model Inversion (MNMI) framework to the resting-state functional MRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to identify brain regions with disrupted E-I balance in a large network during AD progression.

RESULTS: We observe that both intra-regional and inter-regional E-I balance is progressively disrupted from cognitively normal individuals, to mild cognitive impairment (MCI) and to AD. Also, we find that local inhibitory connections are more significantly impaired than excitatory ones and the strengths of most connections are reduced in MCI and AD, leading to gradual decoupling of neural populations. Moreover, we reveal a core AD network comprised mainly of limbic and cingulate regions. These brain regions exhibit consistent E-I alterations across MCI and AD, and thus may represent important AD biomarkers and therapeutic targets. Lastly, the E-I balance of multiple brain regions in the core AD network is found to be significantly correlated with the cognitive test score.

CONCLUSIONS: Our study constitutes an important attempt to delineate E-I imbalance in large-scale neuronal circuits during AD progression, which may facilitate the development of new treatment paradigms to restore physiological E-I balance in AD.}, } @article {pmid39814774, year = {2025}, author = {Rajkumar, M and Davis Presley, SI and Thiyagarajulu, N and Girigoswami, K and Janani, G and Kamaraj, C and Madheswaran, B and Prajapati, B and Ali, N and Khan, MR}, title = {Gelatin/PLA-loaded gold nanocomposites synthesis using Syzygium cumini fruit extract and their antioxidant, antibacterial, anti-inflammatory, antidiabetic and anti-Alzheimer's activities.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {2110}, pmid = {39814774}, issn = {2045-2322}, support = {SSN/CE/SRF/2024//SSN College of Engineering/ ; RSPD2024R940//King Saud University/ ; RSPD2024R940//King Saud University/ ; }, mesh = {*Syzygium/chemistry ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Antioxidants/pharmacology/chemistry ; *Plant Extracts/chemistry/pharmacology ; Animals ; *Gold/chemistry ; *Nanocomposites/chemistry ; *Hypoglycemic Agents/chemistry/pharmacology ; *Anti-Inflammatory Agents/pharmacology/chemistry ; *Alzheimer Disease/drug therapy ; *Gelatin/chemistry ; Zebrafish ; Fruit/chemistry ; Humans ; Staphylococcus aureus/drug effects ; Metal Nanoparticles/chemistry ; }, abstract = {Nanotechnology has experienced significant advancements, attracting considerable attention in various biomedical applications. This innovative study synthesizes and characterizes Ge/PLA/AuNCs (gelatin/PLA/gold nanocomposites) using Syzygium cumini extract to evaluate their various biomedical applications. The UV-Visible spectroscopy results in an absorption peak at 534 nm were primarily confirmed by Ge/PLA/AuNCs synthesis. The FTIR spectrum showed various functional groups and the XRD patterns confirmed the crystalline shape and structure of nanocomposites. The FESEM and HRTEM results showed a oval shape of Ge/PLA/AuNCs with an average particle size of 21 nm. The Ge/PLA/AuNC's remarkable antioxidant activity, as evidenced by DPPH (70.84 ± 1.64%), ABTS activity (86.17 ± 1.96%), and reducing power activity (78.42 ± 1.48%) at a concentration of 100 μg/mL was observed. The zone of inhibition against Staphylococcus aureus (19.45 ± 0.89 mm) and Echericia coli (20.83 ± 0.97 mm) revealed the excellent antibacterial activity of Ge/PLA/AuNCs. The anti-diabetic activity of Ge/PLA/AuNCs was supported by inhibition of α-amylase (82.56 ± 1.49%) and α-glucosidase (80.27 ± 1.57%). The anti-Alzheimer activity was confirmed by inhibition of the AChE (76.37 ± 1.18%) and BChE (85.94 ± 1.38%) enzymes. In vivo studies of zebrafish embryos showed that Ge/PLA/AuNCs have excellent biocompatibility and nontoxicity. The SH-SY5Y cell line study demonstrated improved cell viability (95.27 ± 1.62%) and enhanced neuronal cell growth following Ge/PLA/AuNCs treatment. In conclusion, the present study highlights the cost-effective and non-toxic properties of Ge/PLA/AuNCs. Furthermore, it presents an attractive and promising approach for various future biomedical applications.}, } @article {pmid39814656, year = {2025}, author = {Schöll, M and Vrillon, A and Ikeuchi, T and Quevenco, FC and Iaccarino, L and Vasileva-Metodiev, SZ and Burnham, SC and Hendrix, J and Epelbaum, S and Zetterberg, H and Palmqvist, S}, title = {Cutting through the noise: A narrative review of Alzheimer's disease plasma biomarkers for routine clinical use.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100056}, doi = {10.1016/j.tjpad.2024.100056}, pmid = {39814656}, issn = {2426-0266}, abstract = {As novel, anti-amyloid therapies have become more widely available, access to timely and accurate diagnosis has become integral to ensuring optimal treatment of patients with early-stage Alzheimer's disease (AD). Plasma biomarkers are a promising tool for identifying AD pathology; however, several technical and clinical factors need to be considered prior to their implementation in routine clinical use. Given the rapid pace of advancements in the field and the wide array of available biomarkers and tests, this review aims to summarize these considerations, evaluate available platforms, and discuss the steps needed to bring plasma biomarker testing to the clinic. We focus on plasma phosphorylated(p)-tau, specifically plasma p-tau217, as a robust candidate across both primary and secondary care settings. Despite the high performance and robustness demonstrated in research, plasma p-tau217, like all plasma biomarkers, can be affected by analytical and pre-analytical variability as well as patient comorbidities, sex, ethnicity, and race. This review also discusses the advantages of the two-point cut-off approach to mitigating these factors, and the challenges raised by the resulting intermediate range measurements, where clinical guidance is still unclear. Further validation of plasma p-tau217 in heterogeneous, real-world cohorts will help to increase confidence in testing and support establishing a standardized approach. Plasma biomarkers are poised to become a more affordable and less invasive alternative to PET and CSF testing. However, understanding the factors that impact plasma biomarker measurement and interpretation is critical prior to their implementation in routine clinical use.}, } @article {pmid39814340, year = {2025}, author = {Yang, W and Yu, W and Lv, Y}, title = {Neuroprotective effects of chitinase-1 and calcitonin gene-related peptide on Alzheimer's disease by promoting lysosomal function.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877241307257}, doi = {10.1177/13872877241307257}, pmid = {39814340}, issn = {1875-8908}, abstract = {BACKGROUND: The amyloid cascade hypothesis still dominates in Alzheimer's disease (AD), and the acceleration of the clearance efficiency of amyloid-β (Aβ) has been always considered as an effective treatment option to slow the occurrence and progression of AD.

OBJECTIVE: This study aims to explore the role of zkscan3 and its related pathways in AD of the microglia-mediated pathogenesis, and whether the combined effect of drugs can exert neuroprotective function.

METHODS: N9 mouse microglia and HT-22 mouse hippocampal neurons were randomly divided into 6 groups, qRT-PCR technique was used to detect the gene expression level of zkscan3 and the genes related to lysosome generation and function. Fourteen C57 mice were randomly divided into two groups, and drug intervention model mice were randomly selected to establish from the AD group. Transmission electron microscope was used to detect the cell status and lysosome function in the hippocampus together with the other two groups.

RESULTS: Compared with the AD model group, the gene expression of zkscan3 in the drug intervention group was downregulated, and the degree of neuronal injury in the hippocampus was reduced, the structure and number of synapses were improved, and the function of intracellular lysosome was enhanced.

CONCLUSIONS: Zkscan3 and its related genes play a vital role in the development of AD. CGRP and CHIT-1, as a combined intervention, imparts effects through zkscan3-related pathways to improve lysosomal function and exert certain neuroprotective effects.}, } @article {pmid39814324, year = {2025}, author = {Fu, Q and Yu, Q and Luo, H and Liu, Z and Ma, X and Wang, H and Cheng, Z}, title = {Protective effects of wogonin in the treatment of central nervous system and degenerative diseases.}, journal = {Brain research bulletin}, volume = {221}, number = {}, pages = {111202}, doi = {10.1016/j.brainresbull.2025.111202}, pmid = {39814324}, issn = {1873-2747}, mesh = {Humans ; *Flavanones/pharmacology/therapeutic use ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; Central Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Wogonin, an O-methylated flavonoid extracted from Scutellaria baicalensis, has demonstrated profound neuroprotective effects in a range of central nervous system (CNS) diseases. This review elucidates the pharmacological mechanisms underlying the protective effects of wogonin in CNS diseases, including ischemic stroke, hemorrhagic stroke, traumatic brain injury, epilepsy, anxiety, neurodegenerative diseases, and CNS infections. Wogonin modulates key signaling pathways, such as the MAPK, NF-κB, and ROS pathways, contributing to its anti-inflammatory, antioxidant, and antiapoptotic properties. In ischemic stroke models, wogonin reduces infarct size and enhances neurological outcomes by mitigating inflammation and oxidative stress. For patients with hemorrhagic stroke and traumatic brain injury, it accelerates hematoma regression, mitigates secondary brain damage, and promotes neurogenesis, making it an entirely new treatment option for patients with limited access to this type of therapy. Its anticonvulsant and anxiolytic effects are mediated through GABA-A receptor modulation. Moreover, wogonin shows promise in treating neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease by promoting autophagy and reducing neuroinflammation. Additionally, it exhibits antiviral properties, offering potential benefits against CNS infections. Despite extensive preclinical evidence, further clinical studies are warranted to confirm its efficacy and safety in humans. This review highlights the great therapeutic potential of wogonin in terms of CNS protection. However, despite the substantial preclinical evidence, further large-scale clinical studies are necessary. Future researchers need to further explore the long-term efficacy and safety of wogonin in clinical trials and translate it for early application in the clinical treatment of true CNS disorders.}, } @article {pmid39814203, year = {2025}, author = {Chen, B and Yang, H and Bai, R and Du, X and Gao, Y and Zheng, L}, title = {Engineering silica nanocoated whole-cell asymmetric biocatalyst for efficient preparation of a key chiral intermediate of (S)-Rivastigmine.}, journal = {Journal of biotechnology}, volume = {399}, number = {}, pages = {19-27}, doi = {10.1016/j.jbiotec.2025.01.005}, pmid = {39814203}, issn = {1873-4863}, abstract = {In our previous study, the whole cells containing an aldo-keto reductase (yhdN) and glucose dehydrogenase (GDH) were constructed and applied in a stereoselective carbonyl reduction reaction to prepare (S)-NEMCA-HEPE, being a key chiral intermediate of (S)-Rivastigmine which is widely prescribed for the treatment of Alzheimer's disease. Although the conversion and enantiomeric excess (e.e.) could reach to 78.2 % and 99 %, respectively, ionic liquid as an additive was required to improve the permeability of cell membrane. To further simplify the reaction, the molecular docking and saturation mutagenesis technology were used here to obtain an activity-improved yhdN variant such as G19A. And then, both excellent conversion and e.e. of 99 % for (S)-NEMCA-HEPE could be achieved within 40 min by using only G19A-GDH whole cell as a catalyst without any additive. However, the use of the whole cells still faces the issues of poor operation stability and adverse application prospect. Subsequently, a hydrophobic "cell-in-shell" complex of G19A-GDH@O-Silica was constructed by using a silica nanocoated technology. The obtained G19A-GDH@O-Silica exhibited an excellent conversion towards the asymmetric carbonyl reduction, and a good tolerance in changing thermal, pH, and storage environmental. Giving 76.3 % of reaction conversion even after the 11th cycle of reuse, indicated that G19A-GDH@O-Silica also possessed ideal recyclability. The aim of this study is to provide a rapid, and cost-effective nanocoated whole-cell biocatalyst for efficient preparation of (S)-NEMCA-HEPE. The simplicity and robustness of the immobilization approach may become a powerful tool to utilize whole-cell catalysts towards organic catalysis.}, } @article {pmid39814004, year = {2025}, author = {Xu, M and Wang, L and Meng, Y and Kang, G and Jiang, Q and Yan, T and Che, F}, title = {The role of lipid metabolism in cognitive impairment.}, journal = {Arquivos de neuro-psiquiatria}, volume = {83}, number = {1}, pages = {1-13}, pmid = {39814004}, issn = {1678-4227}, support = {2023M732121//China Postdoctoral Science Foundation/ ; ZR2023QH090//Natural Science Foundation of Shandong Province/ ; ZR2022MH119//Natural Science Foundation of Shandong Province/ ; XYFY202343//Development fund of the Affiliated Hospital of Xuzhou Medical University/ ; }, mesh = {Humans ; *Lipid Metabolism/physiology ; *Cognitive Dysfunction/metabolism/physiopathology/etiology ; *Insulin Resistance/physiology ; *Alzheimer Disease/metabolism/physiopathology ; Amyloid beta-Peptides/metabolism ; Apolipoproteins E/metabolism ; Dementia, Vascular/metabolism/physiopathology ; Disease Progression ; tau Proteins/metabolism ; Brain/metabolism ; }, abstract = {Alzheimer's disease (AD), diabetic cognitive impairment (DCI), and vascular dementia (VD) are considered the most common causes of severe cognitive impairment in clinical practice. Numerous factors can influence their progression, and many studies have recently revealed that metabolic disorders play crucial roles in the progression of cognitive impairment. Mounting evidence indicate that the regulation of lipid metabolism is a major factor in maintaining brain homeostasis. Generally, abnormalities in lipid metabolism can affect amyloid-beta (Aβ) deposition, tau hyperphosphorylation, and insulin resistance through lipid metabolic signaling cascades; affect the neuronal membrane structure, neurotransmitter synthesis and release; and promote synapse growth, which can impact neural signal transmission and exacerbate disease progression in individuals with cognitive impairment, including AD, DCI, and VD. Moreover, apolipoprotein E (APOE), a key protein in lipid transport, is involved in the occurrence and development of the aforementioned diseases by regulating lipid metabolism. The present article mainly discusses how lipid metabolic disorders in the brain microenvironment are involved in regulating the progression of cognitive impairment, and it explores the regulatory effects of targeting the key lipid transport protein APOE in the context of the role of lipid metabolism in the common pathogenesis of three diseases-Aβ deposition, tau hyperphosphorylation, and insulin resistance-which will help elucidate the potential of targeting lipid metabolism for the treatment of cognitive impairment.}, } @article {pmid39813887, year = {2025}, author = {Maji, M and Khajanchi, S}, title = {Mathematical models on Alzheimer's disease and its treatment: A review.}, journal = {Physics of life reviews}, volume = {52}, number = {}, pages = {207-244}, doi = {10.1016/j.plrev.2025.01.004}, pmid = {39813887}, issn = {1873-1457}, abstract = {Alzheimer's disease is a gradually advancing neurodegenerative disease. According to the report by "World Health Organization (WHO)", there are over 55 million individuals currently living with Alzheimer's disease and other dementia globally, and the number of sufferers is increasing every day. In absence of effective cures and preventive measures, this number is predicted to triple by 2050. The disease's origin is still unclear, and also no such treatment is available for eradicating the disease. Based on the crucial factors that are connected to the disease's progression, the authors developed several types of mathematical models. We review such mathematical models that are utilized to better understand the pathophysiology of Alzheimer's disease. Section-wise, we categorize the mathematical models in terms of different components that might be responsible for Alzheimer's disease. We explain the mathematical models with their descriptions and respective conclusions. In addition to mathematical models, we concentrate on biological aspects of the disease and possible therapeutic targets. We explore the disease's biological basis primarily to understand how proteins, glial cells, cytokines, genes, calcium signaling and oxidative stress contribute to the disease. We go through several treatment targets that might stop the progression of the disease or at least slow it down. We present a table that summarizes the mathematical models in terms of their formalisms, highlighting key components and important remarks.}, } @article {pmid39813317, year = {2025}, author = {Brandao, W and Jain, N and Yin, Z and Kleemann, KL and Carpenter, M and Bao, X and Serrano, JR and Tycksen, E and Durao, A and Barry, JL and Baufeld, C and Guneykaya, D and Zhang, X and Litvinchuk, A and Jiang, H and Rosenzweig, N and Pitts, KM and Aronchik, M and Yahya, T and Cao, T and Takahashi, MK and Krishnan, R and Davtyan, H and Ulrich, JD and Blurton-Jones, M and Ilin, I and Weiner, HL and Holtzman, DM and Butovsky, O}, title = {Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy.}, journal = {Science translational medicine}, volume = {17}, number = {781}, pages = {eadk3690}, doi = {10.1126/scitranslmed.adk3690}, pmid = {39813317}, issn = {1946-6242}, mesh = {Animals ; *Microglia/drug effects/metabolism/pathology ; *Xenon/pharmacology/administration & dosage ; *Disease Models, Animal ; Administration, Inhalation ; *Tauopathies/drug therapy/pathology ; Mice ; Amyloidosis/drug therapy/pathology ; Mice, Transgenic ; Alzheimer Disease/drug therapy/pathology ; Humans ; Brain/pathology/drug effects/metabolism ; Plaque, Amyloid/pathology ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre-neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-γ signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD.}, } @article {pmid39812690, year = {2025}, author = {Zhao, C and Li, T and Hao, S and Zhao, L and Han, Y and Cai, Y}, title = {Dysregulation of the molecular clock by blood-borne factors in Alzheimer's disease patients.}, journal = {Journal of neurology}, volume = {272}, number = {2}, pages = {121}, pmid = {39812690}, issn = {1432-1459}, support = {2021YFC2501205//Key Technologies Research and Development Program of Anhui Province/ ; 2021ZD0201101//the STI2030-Major Project/ ; 2022ZD0211800//the STI2030-Major Project/ ; YC202301QX0148//Beijing Translational Medicine Promotion Project/ ; 82020108013//the National Nature Science Foundation of China/ ; }, mesh = {Humans ; *Alzheimer Disease/blood ; Male ; Female ; Aged ; *Cognitive Dysfunction/etiology/blood/physiopathology ; Longitudinal Studies ; Aged, 80 and over ; Circadian Rhythm/physiology ; Middle Aged ; Amyloid beta-Peptides/blood/metabolism ; ARNTL Transcription Factors/genetics ; Nuclear Receptor Subfamily 1, Group D, Member 1/genetics ; Biomarkers/blood ; }, abstract = {BACKGROUND: Circadian disruptions are increasingly recognized in Alzheimer's disease (AD) patients and may influence disease onset and progression. This study examines how AD pathology affects blood-borne factors that regulate circadian rhythms.

METHODS: Eighty-five participants from the Sino Longitudinal Study on Cognitive Decline were enrolled: 35 amyloid-beta negative normal controls (Aβ- NCs), 23 amyloid-beta positive normal controls (Aβ+ NCs), 15 patients with amnestic mild cognitive impairment (aMCI), and 12 with Alzheimer's disease dementia (ADD). Patients with aMCI and ADD were grouped as cognitively impaired (CI). Cellular circadian period length was assessed using a serum-based assay. Expression levels of clock genes in serum-treated cells and in leukocytes of participants were measured via real-time PCR. Plasma biomarkers were quantified using a single-molecule array immunoassay. Pineal parenchymal and hippocampal volumes were determined by magnetic resonance imaging.

RESULTS: The cellular circadian period length was significantly extended by serum from CI patients than by that from Aβ- NCs (p < 0.01). Treatment of cells with serum from the CI patients resulted in suppressed expression of the clock genes Bmal1 and Nr1d1. Strong relationships between the expression levels of clock genes observed in leukocytes of the Aβ- NC group did not appear in those of the Aβ+ NC or CI groups. The significant correlation of cellular circadian period length and the pineal volume was only observed in the Aβ- NC group, but not in the Aβ+ NC or CI groups.

CONCLUSIONS: This study indicates the presence of significant changes in blood-borne factors that could affect the circadian rhythms in AD, starting even at preclinical stages. These alterations could precede cognitive decline and contribute to AD pathogenesis.

TRIAL REGISTRATION: The cohort is registered at ClinicalTrials.gov (SILCODE: NCT03370744; Registered on Mar 15[th], 2017).}, } @article {pmid39812543, year = {2025}, author = {Zong, NC and Zhang, Y and Huang, Y and Cai, H}, title = {Addressing Healthy Aging: Time to Stop a Tsunami of Rising Alzheimer's Disease.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.1476}, pmid = {39812543}, issn = {2152-5250}, abstract = {Alzheimer's disease [AD] disproportionately affects our seniors, diminishing their health and life expectancy. As the world population grows older, the collective burden of AD has become unsustainable. Globally, there were 43.8 million patients in 2016, with a projection of affecting 152 million by 2050. Recent discoveries have shown that molecular changes characteristic to AD manifested 20 years before discernable neurological phenotypes emerge. It is feasible to halt or reverse this pathological process before reaching an irremediable stage. To take advantage of this treatment window, we need to make rapid progress in early detection and monitoring, targeted implementation of preventative measures, invention of novel therapeutics, and pragmatic ramping-up of relevant supporting policies. PET is a powerful tool for prognosis. The utilization of AI technology, on the other hand, has favorable features of low cost per capita, easy dissemination and broad scale data collection to uncover previously unknown hotspots or risk factors. FDA approved drugs, lecanemab and donanemab, have started to show efficacy to put a pause on AD progression. Additional clinical data will enable comprehensive evaluation of the impacts of these drugs. Gene therapy holds the potential of eliciting long term protection, while several candidate loci have been identified. The urgency of a tsunami of rising AD epidemiology demands rapid actions on all fronts of advanced diagnostics, monitoring, preventative and interventive strategies.}, } @article {pmid39812538, year = {2025}, author = {Iqbal, Z and El Hamamy, A and Le, NM and Ranjan, A and Zhang, Y and Qi, L and Manwani, B and Tan, C and McCullough, LD and Li, J}, title = {Targeting Astrogliosis in the Retrotrapezoid Nucleus: A Novel Approach to Ameliorate Respiratory Dysfunction and Alzheimer's Pathology in Mice.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.0523}, pmid = {39812538}, issn = {2152-5250}, abstract = {Alzheimer's disease (AD), a leading cause of dementia, is associated with significant respiratory dysfunctions. Our study explores the role of astrogliosis in the brainstem retrotrapezoid nucleus (RTN), a key breathing regulatory center, and its impact on breathing control and AD pathology in mice. Using Tg-2576 AD and wild-type mice, we investigated the effect of silencing the transforming growth factor-beta receptor II (TGFβR II) in the RTN. We performed behavioral tests, including the Barnes maze and novel object recognition test, along with whole-body plethysmography to assess breathing disorders. Our results showed that AD mice exhibited increased apneas and cognitive impairment, which were significantly mitigated following TGFβR II gene silencing. Immunohistochemistry revealed elevated levels of GFAP and TGFβR II in the RTN of AD mice, which were reduced post-gene silencing, alongside a decrease in amyloid-beta expression in the cortex and hippocampus. These findings suggest that targeting astrogliosis and improving respiratory control may offer a novel therapeutic avenue for managing Alzheimer's disease. Our study provides the first mechanistic insights into how TGFβ signaling influences both respiratory control and AD pathogenesis, highlighting the potential benefits of stabilizing breathing patterns in AD treatment.}, } @article {pmid39812537, year = {2025}, author = {Wu, Y and Zhou, YM and Wu, W and Jiang, WR and Zhang, XY and Song, SY and Yao, ZH}, title = {TBC1D15 Inhibits Autophagy of Microglia through Maintaining the Damaged Swelling Lysosome in Alzheimer's Disease.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.1373}, pmid = {39812537}, issn = {2152-5250}, abstract = {Autophagy in microglia is essential for the clearance of amyloid-beta (Aβ) and amyloid plaques in Alzheimer's disease. However, reports regarding the levels of autophagy in microglia have been inconsistent; some studies indicate an early enhancement followed by a subsequent reduction, while others describe a persistently weakened state. Notably, there is a lack of systematic studies documenting the temporal changes in microglial autophagy. TBC1D15, a Rab GTPase, plays a crucial role in lysosomal membrane repair, yet its function in regulating microglial autophagy in Alzheimer's disease remains unexplored. Current research suggests that microglial autophagy is activated in 3-month-old AD mice but gradually decreases by 12 months of age. Furthermore, TBC1D15 levels are significantly elevated in the lysosomes of microglia in Alzheimer's disease. Silencing TBC1D15 markedly inhibits swelling and Aβ phagocytosis in BV2 cells following Aβ treatment while simultaneously promoting autophagy and lysophagy. LIMP II/ATG8-TBC1D15-Dynamin2/RAB7 might participate in lysosome swelling of microglia in AD. These findings indicate that TBC1D15 in microglia is critical for the decline of autophagy in Alzheimer's disease. It is suggested that targeting microglial TBC1D15 may be an important strategy for enhancing autophagy, which facilitates the clearance of amyloid plaques as a therapeutic approach for Alzheimer's disease.}, } @article {pmid39812331, year = {2025}, author = {Huang, X and Jannu, AJ and Song, Z and Jury-Garfe, N and Lasagna-Reeves, CA and , and Johnson, TS and Huang, K and Zhang, J}, title = {Predicting Alzheimer's disease subtypes and understanding their molecular characteristics in living patients with transcriptomic trajectory profiling.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14241}, pmid = {39812331}, issn = {1552-5279}, support = {5R01NS119280//Indiana University Precision Health Initiative NIH TREAT-AD U54/ ; //Alzheimer's Disease Neuroimaging Initiative/ ; //Alzheimer's Drug Discovery Foundation/ ; U54 AG065181/AG/NIA NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //AbbVie/ ; //F. Hoffmann-La Roche Ltd/ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; R01 NS119280/NS/NINDS NIH HHS/United States ; 5U54AG065181//Indiana University Precision Health Initiative NIH TREAT-AD U54/ ; W81XWH-12-2-0012//Department of Defense/ ; //EuroImmun/ ; //Biogen/ ; //Bristol-Myers Squibb Company/ ; U01 AG024904/AG/NIA NIH HHS/United States ; //Araclon Biotech/ ; U01 AG024904/NH/NIH HHS/United States ; //CereSpir, Inc./ ; //BioClinica, Inc./ ; //Cogstate; Eisai Inc./ ; /EB/NIBIB NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics ; *Transcriptome ; *Disease Progression ; *Biomarkers/blood ; Female ; Aged ; Gene Expression Profiling ; Male ; Leukocytes, Mononuclear/metabolism ; Cohort Studies ; Prognosis ; Monocytes/metabolism ; }, abstract = {INTRODUCTION: Deciphering the diverse molecular mechanisms in living Alzheimer's disease (AD) patients is a big challenge but is pivotal for disease prognosis and precision medicine development.

METHODS: Utilizing an optimal transport approach, we conducted graph-based mapping of transcriptomic profiles to transfer AD subtype labels from ROSMAP monocyte samples to ADNI and ANMerge peripheral blood mononuclear cells. Subsequently, differential expression followed by comparative pathway and diffusion pseudotime analysis were applied to each cohort to infer the progression trajectories. Survival analysis with real follow-up time was used to obtain potential biomarkers for AD prognosis.

RESULTS: AD subtype labels were accurately transferred onto the blood samples of ADNI and ANMerge living patients. Pathways and associated genes in neutrophil degranulation-like immune process, immune acute phase response, and IL-6 signaling were significantly associated with AD progression.

DISCUSSION: The work enhanced our understanding of AD progression in different subtypes, offering insights into potential biomarkers and personalized interventions for improved patient care.

HIGHLIGHTS: We applied an innovative optimal transport-based approach to map transcriptomic data from different Alzheimer's disease (AD) cohort studies and transfer known AD subtype labels from ROSMAP monocyte samples to peripheral blood mononuclear cell (PBMC) samples within ADNI and ANMerge cohorts. Through comprehensive trajectory and comparative analysis, we investigated the molecular mechanisms underlying different disease progression trajectories in AD. We validated the accuracy of our AD subtype label transfer and identified prognostic genetic markers associated with disease progression, facilitating personalized treatment strategies. By identifying and predicting distinctive AD subtypes and their associated pathways, our study contributes to a deeper understanding of AD heterogeneity.}, } @article {pmid39811702, year = {2025}, author = {Terao, CM and Alexander, MW and Chalmers, RP and Boshmaf, SZ and Paterson, J and Black, SE and Papp, KV and Sperling, RA and Rabin, JS}, title = {Identifying cognitive test scores associated with early tau burden in Alzheimer's disease.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {1}, pages = {e70052}, pmid = {39811702}, issn = {2352-8729}, support = {R01 AG063689/AG/NIA NIH HHS/United States ; U19 AG010483/AG/NIA NIH HHS/United States ; U24 AG057437/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: This study aimed to identify cognitive tests that optimally relate to tau positron emission tomography (PET) signal in the inferior temporal cortex (ITC), a neocortical region associated with early tau accumulation in Alzheimer's disease (AD).

METHODS: We analyzed cross-sectional data from the harvard aging brain study (HABS) (n = 128) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study (n = 393). We used elastic net regression to identify the most robust cognitive correlates of tau PET signal in the ITC. Secondary analyses examined whether the cognitive correlates remained significantly associated with tau after adjusting for structural brain measures.

RESULTS: Episodic memory measures, including both total and "process" scores, were the most robust correlates of ITC tau across both cohorts. These cognitive test scores remained significant after accounting for structural brain measures.

DISCUSSION: These findings highlight the potential of specific episodic memory test scores to detect and monitor neuropathological changes associated with early AD.

HIGHLIGHTS: Machine learning identified cognitive correlates of early Alzheimer's disease tau burden.Both traditional and process scores predicted early tau burden.Episodic memory scores were among the strongest correlates.Cognitive scores remained significant after accounting for structural brain measures.}, } @article {pmid39811699, year = {2025}, author = {Blotenberg, I and Wittström, F and Michalowsky, B and Platen, M and Wucherer, D and Teipel, S and Hoffmann, W and Thyrian, JR}, title = {Modifiable risk factors and symptom progression in dementia over up to 8 years-Results of the DelpHi-MV trial.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {1}, pages = {e70050}, pmid = {39811699}, issn = {2352-8729}, abstract = {INTRODUCTION: This study investigated the association between modifiable factors and symptom progression in dementia over up to 8 years.

METHODS: Multilevel growth curve models assessed the role of modifiable risk factors (low education, hearing impairment and its treatment, depression, physical inactivity, diabetes and its treatment, smoking, hypertension and its treatment, obesity, alcohol consumption, social isolation, and visual impairment) on cognitive and functional trajectories in 353 people with dementia.

RESULTS: Higher education was associated with higher initial cognitive status but faster decline. Antidiabetic medication was associated with slower cognitive decline, whereas depression and visual impairment were linked to low baseline functioning and faster cognitive decline.

DISCUSSION: Several modifiable risk factors influenced symptom progression. Education initially had a protective effect, whereas depressive symptoms were linked to worse symptom progression. Treatment of comorbidities (diabetes, visual impairment) could have a positive impact on dementia symptoms. Modifiable risk factors are promising targets for tertiary prevention.

HIGHLIGHTS: Modifiable risk factors were associated with symptom progression in dementia over up to 8 years.More education was associated with higher initial cognitive status but faster decline.Depressive symptoms were linked to less favorable symptom progression.Treatment of comorbidities (diabetes, visual impairment) may positively impact the course of symptoms.Modifiable risk factors are promising targets for tertiary prevention.}, } @article {pmid39810446, year = {2024}, author = {Biswal, B and Satapathy, BS and Mishra, A and Maharana, L and Pattnaik, S}, title = {Potential of Nanoparticle Based Antimicrobial Drug Repurposing to Efficiently Target Alzheimer's: A Concise Update on Evidence-based Research and Challenges Ahead.}, journal = {Current drug discovery technologies}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115701638329824241220055621}, pmid = {39810446}, issn = {1875-6220}, abstract = {Repurposing of drugs through nanocarriers (NCs) based platforms has been a recent trend in drug delivery research. Various routine drugs are now being repurposed to treat challenging neurodegenerative disorders including Alzheimer disease (AD). AD, at present is one of the challenging neurodegenerative disorders characterized by extracellular accumulation of amyloid-β and intracellular accumulations of neurofibrillary tangles. In spite of catchy progress in drug development, effective treatment outcome in AD patients is far-fetched dream. Out of several proposed hypothesis in the development and progression of AD, potential role of microorganisms causing dementia and AD cannot be ruled out. Several recent researches have been documented a clear correlation in between microbial infection and neuronal damage leading to progression of AD. Thus, antimicrobial drugs repurposing has been emerged as alternate, potential, cost-effective strategy to check progression of AD. Further, for efficient delivery of antimicrobial drugs to brain tissue, novel NCs based platforms are the preferred option to bypass blood-brain barrier. Several polymeric and lipid NCs have been extensively studied over the past years to improve antimicrobial drug delivery to brain. The present review encompasses various repurposing strategy of antimicrobial drugs delivered through various NCs to target AD. Evidence-based research outcome compiled from authentic database like Scopus, PubMed, Web of science have been pooled to provide an updated review. Side by side some light has been thrown on the practical problems faced by nanodrug carriers during technology transfer.}, } @article {pmid39810384, year = {2025}, author = {Mandal, PK and Maroon, JC and Guha Roy, R and Patira, R and Gogniat, MA and Sindhu, B}, title = {The Missing Link in Antiamyloid Therapy.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {3}, pages = {276-280}, doi = {10.1021/acschemneuro.4c00825}, pmid = {39810384}, issn = {1948-7193}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Oxidative Stress/drug effects/physiology ; Cognitive Dysfunction/metabolism ; Animals ; Antibodies, Monoclonal, Humanized/pharmacology/therapeutic use ; Glutathione/metabolism ; }, abstract = {Alzheimer's disease (AD) impacts millions of elderly adults worldwide causing cognitive decline and severe deterioration of activities of daily life. The popular causal hypotheses for several decades include beta-amyloid (Aβ) deposition and tau hyperphosphorylation. AD research and more than 34% of clinical trials in AD are based on these two hypotheses. A phase-III clinical trial of lecanemab in early AD and mild cognitive impaired (MCI) patients reported a delay in cognitive decline of 27% over an 18-month treatment schedule. This multicenter trial found high specificity of lecanemab toward toxic protofibrils and subsequent clearance of beta-amyloid. There were, however, adverse events, which included cerebral edema and intracerebral hemorrhages in 23.1% of patients compared to 9.3% for those who received a placebo. Suboptimal clinical outcomes, brain volume loss, and adverse events in lecanemab treatment prompted a search for an alternative etiopathogenic explanation. Our research and others have focused on the oxidative stress (OS) hypothesis in AD. Autopsy studies have found significant depletion of the master antioxidant glutathione (GSH) in the hippocampal region, and is believed to be an early event in AD progression. Hippocampal GSH depletion is positively correlated with memory impairment. We have confirmed non-invasively with magnetic resonance spectroscopy (MRS) the depletion of GSH in patients with MCI and AD. We therefore propose a combinational therapy involving oral supplementation of gamma-glutamylcysteine (GGC), an early precursor of glutathione, to replenish brain GSH in addition to lecanemab, potentially to maximize desirable outcomes from combined therapeutic approach.}, } @article {pmid39809960, year = {2025}, author = {Saunders, MR and Qi, M and Huang, ES and Konetzka, RT}, title = {Trends in Co-morbid Dementia and Chronic Kidney Disease.}, journal = {Journal of general internal medicine}, volume = {}, number = {}, pages = {}, pmid = {39809960}, issn = {1525-1497}, support = {K24AG069080/AG/NIA NIH HHS/United States ; RFIAG069857/AG/NIA NIH HHS/United States ; P50MD17349/MD/NIMHD NIH HHS/United States ; R01DK124597/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND: Little is known about the population of Medicare beneficiaries with both chronic kidney disease (CKD) and Alzheimer's disease and related dementias (ADRD).

METHODS: Using data from Medicare fee-for-service (FFS) beneficiaries aged 65 and over identified through 2011-2019 Master Beneficiary Summary File (MBSF), we estimated the size, growth, and racial-ethnic characteristics of the ADRD and CKD populations. Individuals were classified as having ADRD and CKD based on CMS Chronic Conditions Data Warehouse (CCW) indicators in the MBSF Chronic Conditions file.

RESULTS: Among FFS beneficiaries, the prevalence of CKD has increased from 17.5% in 2011 to 27.9% in 2019, and the prevalence of ADRD has decreased over that time from 13.3 to 12.5%. The prevalence of individuals with co-morbid ADRD and CKD has risen from 4.4 to 6.3% which represents 1.72 million older adults. Black and Hispanic individuals have the highest prevalence of co-morbid CKD and ADRD, averaging 10.0% and 9.0% in 2019, respectively, compared to other racial-ethnic groups (≤ 7.2% all others). In addition, among those previously diagnosed with ADRD, the proportion with co-morbid CKD has been steadily increasing from 25.5% in 2011 to 44.4% in 2019. While the proportion of individuals with ADRD who have co-morbid CKD has increased across all race-ethnicities, it is highest in Black and Hispanic individuals (56.7 and 51%, respectively in 2019).

CONCLUSION/RELEVANCE: The prevalence of Medicare FFS enrollees with both ADRD and CKD is increasing. Although the ADRD prevalence has declined, there is a rising number of individuals with CKD who are diagnosed with ADRD and a rising proportion of those with ADRD who also have CKD. Due to shared clinical and demographic risk factors, interventions to reduce CKD progression could also delay ADRD onset. In patients with both advanced ADRD and advanced CKD, clinicians and policymakers should focus on treatment options that consider both co-morbidities.}, } @article {pmid39809015, year = {2025}, author = {Afşar, E and Kantar, D}, title = {How does zinc chelation affect liver sphingolipid metabolism in an Alzheimer's-like model?.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {87}, number = {}, pages = {127589}, doi = {10.1016/j.jtemb.2025.127589}, pmid = {39809015}, issn = {1878-3252}, mesh = {Animals ; *Alzheimer Disease/metabolism ; *Zinc/metabolism ; *Liver/metabolism/drug effects ; *Disease Models, Animal ; Rats ; Male ; *Sphingolipids/metabolism ; Rats, Wistar ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Chelating Agents/pharmacology ; Caspase 3/metabolism ; Glutathione/metabolism ; Aldehydes/metabolism ; }, abstract = {BACKGROUND: The present study aimed to evaluate the impact of Cyclo-Z, a combination of Cyclo (His-Pro) plus zinc, on hepatic sphingolipid (SL) metabolism and antioxidant properties in a rat model of Alzheimer's disease (AD).

METHODS: Alzheimer's disease rat model created via intracerebroventricular (i.c.v.) amyloid beta-42 oligomer (AβO) injection into the lateral ventricles. Cyclo-Z administration was performed with daily gavage for 3 weeks after the AβO injection. Ceramide, ceramide kinase (CERK), sphingosine 1 phosphate (S1P), glutathione (GSH), total oxidant capacity (TOS), 4-hydroxynonenal (HNE) and caspase-3 levels were measured with Elisa kit in liver tissue.

RESULTS: S1P, CERK and GSH levels increased and ceramide, TOS, 4 HNE, and caspase-3 levels decreased in the liver tissues of AD group. Cyclo-Z treatment decreased S1P, CERK, ceramide and caspase-3 levels but increased TOS and 4-HNE levels in the liver tissues of AD group.

CONCLUSION: These results showed that SL metabolism was modulated to generate an anti-apoptotic defense system in liver tissue of AD rats.}, } @article {pmid39808341, year = {2025}, author = {Gladen-Kolarsky, N and Neff, CJ and Hack, W and Brandes, MS and Wiedrick, J and Meza-Romero, R and Lockwood, DR and Quinn, JF and Offner, H and Vandenbark, AA and Gray, NE}, title = {The CD74 inhibitor DRhQ improves short-term memory and mitochondrial function in 5xFAD mouse model of Aβ accumulation.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {95}, pmid = {39808341}, issn = {1573-7365}, support = {R21NS094881/NH/NIH HHS/United States ; 2I01 BX000226//U.S. Department of Veterans Affairs/ ; P30AG066518/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Mitochondria/drug effects/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Antigens, Differentiation, B-Lymphocyte/metabolism ; *Mice, Transgenic ; Male ; *Amyloid beta-Peptides/metabolism ; Female ; *Disease Models, Animal ; *Memory, Short-Term/drug effects ; Histocompatibility Antigens Class II/metabolism ; Microglia/drug effects/metabolism ; Hippocampus/drug effects/metabolism ; }, abstract = {Neuroinflammation and mitochondrial dysfunction are early events in Alzheimer's disease (AD) and contribute to neurodegeneration and cognitive impairment. Evidence suggests that the inflammatory axis mediated by macrophage migration inhibitory factor (MIF) binding to its receptor, CD74, plays an important role in many central nervous system (CNS) disorders such as AD. Our group has developed DRhQ, a novel CD74 binding construct which competitively inhibits MIF binding, blocks macrophage activation and migration into the CNS, enhances anti-inflammatory microglia cell numbers and reduces pro-inflammatory gene expression. Here, we evaluate its effects in amyloid-β (Aβ) overexpressing mice. 5xFAD mice and their wild type littermates were treated with DRhQ (100 µg) or vehicle for 4 weeks. DRhQ improved cognition and cortical mitochondrial function in both male and female 5xFAD mice. Aβ plaque burden in 5xFAD animals was not robustly impacted by DRhQ treatment in either the hippocampus or the cortex. Cortical microglial activation was similarly not apparently affected by DRhQ treatment, although in the hippocampus there was evidence of a reduction in activated microglia for female 5xFAD mice. Future studies are needed to confirm this possible sex-dependent response on microglial activation, as well as to optimize the dose and timing of DRhQ treatment and gain a better understanding of its mechanism of action in AD.}, } @article {pmid39808238, year = {2025}, author = {Kumari, S and Bagri, K and Deshmukh, R}, title = {Connecting dots: Preclinical foundations to clinical realities of PDE4 inhibitors in Alzheimer's disease.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {39808238}, issn = {1568-5608}, abstract = {Alzheimer's Disease (AD), a progressive and age-associated neurodegenerative disorder, is primarily characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Despite advances in targeting Aβ-mediated neuronal damage with anti-Aβ antibodies, these treatments provide only symptomatic relief and fail to address the multifactorial pathology of the disease. This necessitates the exploration of novel therapeutic approaches and a deeper understanding of molecular signaling mechanisms underlying AD. Phosphodiesterases (PDEs), particularly Phosphodiesterase 4 (PDE4), play a pivotal role in regulating cyclic adenosine monophosphate (cAMP), a key molecule involved in memory consolidation and cognitive function. PDE4 inhibitors have demonstrated potential in enhancing memory and cognition in preclinical models of AD by modulating cAMP signaling. However, their clinical translation has been limited due to challenges such as adverse effects, narrow therapeutic windows, and low specificity in mechanism of action. This review bridges the gap between preclinical discoveries and clinical applications of PDE4 inhibitors in AD. It highlights preclinical evidence supporting the neuroprotective and anti-inflammatory effects of PDE4 inhibitors while addressing challenges in their clinical development, including issues of safety, efficacy, and disease-specific targeting. By integrating findings from both preclinical and clinical studies, we provide a comprehensive understanding of the therapeutic potential of PDE4 inhibitors in AD. Furthermore, this review outlines future research directions aimed at optimizing PDE4 inhibition strategies for AD treatment, offering a roadmap to translate foundational insights into clinical realities.}, } @article {pmid39807706, year = {2025}, author = {Karakatsani, ME and Nozdriukhin, D and Tiemann, S and Yoshihara, HAI and Storz, R and Belau, M and Ni, R and Razansky, D and Deán-Ben, XL}, title = {Multimodal imaging of murine cerebrovascular dynamics induced by transcranial pulse stimulation.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {e14511}, doi = {10.1002/alz.14511}, pmid = {39807706}, issn = {1552-5279}, support = {51767.1 IP-LS//Innosuisse - Swiss Innovation Agency/ ; RF1-NS126102/NH/NIH HHS/United States ; }, abstract = {INTRODUCTION: Transcranial pulse stimulation (TPS) is increasingly being investigated as a promising potential treatment for Alzheimer's disease (AD). Although the safety and preliminary clinical efficacy of TPS short pulses have been supported by neuropsychological scores in treated AD patients, its fundamental mechanisms are uncharted.

METHODS: Herein, we used a multi-modal preclinical imaging platform combining real-time volumetric optoacoustic tomography, contrast-enhanced magnetic resonance imaging, and ex vivo immunofluorescence to comprehensively analyze structural and hemodynamic effects induced by TPS. Cohorts of healthy and AD transgenic mice were imaged during and after TPS exposure at various per-pulse energy levels.

RESULTS: TPS enhanced the microvascular network, whereas the blood-brain barrier remained intact following the procedure. Notably, higher pulse energies were necessary to induce hemodynamic changes in AD mice, arguably due to their impacted vessels.

DISCUSSION: These findings shed light on cerebrovascular dynamics induced by TPS treatment, and hence are expected to assist improving safety and therapeutic outcomes.

HIGHLIGHTS: ·Transcranial pulse stimulation (TPS) facilitates transcranial wave propagation using short pulses to avoid tissue heating. ·Preclinical multi-modal imaging combines real-time volumetric optoacoustic (OA) tomography, contrast-enhanced magnetic resonance imaging (CE-MRI), and ex vivo immunofluorescence to comprehensively analyze structural and hemodynamic effects induced by TPS. ·Blood volume enhancement in microvascular networks was reproducibly observed with real-time OA imaging during TPS stimulation. ·CE-MRI and gross pathology further confirmed that the brain architecture was maintained intact without blood-brain barrier (BBB) opening after TPS exposure, thus validating the safety of the procedure. ·Higher pulse energies were necessary to induce hemodynamic changes in AD compared to wild-type animals, arguably due to their pathological vessels.}, } @article {pmid39807644, year = {2025}, author = {Ma, L and Tan, ECK and Goudey, B and Jin, L and Pan, Y}, title = {Unraveling the bidirectional link between cancer and dementia and the impact of cancer therapies on dementia risk: A systematic review and meta-analysis.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {e14540}, doi = {10.1002/alz.14540}, pmid = {39807644}, issn = {1552-5279}, support = {23AARF-1020292/ALZ/Alzheimer's Association/United States ; GNT2022203//National Health and Medical Research Council/ ; GNT2007912//National Health and Medical Research Council/ ; GNT2028025//National Health and Medical Research Council/ ; }, abstract = {Observational studies on the cancer-dementia relationship have yielded controversial results. This study systematically reviews the evidence to clarify this association. We searched Embase, Global Health, Ovid Medline, and APA PsycInfo. Colorectal and lung cancers showed the greatest risk reduction for all-cause dementia (ACD) and Alzheimer's disease (AD), respectively, while melanoma and colorectal cancers had the largest reduction in vascular dementia (VaD). Prostate cancer survivors on androgen deprivation therapy (ADT) had a higher risk of ACD/AD, while breast cancer patients on tamoxifen had a lower AD risk. Chemotherapy was linked to a reduced AD risk. ACD patients saw a 30% risk reduction for bladder, colorectal, and lung cancers, while AD patients had a ≈ 35% reduction for bladder and lung cancers. Our study urges clinicians to monitor cognitive function in cancer patients, especially those on ADT, tamoxifen, or chemotherapy and highlights the need for research into cancer-dementia mechanisms. HIGHLIGHTS: Cancer survivors have an 8% to 14% lower risk of dementia, while those with dementia have a 25% lower cancer risk. Colorectal and non-melanoma skin cancers were associated with reduced risks of all-cause dementia (ACD; 16%/9%), Alzheimer's disease (AD; 13%/5%), and vascular dementia (VaD; 24%/9%). Lung cancer reduced AD risk by 17%, and melanoma reduced VaD risk by 27%. ACD and AD patients had lower risks of lung (30%/36%), bladder (32%/34%), breast (26%/20%), and colorectal (31%/28%) cancers. Tamoxifen and chemotherapy reduced AD risk, while androgen deprivation therapy increased ACD risk.}, } @article {pmid39807629, year = {2025}, author = {Feng, Y and Wang, S and Yang, D and Zheng, W and Xia, H and Zhu, Q and Wang, Z and Hu, B and Jiang, X and Qin, X and Ni, C and Pan, W and Zhao, Y and Pan, S and Zhang, Y and Song, W}, title = {Inhibition of IFITM3 in cerebrovascular endothelium alleviates Alzheimer's-related phenotypes.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {e14543}, doi = {10.1002/alz.14543}, pmid = {39807629}, issn = {1552-5279}, support = {82230043//National Natural Science Foundation of China/ ; 82293642//National Natural Science Foundation of China/ ; }, abstract = {INTRODUCTION: Interferon-induced transmembrane protein 3 (IFITM3) modulates γ-secretase in Alzheimer's Disease (AD). Although IFITM3 knockout reduces amyloid β protein (Aβ) production, its cell-specific effect on AD remains unclear.

METHODS: Single nucleus RNA sequencing (snRNA-seq) was used to assess IFITM3 expression. Adeno-associated virus-BI30 (AAV-BI30) was injected to reduce IFITM3 expression in the cerebrovascular endothelial cells (CVECs). The effects on AD phenotypes in cells and AD mice were examined through behavioral tests, two-photon imaging, flow cytometry, Western blot, immunohistochemistry, and quantitative polymerase chain reaction assay (qPCR).

RESULTS: IFITM3 expression was increased in the CVECs of patients with AD. Overexpression of IFITM3 in primary endothelial cells enhanced Aβ generation through regulating beta-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Aβ further increased IFITM3 expression, creating a vicious cycle. Knockdown of IFITM3 in CVECs decreased Aβ accumulation within cerebrovascular walls, reduced Alzheimer's-related pathology, and improved cognitive performance in AD transgenic mice.

DISCUSSION: Knockdown of IFITM3 in CVECs alleviates AD pathology and cognitive impairment. Targeting cerebrovascular endothelial IFITM3 holds promise for AD treatment.

HIGHLIGHTS: Interferon-induced transmembrane protein 3 (IFITM3) expression was increased in the cerebrovascular endothelial cells (CVECs) of patients with Alzheimer's Disease (AD). Cerebrovascular endothelial IFITM3 regulates amyloid β protein (Aβ) generation through regulating beta-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Knockdown of IFITM3 in CVECs reduces Aβ deposits and improves cognitive impairments in AD transgenic mice. Cerebrovascular endothelial IFITM3 could be a potential target for the treatment of AD.}, } @article {pmid39807622, year = {2025}, author = {Kennedy, JT and Wisch, JK and Dincer, A and Roman, J and Gordon, BA and Handen, B and Benzinger, TLS and Head, E and Mapstone, M and Christian, BT and Tudorascu, DL and Laymon, CL and Hartley, SL and Lao, P and Brickman, AM and Zaman, SH and Ances, BM and , }, title = {Decoding brain structure to stage Alzheimer's disease pathology in Down syndrome.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {e14519}, doi = {10.1002/alz.14519}, pmid = {39807622}, issn = {1552-5279}, support = {//AMED/ ; SG-20-690363-DIAN/ALZ/Alzheimer's Association/United States ; //KHIDI/ ; //DZNE/ ; U19AG032438/AG/NIA NIH HHS/United States ; HI21C0066//KDRC/ ; //FLENI/ ; U19AG068054/AG/NIA NIH HHS/United States ; UF1 AG032438/AG/NIA NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; //Paula and Rodger O. Riney fund/ ; //Daniel J Brennan MD fund/ ; //ISCIII/ ; P01 AG003991/AG/NIA NIH HHS/United States ; NIHR203312//NIHR/ ; R01 AG052550/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) in Down syndrome (DS) is associated with changes in brain structure. It is unknown if thickness and volumetric changes can identify AD stages and if they are similar to other genetic forms of AD.

METHODS: Magnetic resonance imaging scans were collected for 178 DS adults (106 nonclinical, 45 preclinical, and 27 symptomatic). Cortical thickness and subcortical volumes were compared between DS groups and evaluated as a staging metric using receiver operating characteristic analyses. Thickness patterns were compared to those previously reported in autosomal-dominant AD (ADAD).

RESULTS: Decreased parietal and temporal lobe thickness differentiated amyloid positivity (area under the curve [AUC] = 0.83) and impairment (AUC = 0.81), and slightly outperformed subcortical volumes (AUC = 0.8/0.74). Thickness differences in DS were more widespread, severe, and had better discriminative ability than ADAD.

DISCUSSION: Cortical thickness can stage AD pathology in DS. Identification of brain regions affected by AD may aid in tracking disease course and evaluating treatment effects.

HIGHLIGHTS: DSAD is associated with reduced temporal and parietal cortical thickness. DSAD is associated with smaller hippocampal and striatal volumes. Thickness differences can stage DSAD better than other forms of AD. DSAD thickness differences are more extensive and severe than ADAD.}, } @article {pmid39807377, year = {2024}, author = {Irsal, RAP and Gholam, GM and Dwicesaria, MA and Mansyah, TF and Chairunisa, F}, title = {Computational exploration of palmitoyl-protein thioesterase 1 inhibition by Juniperus phoenicea L. for anti-dementia treatment.}, journal = {Journal of Taibah University Medical Sciences}, volume = {19}, number = {6}, pages = {1165-1180}, pmid = {39807377}, issn = {1658-3612}, abstract = {OBJECTIVES: Dementia, a growing concern globally, affects more than 55 million people-a number projected to rise to 152 million by 2050. Current medications target Alzheimer's disease, the most prevalent form of dementia. This study investigated Juniperus phoenicea L., a plant used in traditional Chinese medicine, as a potential inhibitor of palmitoyl-protein thioesterase 1 (PPT1), an enzyme associated with dementia.

METHODS: J. phoenicea phytochemicals were subjected to in silico docking against PPT1 (PDB ID: 1EH5). Docking simulations were performed in YASARA Structure with VINA scoring. Top-ranked ligands were subjected to ADMET analysis (admetlab 2.0, Protox 3.0) and PASS bioactivity prediction. Stability and reactivity were analyzed with DFT calculations (Gaussian 09), and 500 ns MD simulations (YASARA Structure, AMBER 14 force field) to assess protein-ligand complex stability. MM-PBSA was used to calculate binding free energies.

RESULTS: The docking simulations identified amentoflavone (-9.6 kcal/mol) as the top hit, followed by ferruginol and quercetin 3-O-pentoside. Amentoflavone formed the most interactions (19) with PPT1. In silico toxicity analysis predicted amentoflavone and quercetin 3-O-pentoside to be safe, whereas ferruginol violated the Pfizer rule. The PASS server indicated a higher probability of activity for quercetin 3-O-pentoside (0.423) than amentoflavone (0.287) for dementia treatment. DFT calculations revealed similar electronic properties for both ligands, although amentoflavone showed slightly more favorable values. MD simulations demonstrated that amentoflavone, compared with to galantamine, had superior binding stability in the PPT1 binding pocket.

CONCLUSION: This in silico study was aimed at identifying potential inhibitors of PPT1 from J. phoenicea phytochemicals, given that PPT1 is a target for developing new dementia medications. Our findings identified amentoflavone as a promising candidate for further investigation. These findings warrant further research to validate this compound's potential as a PPT1 inhibitor for dementia treatment.}, } @article {pmid39807026, year = {2025}, author = {Li, X and Wang, X and Chen, G and Tian, B}, title = {Application trends of hydrogen-generating nanomaterials for the treatment of ROS-related diseases.}, journal = {Biomaterials science}, volume = {13}, number = {4}, pages = {896-912}, doi = {10.1039/d4bm01450b}, pmid = {39807026}, issn = {2047-4849}, mesh = {*Reactive Oxygen Species/metabolism ; *Hydrogen/chemistry/administration & dosage/pharmacology ; Humans ; *Nanostructures/chemistry ; Animals ; Neoplasms/drug therapy ; Neurodegenerative Diseases/drug therapy/metabolism ; Oxidative Stress/drug effects ; Inflammation/drug therapy ; Antioxidants/chemistry/pharmacology/administration & dosage ; }, abstract = {Reactive oxygen species (ROS) play essential roles in both physiological and pathological processes. Under physiological conditions, appropriate amounts of ROS play an important role in signaling and regulation in cells. However, too much ROS can lead to many health problems, including inflammation, cancer, delayed wound healing, neurodegenerative diseases (such as Parkinson's disease and Alzheimer's disease), and autoimmune diseases, and oxidative stress from excess ROS is also one of the most critical factors in the pathogenesis of cardiovascular and metabolic diseases such as atherosclerosis. Hydrogen gas effectively removes ROS from the body due to its good antioxidant properties, and hydrogen therapy has become a promising gas therapy strategy due to its inherent safety and stability. The combination of nanomaterials can achieve targeted delivery and effective accumulation of hydrogen, and has some ameliorating effects on diseases. Herein, we summarize the use of hydrogen-producing nanomaterials for the treatment of ROS-related diseases and talk about the prospects for the treatment of other ROS-induced disease models, such as acute kidney injury.}, } @article {pmid39806956, year = {2025}, author = {Aundhia, C and Parmar, G and Talele, C and Trivedi, R and Kumari, M and Chudasama, J}, title = {Impact and Significance of Viral Vectors for siRNA Delivery in the Treatment of Alzheimer's Disease.}, journal = {Current pharmaceutical biotechnology}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892010334094241112190337}, pmid = {39806956}, issn = {1873-4316}, abstract = {Alzheimer's disease (AD) remains a major challenge in developing effective treatments due to its complex pathophysiology, including the accumulation of amyloid-beta plaques and tau tangles. Small interfering RNA (siRNA) technology offers promise for targeted gene silencing, but effective delivery to the central nervous system remains a significant obstacle. Viral vectors have emerged as potent delivery vehicles for transporting siRNA to neural tissues. This review explores the utilization of viral vectors for siRNA delivery in AD, focusing on delivery strategies and challenges. We discuss the design and optimization of viral vectors, targeting strategies, and safety considerations. Additionally, we examine recent advancements and prospects for enhancing viral vector-mediated siRNA delivery in AD.}, } @article {pmid39806952, year = {2025}, author = {Li, W and Huang, J and Chen, Z and Zhang, D and He, L and Guo, Y and Zhong, L and Yang, C and Yang, C and Zeng, M and Zhu, J and Cao, Z}, title = {Design, Synthesis, Biological Evaluation and Docking Studies of 2-hydroxy-4-benzyloxy Chalcone Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673328877241113091539}, pmid = {39806952}, issn = {1875-533X}, abstract = {OBJECTIVES: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, but no drugs can cure this disease. Chalcones possess good antioxidant activity, anti-neuroinflammatory activity, neuroprotective effects, inhibitory effects on Aβ aggregation, and Aβ disaggregation ability. Therefore, chalcones are ideal lead compounds, and the discovery of novel anti-AD agent-based chalcones is necessary.

METHODS: Hydroxy groups and aryl benzyl ether groups were introduced into chalcone scaffolds to obtain a series of 2-hydroxyl-4-benzyloxy chalcone derivatives. These derivatives were further synthesized, biologically evaluated, and docked.

RESULTS: Most target derivatives exhibited good anti-AD activities. In particular, compound 11d had excellent inhibitory effects on self-induced Aβ1-42 aggregation (90.8% inhibition rate at 25 μM) and Cu2+ induced Aβ1-42 aggregation (93.4% inhibition rate at 25 μM). In addition, it also exhibited good Aβ1-42 fibril disaggregation ability (64.7% at 25 μM), significant antioxidative activity (ORAC = 2.03 Trolox equivalent), moderate MAO-B inhibition (IC50 = 4.81 μM), selective metal chelation, appropriate BBB permeation, and dramatic anti-neuroinflammatory ability. In addition, compound 11d relieved AD symptoms and protected hippocampal neurons in vivo.

CONCLUSION: Compound 11d is a promising multifunctional anti-Aβ agent.}, } @article {pmid39806490, year = {2025}, author = {Shen, Y and Zhang, X and Liu, S and Xin, L and Xuan, W and Zhuang, C and Chen, Y and Chen, B and Zheng, X and Wu, R and Lin, Y}, title = {CEST imaging combined with [1]H-MRS reveal the neuroprotective effects of riluzole by improving neurotransmitter imbalances in Alzheimer's disease mice.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {20}, pmid = {39806490}, issn = {1758-9193}, support = {240428226498013//Shantou Science and Technology Project/ ; 213769/SNSF_/Swiss National Science Foundation/Switzerland ; 82020108016//National Natural Science Foundation of China/ ; 82071973//National Natural Science Foundation of China/ ; 2023A1515010326//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2022ZDZX2020//Key Research Platform and Project of Guangdong University/ ; }, mesh = {Animals ; *Riluzole/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Neuroprotective Agents/pharmacology ; Mice ; *Mice, Transgenic ; *Glutamic Acid/metabolism ; *gamma-Aminobutyric Acid/metabolism ; Proton Magnetic Resonance Spectroscopy/methods ; Brain/drug effects/metabolism/diagnostic imaging ; Disease Models, Animal ; Male ; Magnetic Resonance Imaging/methods ; Neurotransmitter Agents/metabolism ; }, abstract = {BACKGROUND: The imbalance of glutamate (Glu) and gamma-aminobutyric acid (GABA) neurotransmitter system plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Riluzole is a Glu modulator originally approved for amyotrophic lateral sclerosis that has shown potential neuroprotective effects in various neurodegenerative disorders. However, whether riluzole can improve Glu and GABA homeostasis in AD brain and its related mechanism of action remain unknown. This study utilized chemical exchange saturation transfer (CEST) imaging combined with proton magnetic resonance spectroscopy ([1]H-MRS) to monitor the dynamic changes of Glu and GABA in riluzole-treated AD mice, aiming to evaluate the efficacy and mechanism of riluzole in AD treatment.

METHODS: GluCEST, GABACEST and [1]H-MRS were used to longitudinally monitor Glu and GABA levels in 3xTg AD mice treated with riluzole (12.5 mg/kg/day) or vehicle for 20 weeks. Magnetic resonance measurements were performed at baseline, 6, 12, and 20 weeks post-treatment. Cognitive performance was assessed using the Morris Water Maze (MWM) at baseline, 10, and 20 weeks. At the study endpoint, immunohistochemistry, Nissl staining, and Western blot were used to evaluate the brain pathology, neuronal survival, and protein expression.

RESULTS: GluCEST, GABACEST and [1]H-MRS consistently revealed higher levels of Glu and GABA in the brain of riluzole-treated AD mice compared to untreated controls, which were associated with improvements in spatial learning and memory. The cognitive improvements significantly correlated with the increased GluCEST signals and Glu levels. Immunohistochemistry and Nissl staining demonstrated that riluzole treatment reduced amyloid-beta (Aβ) deposition, tau hyperphosphorylation, GFAP-positive astrocyte activation, and prevented neuronal loss. Moreover, riluzole upregulated the expression of excitatory amino acid transporter 2 (EAAT2), glutamic acid decarboxylase 65/67 (GAD65/67), and glutamine synthetase (GS), suggesting enhanced neurotransmitter metabolism.

CONCLUSIONS: CEST imaging combined with [1]H-MRS demonstrated the effectiveness of riluzole in modulating Glu- and GABA-related changes and improving cognitive function in 3xTg AD mice, potentially through regulating key proteins involved in neurotransmitter metabolism. These findings suggest riluzole as a therapeutic agent for Alzheimer's disease and highlight the utility of multimodal MR imaging in monitoring treatment response and exploring disease mechanisms.}, } @article {pmid39805913, year = {2025}, author = {Sahin, F and Gunel, A and Atasoy, BT and Guler, U and Salih, B and Kuzu, I and Taspinar, M and Cinar, O and Kahveci, S}, title = {Enhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseases.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1165}, pmid = {39805913}, issn = {2045-2322}, mesh = {*Proteasome Endopeptidase Complex/metabolism ; Animals ; Mice ; *Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors ; *Neurodegenerative Diseases/drug therapy/metabolism ; Ketamine/pharmacology/therapeutic use ; Memantine/pharmacology/therapeutic use ; Disease Models, Animal ; Humans ; Male ; Mental Disorders/drug therapy/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Brain/metabolism/drug effects ; }, abstract = {NMDAR antagonists, such as memantine and ketamine, have shown efficacy in treating neurodegenerative diseases and major depression. The mechanism by which these drugs correct the aforementioned diseases is still unknown. Our study reveals that these antagonists significantly enhance 20S proteasome activity, crucial for degrading intrinsically disordered, oxidatively damaged, or misfolded proteins, factors pivotal in neurodegenerative diseases like Alzheimer's and Parkinson's. In our mouse model experiment, ketamine administration notably altered brain synaptic protein profiles within two hours, significantly downregulating proteins strongly associated with Alzheimer's and Parkinson's diseases. Furthermore, the altered proteins exhibited enrichment in terms related to plasticity and potentiation, including retrograde endocannabinoid signaling-a pivotal pathway in both short- and long-term plasticity that may elucidate the long-lasting effects of ketamine in major depression. Via the ubiquitin-independent 20S proteasome pathway (UIPS), these drugs maintain cellular protein homeostasis, which is crucial as proteasome activity declines with age, leading to protein aggregation and disease symptoms. Therefore, these findings hold promise for new treatment options not only for brain diseases but also for other systemic conditions associated with unfolded or misfolded proteins.}, } @article {pmid39805752, year = {2024}, author = {Zhu, FQ and Ma, JY and Zhang, YY and Yu, Y}, title = {[Research progress on mechanisms and pharmacokinetics of ligustilide in treatment of locomotor system diseases].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {49}, number = {24}, pages = {6625-6634}, doi = {10.19540/j.cnki.cjcmm.20240716.701}, pmid = {39805752}, issn = {1001-5302}, mesh = {*4-Butyrolactone/analogs & derivatives/pharmacology/pharmacokinetics/chemistry ; Humans ; Animals ; Drugs, Chinese Herbal/pharmacokinetics/chemistry/pharmacology ; Osteoporosis/drug therapy/metabolism ; Osteoarthritis/drug therapy/metabolism ; Locomotion/drug effects ; Osteosarcoma/drug therapy/metabolism ; }, abstract = {Ligustilide, a phthalide compound extracted from Umbelliferae plants such as Angelica sinensis and Ligusticum chuanxiong, has been proven to possess various pharmacological activities, such as anti-inflammatory, anti-tumor, anti-atherosclerosis, anti-ischemic stroke injury, and anti-Alzheimer's disease properties. In recent years, it has shown great potential, particularly in the treatment of locomotor system diseases. Studies have shown that ligustilide has significant therapeutic effects on various locomotor system diseases, including osteoporosis, osteoarthritis, femoral head necrosis, osteosarcoma, and muscle aging and injury. Its mechanisms of action include enhancing the differentiation ability of osteoblasts(OBs), inhibiting the formation ability of osteoclasts(OCs), downregulating inflammatory factors, promoting the synthesis of extracellular matrix(ECM), improving local blood supply to the femoral head, balancing lipid metabolism, inhibiting the proliferation and migration of osteosarcoma cells, inducing cell cycle arrest, enhancing glucose utilization in skeletal muscle, and regulating autophagy and apoptosis. However, its clinical application is severely limited by drawbacks such as structural instability, poor water solubility, and low bioavailability. Currently, formulation techniques such as dripping pills, micropills, inclusion complexes, and liposomes are being used to improve its stability and water solubility, thereby enhancing its therapeutic efficacy. This article summarized the effects, mechanisms of action, and pharmacokinetics of ligustilide monomers and preparations in the treatment of locomotor system diseases in China and abroad in recent years, aiming to provide reference and guidance for further development and application of ligustilide in this field.}, } @article {pmid39805666, year = {2025}, author = {Ricaurte-Fajardo, A and Ivanidze, J and Zhang, D and Mahmud, M and Yasen, W and Ravdin, L and Pahlajani, S and de Leon, M and Nordvig, AS and Chiang, GC}, title = {Anti-amyloid therapy and cerebral blood flow changes on Magnetic Resonance Imaging: a potential longitudinal biomarker of treatment response?.}, journal = {AJNR. American journal of neuroradiology}, volume = {}, number = {}, pages = {}, doi = {10.3174/ajnr.A8654}, pmid = {39805666}, issn = {1936-959X}, abstract = {Amyloid-targeting therapy has recently become widely available in the U.S. for the treatment of patients with symptomatic mild Alzheimer's disease (AD). At present, there are no biomarkers that have been clinical validated to assess treatment response in routine clinical practice; longitudinal amyloid PET could play a role but is not cost effective. This report presents a case series of six patients with AD, whose amyloid positivity was confirmed by PET or CSF biomarkers, who underwent baseline and longitudinal arterial spin-labeling magnetic resonance imaging (ASL-MR) as part of FDA-mandated, clinical standard-of-care, non-contrast MR monitoring to assess for amyloid-related imaging abnormalities (ARIA). We and others have previously reported that ASL-MR can screen for neurodegenerative disease, as a proxy for FDG-PET, and can be easily added on as a cost-effective, repeatable method to monitor post-therapy changes. This series highlights varied cerebral blood flow (CBF) changes in response to lecanemab therapy. For instance, Cases 1, 3, and 5 showed increased CBF after multiple infusions, with subjective cognitive improvement in Case 1 and improved MoCA scores in Case 3. Case 2 showed improved CBF initially before the 5[th] infusion, but this returned to baseline on the subsequent study, with no cognitive improvement over the course of therapy. Cases 4 and 6 have demonstrated no significant changes in regional CBF thus far on therapy, with cognitive decline in Case 4. This case series underscores the potential utility of ASL-MR as an adjunct sequence to current imaging protocols to monitor treatment response to anti-amyloid therapy.ABBREVIATIONS: ASL-MR= arterial spin-labeling magnetic resonance imaging; MRI= magnetic resonance imaging; CBF= cerebral blood flow; AD= Alzheimer's disease; PET= positron emission tomography; CSF= cerebrospinal fluid; FDG= fluorodeoxyglucose.}, } @article {pmid39805473, year = {2025}, author = {Li, SY and Gong, XY and Ndikuryayo, F and Yang, WC}, title = {The emerging role of oxygen redox in pathological progression of disorders.}, journal = {Ageing research reviews}, volume = {104}, number = {}, pages = {102660}, doi = {10.1016/j.arr.2025.102660}, pmid = {39805473}, issn = {1872-9649}, mesh = {Humans ; *Oxidative Stress/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; *Oxidation-Reduction ; *Disease Progression ; *Mitochondria/metabolism/pathology ; Animals ; Oxygen/metabolism ; Antioxidants/metabolism/therapeutic use ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington disease, pose serious threats to human health, leading to substantial economic burdens on society and families. Despite extensive research, the underlying mechanisms driving these diseases remain incompletely understood, impeding effective diagnosis and treatment. In recent years, growing evidence has highlighted the crucial role of oxidative stress in the pathogenesis of various neurodegenerative diseases. However, there is still a lack of comprehensive reviews that systematically summarize the impact of mitochondrial oxidative stress on neurodegenerative diseases. This review aims to address this gap by summarizing the molecular mechanisms by which mitochondrial oxidative stress promotes the initiation and progression of neurodegenerative disorders. Furthermore, it discusses the potential of antioxidant-based therapeutic strategies for the treatment of these diseases. By shedding light on the role of mitochondrial oxidative stress in neurodegenerative diseases, this review not only serves as a valuable reference for further research on the disease mechanisms, but also offers novel perspectives for the treatment of these disorders.}, } @article {pmid39805463, year = {2025}, author = {Shastri, D and Raorane, CJ and Raj, V and Lee, S}, title = {Human serum albumin-3-amino-1-propanesulfonic acid conjugate inhibits amyloid-β aggregation and mitigates cognitive decline in Alzheimer's disease.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {379}, number = {}, pages = {390-408}, doi = {10.1016/j.jconrel.2025.01.019}, pmid = {39805463}, issn = {1873-4995}, abstract = {Alzheimer's disease (AD) is the most commonly occurring brain disorder, characterized by the accumulation of amyloid-β (Aβ) and tau, subsequently leading to neurocognitive decline. 3-Amino-1-propanesulfonic acid (TPS) and its prodrug, currently under clinical trial III, serve as promising therapeutic agents targeting Aβ pathology by specifically preventing monomer-to-oligomer formation. Inspired by the potency of TPS prodrug, we hypothesized that conjugating TPS with human serum albumin (HSA) could enhance brain delivery and synergistically inhibit Aβ aggregation in mild to moderate AD. Thus, we prepared and extensively characterized HSA-TPS (h-TPS) conjugate using an eco-friendly coupling method. In vitro studies on Aβ aggregation kinetics and AFM imaging revealed significant prevention of Aβ aggregation. Additionally, h-TPS significantly reduced Aβ-induced neurotoxicity and H2O2-mediated reactive oxygen species (ROS) stress in SH-SY5Y cells. Moreover, h-TPS administration improved blood-brain barrier permeability and cellular uptake into neuronal cells as well as showed in vivo uptake inside the brain within 1 h. In vivo studies using an Aβ1-42-induced acute AD rat model exhibited a dose-dependent significant reduction in hippocampal Aβ levels and restoration of declined spatial learning and memory with h-TPS treatment. Overall, findings suggest that h-TPS conjugate might be a promising neuroprotective agent for preventing Aβ aggregation in mild to moderate AD.}, } @article {pmid39805185, year = {2025}, author = {Huang, J and Wu, F and Cao, W and Chen, Y and Yao, Q and Cen, P and Wang, J and Hong, L and Zhang, X and Zhou, R and Jin, C and Tian, M and Zhang, H and Zhong, Y}, title = {Ultrasmall iron-gallic acid coordination polymer nanoparticles for scavenging ROS and suppressing inflammation in tauopathy-induced Alzheimer's disease.}, journal = {Biomaterials}, volume = {317}, number = {}, pages = {123042}, doi = {10.1016/j.biomaterials.2024.123042}, pmid = {39805185}, issn = {1878-5905}, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Gallic Acid/pharmacology/chemistry/therapeutic use ; *Reactive Oxygen Species/metabolism ; *Nanoparticles/chemistry ; *Polymers/chemistry ; *Iron/chemistry/metabolism ; *Inflammation/drug therapy/pathology ; Rats, Sprague-Dawley ; Tauopathies/drug therapy ; Rats ; Male ; tau Proteins/metabolism ; Oxidative Stress/drug effects ; Antioxidants/pharmacology/chemistry ; Humans ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder globally, with no effective treatment available yet. A crucial pathological hallmark of AD is the accumulation of hyperphosphorylated tau protein, which is deteriorated by reactive oxygen species (ROS) and neuroinflammation in AD progression. Thus, alleviation of ROS and inflammation has become a potential therapeutic strategy in many studies. Herein, we reported ultrasmall coordination polymer nanoparticles formed by ferric ions and gallic acid (Fe-GA CPNs), which owned antioxidant and anti-inflammation properties for AD therapeutics. The facilely prepared Fe-GA CPNs exhibited remarkable superoxide dismutase-like, peroxidase-like enzyme activity, and ROS eliminating ability with great water solubility, compared with gallic acid. We demonstrated that Fe-GA CPNs effectively relieved oxidative stress, ameliorated inflammation by modulating microglial polarization towards anti-inflammation phenotype, and reduced hyperphosphorylated tau protein levels. Furthermore, Fe-GA CPNs treatment significantly improved cognitive function in tauopathy-induced AD rats, and achieved a neuroprotective effect against AD pathology. This study highlights the potential of coordination polymer nanoparticles as promising therapeutic candidates for AD and other tau-related neurodegenerative diseases.}, } @article {pmid39804693, year = {2025}, author = {De Silva, U and Madanian, S and Olsen, S and Templeton, JM and Poellabauer, C and Schneider, SL and Narayanan, A and Rubaiat, R}, title = {Clinical Decision Support Using Speech Signal Analysis: Systematic Scoping Review of Neurological Disorders.}, journal = {Journal of medical Internet research}, volume = {27}, number = {}, pages = {e63004}, pmid = {39804693}, issn = {1438-8871}, mesh = {Humans ; *Decision Support Systems, Clinical ; *Nervous System Diseases/physiopathology/diagnosis ; *Speech ; Parkinson Disease/physiopathology ; }, abstract = {BACKGROUND: Digital biomarkers are increasingly used in clinical decision support for various health conditions. Speech features as digital biomarkers can offer insights into underlying physiological processes due to the complexity of speech production. This process involves respiration, phonation, articulation, and resonance, all of which rely on specific motor systems for the preparation and execution of speech. Deficits in any of these systems can cause changes in speech signal patterns. Increasing efforts are being made to develop speech-based clinical decision support systems.

OBJECTIVE: This systematic scoping review investigated the technological revolution and recent digital clinical speech signal analysis trends to understand the key concepts and research processes from clinical and technical perspectives.

METHODS: A systematic scoping review was undertaken in 6 databases guided by a set of research questions. Articles that focused on speech signal analysis for clinical decision-making were identified, and the included studies were analyzed quantitatively. A narrower scope of studies investigating neurological diseases were analyzed using qualitative content analysis.

RESULTS: A total of 389 articles met the initial eligibility criteria, of which 72 (18.5%) that focused on neurological diseases were included in the qualitative analysis. In the included studies, Parkinson disease, Alzheimer disease, and cognitive disorders were the most frequently investigated conditions. The literature explored the potential of speech feature analysis in diagnosis, differentiating between, assessing the severity and monitoring the treatment of neurological conditions. The common speech tasks used were sustained phonations, diadochokinetic tasks, reading tasks, activity-based tasks, picture descriptions, and prompted speech tasks. From these tasks, conventional speech features (such as fundamental frequency, jitter, and shimmer), advanced digital signal processing-based speech features (such as wavelet transformation-based features), and spectrograms in the form of audio images were analyzed. Traditional machine learning and deep learning approaches were used to build predictive models, whereas statistical analysis assessed variable relationships and reliability of speech features. Model evaluations primarily focused on analytical validations. A significant research gap was identified: the need for a structured research process to guide studies toward potential technological intervention in clinical settings. To address this, a research framework was proposed that adapts a design science research methodology to guide research studies systematically.

CONCLUSIONS: The findings highlight how data science techniques can enhance speech signal analysis to support clinical decision-making. By combining knowledge from clinical practice, speech science, and data science within a structured research framework, future research may achieve greater clinical relevance.}, } @article {pmid39804285, year = {2025}, author = {Yildirim, E and Soncu Buyukiscan, E and Akça Kalem, Ş and Gürvit, H}, title = {Reliability of direct-to-home teleneuropsychological assessment: a within-subject design study.}, journal = {The Clinical neuropsychologist}, volume = {}, number = {}, pages = {1-22}, doi = {10.1080/13854046.2025.2451247}, pmid = {39804285}, issn = {1744-4144}, abstract = {Objective: During the COVID-19 pandemic, the need to continue diagnosis and treatment processes, in addition to scientific research, led to a rapid shift towards direct-to-home tele-neuropsychology administrations, the reliability and validity of which had not been clearly established then. This study, therefore, aimed to examine the reliability of direct-to-home tele-neuropsychological assessment (TNP). Method: The sample included 105 cognitively healthy individuals aged between 50-83 years, and 47 patients diagnosed with neurocognitive disorders (mild cognitive impairment and early-stage Alzheimer's type dementia). All participants underwent both face-to-face and teleneuropsychological assessments in a counterbalanced order. Results: The results revealed that performances across measures of attention, working memory, verbal fluency, verbal and visual memory, and visual perception were comparable across assessment modalities. Intraclass correlation coefficients of the tests ranged from .54 to .92. Conclusions: The findings of the study provide support for direct-to-home teleneuropsychological assessment among patients with neurocognitive disorders. Neuropsychological tests relying on verbal administration and independent of motor performance may represent a reliable alternative for this patient group when administered in settings where external distractions or technological limitations are controlled. For cognitively healthy individuals, on the other hand, the reliability of the TNP application is more questionable for memory and some executive function tests and therefore needs further exploration.}, } @article {pmid39803455, year = {2024}, author = {Stephenson, RA and Johnson, KR and Cheng, L and Yang, LG and Root, JT and Gopalakrishnan, J and Shih, HY and Narayan, PS}, title = {Triglyceride metabolism controls inflammation and APOE4 -associated disease states in microglia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.04.11.589145}, pmid = {39803455}, issn = {2692-8205}, abstract = {Microglia modulate their cell state in response to various stimuli. Changes to cellular lipids often accompany shifts in microglial cell state, but the functional significance of these metabolic changes remains poorly understood. In human induced pluripotent stem cell-derived microglia, we observed that both extrinsic activation (by lipopolysaccharide treatment) and intrinsic triggers (the Alzheimer's disease-associated APOE4 genotype) result in accumulation of triglyceride-rich lipid droplets. We demonstrate that lipid droplet accumulation is not simply concomitant with changes in cell state but rather necessary for microglial activation. We discovered that both triglyceride biosynthesis and catabolism are needed for the transcription and secretion of proinflammatory cytokines and chemokines in response to extrinsic stimuli. Additionally, we reveal that triglyceride biosynthesis and catabolism are necessary for the activation-associated phagocytosis of multiple substrates including the disease-associated amyloid-beta peptide. In microglia harboring the Alzheimer's disease risk APOE4 genotype, triglyceride-rich lipid droplets accumulate even in the absence of any external stimuli. Inhibiting triglyceride biosynthesis in APOE4 microglia not only modifies the transcription of immune response genes but also attenuates disease-associated transcriptional states. This work establishes that triglyceride metabolism is necessary for microglia to respond to extrinsic activation. In APOE4 microglia, this metabolic process modulates both immune signaling and a disease-associated transcriptional state. Importantly, our work identifies metabolic pathways that can be used to tune microglial immunometabolism in APOE4- associated disease.}, } @article {pmid39802885, year = {2024}, author = {Buttar, AM and Shaheen, Z and Gumaei, AH and Mosleh, MAA and Gupta, I and Alzanin, SM and Akbar, MA}, title = {Enhanced neurological anomaly detection in MRI images using deep convolutional neural networks.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1504545}, pmid = {39802885}, issn = {2296-858X}, abstract = {INTRODUCTION: Neurodegenerative diseases, including Parkinson's, Alzheimer's, and epilepsy, pose significant diagnostic and treatment challenges due to their complexity and the gradual degeneration of central nervous system structures. This study introduces a deep learning framework designed to automate neuro-diagnostics, addressing the limitations of current manual interpretation methods, which are often time-consuming and prone to variability.

METHODS: We propose a specialized deep convolutional neural network (DCNN) framework aimed at detecting and classifying neurological anomalies in MRI data. Our approach incorporates key preprocessing techniques, such as reducing noise and normalizing image intensity in MRI scans, alongside an optimized model architecture. The model employs Rectified Linear Unit (ReLU) activation functions, the Adam optimizer, and a random search strategy to fine-tune hyper-parameters like learning rate, batch size, and the number of neurons in fully connected layers. To ensure reliability and broad applicability, cross-fold validation was used.

RESULTS AND DISCUSSION: Our DCNN achieved a remarkable classification accuracy of 98.44%, surpassing well-known models such as ResNet-50 and AlexNet when evaluated on a comprehensive MRI dataset. Moreover, performance metrics such as precision, recall, and F1-score were calculated separately, confirming the robustness and efficiency of our model across various evaluation criteria. Statistical analyses, including ANOVA and t-tests, further validated the significance of the performance improvements observed with our proposed method. This model represents an important step toward creating a fully automated system for diagnosing and planning treatment for neurological diseases. The high accuracy of our framework highlights its potential to improve diagnostic workflows by enabling precise detection, tracking disease progression, and supporting personalized treatment strategies. While the results are promising, further research is necessary to assess how the model performs across different clinical scenarios. Future studies could focus on integrating additional data types, such as longitudinal imaging and multimodal techniques, to further enhance diagnostic accuracy and clinical utility. These findings mark a significant advancement in applying deep learning to neuro-diagnostics, with promising implications for improving patient outcomes and clinical practices.}, } @article {pmid39802402, year = {2024}, author = {Maisto, N and Mango, D}, title = {Nose to brain strategy coupled to nano vesicular system for natural products delivery: Focus on synaptic plasticity in Alzheimer's disease.}, journal = {Journal of pharmaceutical analysis}, volume = {14}, number = {12}, pages = {101057}, pmid = {39802402}, issn = {2214-0883}, abstract = {A wide number of natural molecules demonstrated neuroprotective effects on synaptic plasticity defects induced by amyloid-β (Aβ) in ex vivo and in vivo Alzheimer's disease (AD) models, suggesting a possible use in the treatment of this neurodegenerative disorder. However, several compounds, administered parenterally and orally, are unable to reach the brain due to the presence of the blood-brain barrier (BBB) which prevents the passage of external substances, such as proteins, peptides, or phytocompounds, representing a limit to the development of treatment for neurodegenerative diseases, such as AD. The combination of nano vesicular systems, as colloidal systems, and nose to brain (NtB) delivery depicts a new nanotechnological strategy to overtake this limit and to develop new treatment approaches for brain diseases, including the use of natural molecules in combination therapy for AD. Herein, we will provide an updated overview, examining the literature of the last 20 years and using specific keywords that provide evidence on natural products with the ability to restore synaptic plasticity alterations in AD models, and the possible application using safe and non-invasive strategies focusing on nano vesicular systems for NtB delivery.}, } @article {pmid39802364, year = {2025}, author = {Fard, TM and Hosseinzadeh, M and Shokri, M and Almasi-Dooghaee, M and Mirfazeli, FS}, title = {When Stroke Disguises as Dementia: A Case of Missed Cerebral Venous Thrombosis.}, journal = {Clinical case reports}, volume = {13}, number = {1}, pages = {e70038}, pmid = {39802364}, issn = {2050-0904}, abstract = {Cerebrovascular thrombosis is among the most critical medical conditions, making early diagnosis and management crucial. Although some symptoms of cerebrovascular thrombosis are typical and lead to early diagnosis, they can sometimes present with rare and unusual symptoms, complicating the diagnostic process. Given the morbidity and mortality associated with these events, it is important to be aware of unexpected symptoms to diagnose and manage these patients more accurately and rapidly. We report a 74-year-old female initially misdiagnosed with Alzheimer's because of cognitive decline and disorganized speech. Her symptoms did not improve with Alzheimer's treatment. She was reevaluated by a neurologist, and her cognitive test results were impaired. Her brain MRI revealed a previously undetected left transverse sinus cerebral venous thrombosis with subcortical white matter lesions. The patient was managed acutely with subcutaneous enoxaparin and transitioned to oral rivaroxaban, resulting in significant improvement. This case report aimed to draw attention to the pitfalls of diagnosing dementia-like syndromes in the elderly, advocating for a systematic approach to differential diagnosis. It emphasizes that a collaborative effort between psychiatrists, neurologists, radiologists, and other healthcare members is essential for accurate diagnosis and timely intervention, which can significantly alter the management and outcome for the patient.}, } @article {pmid39801712, year = {2025}, author = {Liu, KY and Betts, MJ and Hämmerer, D and Düzel, E and Mather, M and Roiser, JP and Schneider, A and Spottke, A and Rostamzadeh, A and Schott, BH and Rauchmann, BS and Laske, C and Janowitz, D and Spruth, EJ and Ersözlü, E and Lüsebrink, F and Jessen, F and Frommann, I and Kilimann, I and Wiltfang, J and Brustkern, J and Priller, J and Hellman-Regen, J and Buerger, K and Fliessbach, K and Scheffler, K and Kleineidam, L and Stark, M and Ewers, M and Wagner, M and Peters, O and Dechent, P and Perneczky, R and Sodenkamp, S and Hetzer, S and Teipel, S and Glanz, W and Howard, R}, title = {Locus coeruleus signal intensity and emotion regulation in agitation in Alzheimer's disease.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcae457}, pmid = {39801712}, issn = {2632-1297}, abstract = {Hyperphosphorylated tau accumulation is seen in the noradrenergic locus coeruleus from the earliest stages of Alzheimer's disease onwards and has been associated with symptoms of agitation. It is hypothesized that compensatory locus coeruleus-noradrenaline system overactivity and impaired emotion regulation could underlie agitation propensity, but to our knowledge this has not previously been investigated. A better understanding of the neurobiological underpinnings of agitation would help the development of targeted prevention and treatment strategies. Using a sample of individuals with amnestic mild cognitive impairment and probable mild Alzheimer's disease dementia from the German Center for Neurodegenerative Diseases (DZNE)-Longitudinal Cognitive Impairment and Dementia (DELCODE) study cohort (N = 309, aged 67-96 years, 51% female), we assessed cross-sectional relationships between a latent factor representing the functional integrity of an affect-related executive regulation network and agitation point prevalence and severity scores. In a subsample of individuals with locus coeruleus MRI imaging data (N = 37, aged 68-93 years, 49% female), we also investigated preliminary associations between locus coeruleus MRI contrast ratios (a measure of structural integrity, whole or divided into rostral, middle, and caudal thirds) and individual affect-related regulation network factor scores and agitation measures. Regression models controlled for effects of age and clinical disease severity and, for models including resting-state functional MRI connectivity variables, grey matter volume and education years. Agitation point prevalence showed a positive relationship with a latent factor representing the functional integrity (and a negative relationship with a corresponding structural measure) of the affect-related executive regulation network. Locus coeruleus MRI contrast ratios were positively associated with agitation severity (but only for the rostral third, in N = 13) and negatively associated with the functional affect-related executive regulation latent factor scores. Resting-state functional connectivity between a medial prefrontal cortex region and the left amygdala was related to locus coeruleus MRI contrast ratios. These findings implicate the involvement of locus coeruleus integrity and emotion dysregulation in agitation in Alzheimer's disease and support the presence of potential compensatory processes. At the neural level, there may be a dissociation between mechanisms underlying agitation risk per se and symptom severity. Further studies are needed to replicate and extend these findings, incorporating longitudinal designs, measures of autonomic function and non-linear modelling approaches to explore potential causal and context-dependent relationships across Alzheimer's disease stages.}, } @article {pmid39801412, year = {2025}, author = {Yang, M and Zhao, Y and Yu, H and Chen, S and Gao, G and Li, D and Wu, X and Huang, L and Ye, S}, title = {A Multi-Label Deep Learning Model for Detailed Classification of Alzheimer's Disease.}, journal = {Actas espanolas de psiquiatria}, volume = {53}, number = {1}, pages = {89-99}, pmid = {39801412}, issn = {1578-2735}, mesh = {*Alzheimer Disease/classification/diagnosis ; Humans ; *Deep Learning ; Aged ; Female ; Severity of Illness Index ; Male ; }, abstract = {BACKGROUND: Accurate diagnosis and classification of Alzheimer's disease (AD) are crucial for effective treatment and management. Traditional diagnostic models, largely based on binary classification systems, fail to adequately capture the complexities and variations across different stages and subtypes of AD, limiting their clinical utility.

METHODS: We developed a deep learning model integrating a dot-product attention mechanism and an innovative labeling system to enhance the diagnosis and classification of AD subtypes and severity levels. This model processed various clinical and demographic data, emphasizing the most relevant features for AD diagnosis. The approach emphasized precision in identifying disease subtypes and predicting their severity through advanced computational techniques that mimic expert clinical decision-making.

RESULTS: Comparative tests against a baseline fully connected neural network demonstrated that our proposed model significantly improved diagnostic accuracy. Our model achieved an accuracy of 83.1% for identifying AD subtypes, compared to 72.9% by the baseline. In severity prediction, our model reached an accuracy of 83.3%, outperforming the baseline (73.5%).

CONCLUSIONS: The incorporation of a dot-product attention mechanism and a tailored labeling system in our model significantly enhances the accuracy of diagnosing and classifying AD. This improvement highlights the potential of the model to support personalized treatment strategies and advance precision medicine in neurodegenerative diseases.}, } @article {pmid39801125, year = {2025}, author = {Abeywickrama, N and Miraval, MNE and Subramaniam, H and Arshad, Q and Pollard, S and Chauhan, G and Jussab, S and Mukaetova-Ladinska, EB}, title = {Efficacy of music-based intervention for people living with dementia in an inpatient setting: A pilot study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877241307311}, doi = {10.1177/13872877241307311}, pmid = {39801125}, issn = {1875-8908}, abstract = {BACKGROUND: Pharmacological treatment of behavioral and psychological symptoms of dementia is of limited benefit. The addition of non-pharmacological interventions is often essential for optimal symptom control. Music is a viable way to help patients communicate and improve their quality of life.

OBJECTIVE: This study aims to find the most effective way to use music in a busy dementia ward.

METHODS: 17 inpatients (aged 63-93 years) with a clinical diagnosis of Alzheimer's disease and dementia took part over five weeks. Music lyrics presented via free-field speakers were individualized to personal preferences. Instruments (e.g., maracas) were used in some group sessions. We used the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Music in Dementia Assessment Scales (MiDAS) to evaluate patients' behavior before and after musical intervention.

RESULTS: There was a significant difference in mean NPI-Q scores before and after the music intervention. Specifically, Delusion, Motor Disturbances, and Agitation scores were significantly reduced after music intervention. This was accompanied by significant improvements in Interest, Response, and Enjoyment of MiDAS items during specific intervals.

CONCLUSIONS: Clinical professionals can successfully deliver music-based intervention to inpatients with advanced dementia to help manage their behavioral symptoms in the short term. Music-based interventions' use for inpatient wards must be further investigated as an economical and personalized non-pharmacological therapeutic tool for patients with dementia.}, } @article {pmid39800469, year = {2025}, author = {Aye, S and Johansson, G and Hock, C and Lannfelt, L and Sims, JR and Blennow, K and Frederiksen, KS and Graff, C and Molinuevo, JL and Scheltens, P and Palmqvist, S and Schöll, M and Wimo, A and Kivipelto, M and Handels, R and Frölich, L and Zilka, N and Tolar, M and Johannsen, P and Jönsson, L and Winblad, B}, title = {Point of view: Challenges in implementation of new immunotherapies for Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {1}, pages = {100022}, doi = {10.1016/j.tjpad.2024.100022}, pmid = {39800469}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy/therapy/immunology ; *Immunotherapy/methods ; Cost-Benefit Analysis ; }, abstract = {The advancement of disease-modifying treatments (DMTs) for Alzheimer's disease (AD), along with the approval of three amyloid-targeting therapies in the US and several other countries, represents a significant development in the treatment landscape, offering new hope for addressing this once untreatable chronic progressive disease. However, significant challenges persist that could impede the successful integration of this class of drugs into clinical practice. These challenges include determining patient eligibility, appropriate use of diagnostic tools and genetic testing in patient care pathways, effective detection and monitoring of side effects, and improving the healthcare system's readiness by engaging both primary care and dementia specialists. Additionally, there are logistical concerns related to infrastructure, as well as cost-effectiveness and reimbursement issues. This article brings together insights from a diverse group of international researchers and dementia experts and outlines the potential challenges and opportunities, urging all stakeholders to prepare for the introduction of DMTs. We emphasize the need to develop appropriate use criteria, including patient characteristics, specifically for the European healthcare system, to ensure that treatments are administered to the most suitable patients. It is crucial to improve the skills and knowledge of physicians to accurately interpret biomarker results, share decision-making with patients, recognize treatment-related side effects, and monitor long-term treatment. We advocate for investment in patient registries and unbiased follow-up studies to better understand treatment effectiveness, evaluate treatment-related side effects, and optimize long-term treatment. Utilizing amyloid-targeting therapies as a starting point for combination therapies should also be a priority.}, } @article {pmid39800468, year = {2025}, author = {Asken, BM and Cid, REC and Crocco, EA and Armstrong, MJ and Levy, SA and Arias, F and Rosselli, M and Uribe, IV and Barker, WW and Matusz, EF and DeSimone, JC and Wang, WE and Fiala, J and Marsiske, MM and DeKosky, ST and Vaillancourt, DE and Duara, R and Loewenstein, DA and Smith, GE}, title = {Informing etiological heterogeneity of mild cognitive impairment and risk for progression to dementia with plasma p-tau217.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {1}, pages = {100011}, doi = {10.1016/j.tjpad.2024.100011}, pmid = {39800468}, issn = {2426-0266}, support = {U24 AG072122/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Cognitive Dysfunction/blood/diagnosis ; *Disease Progression ; *tau Proteins/blood ; Female ; Male ; Aged ; *Biomarkers/blood ; Alzheimer Disease/blood/diagnosis ; Dementia/blood/diagnosis ; Middle Aged ; Aged, 80 and over ; }, abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a clinical diagnosis representing early symptom changes with preserved functional independence. There are multiple potential etiologies of MCI. While often presumed to be related to Alzheimer's disease (AD), other neurodegenerative and non-neurodegenerative causes are common. Wider availability of relatively non-invasive plasma AD biomarkers, such as p-tau217, can provide invaluable insights into MCI clinico-pathology and the associated implications for symptom etiology, prognosis (e.g., risk for progression to dementia), and treatment options.

OBJECTIVES: The main goal of this study was to evaluate differences between individuals with MCI with and without plasma p-tau217 biomarker evidence of AD (MCIAD+ and MCIAD-) as well as a control group of clinically normal older adults with negative AD biomarkers (CNAD-). We evaluated group differences in demographics, recruitment, clinical scales, fluid biomarkers, and brain imaging. We further probed these factors as independent contributors to symptoms among MCIAD- participants, for whom symptom etiology is most poorly understood. Lastly, in a subset of participants followed longitudinally, we investigated how these factors related to odds of clinical progression to dementia.

DESIGN: We conducted an observational cross-sectional and longitudinal clinical research study. Study groups were compared cross-sectionally on demographics, recruitment, clinical measures, and biomarkers (chi square analyses, analyses of covariance). Contributors to functional changes were evaluated with multiple linear regression. Factors associated with the odds of progression from MCI to dementia longitudinally were evaluated with binary logistic regression.

SETTING: 1Florida Alzheimer's Disease Research Center.

PARTICIPANTS: Cross-sectional analyses included 378 older adults classified as CNAD- (N = 76, age 66.1 ± 7.2, 63.2% female, 23.7% non-Hispanic/White), MCIAD- (N = 198, age 68.9 ± 7.9, 51.5% female, 29.3% non-Hispanic/White), or MCIAD+ (N = 104, age 73.9 ± 7.4, 52.9% female, 49.0% non-Hispanic/White). Longitudinal analyses focused on 207 participants with MCI (68.5% of cross-sectional MCI sample) followed for an average of 3 years.

MEASUREMENTS: Demographics (age, sex, years of education, self-identified race and ethnicity, primary spoken language), National Alzheimer's Coordinating Center-defined clinical phenotypes (Clinically Normal, Impaired - Not MCI, Amnestic MCI, Nonamnestic MCI, Dementia), recruitment source (clinic-based versus community-based), genetics (APOE genotype), functional evaluation (Clinical Dementia Rating scale), global cognition (Mini Mental State Exam), vascular history (Vascular Burden Score), neuropsychiatric symptoms (NPI-Q Total score), plasma biomarkers (ALZPath p-tau217, Quanterix Simoa-based GFAP and NfL), and brain imaging (grey matter volume in select AD-relevant regions of interest, global white matter hyperintensity volume).

RESULTS: Among those with MCI, 104 (34.4%) had plasma biomarker evidence of AD. MCIAD+ participants were more frequently recruited from clinic-based settings than MCIAD- (74.8% vs. 47.5%, p<.001). Over half (51.5%) of MCIAD+ carried at least one APOE e4 allele compared to 26.6% of MCIAD- and 29.4% of CNAD- (p<.001). Both MCIAD+ (p<.001, Cohen's d = 0.93) and MCIAD- (p<.001, d = 0.75) reported more severe neuropsychiatric symptoms than CNAD. MCIAD+ had higher plasma GFAP and NfL than both MCIAD- (GFAP: p<.001, d = 0.88, NfL: p<.001, d = 0.86) and CNAD- (GFAP: p<.001, d = 0.80; NfL: p<.001, d = 0.89). For the AD signature region of interest, MCIAD+ had lower volume than both CNAD- (p<.001, d = 0.78) and MCIAD- (p=.018, d = 0.39). For the hippocampus, both MCIAD+ (p<.001, d = 0.87) and MCIAD- (p<.001, d = 0.64) had lower volume than CNAD-. Longitudinally, older age (OR=1.14 [1.06-1.22], p<.001), higher levels of p-tau217 (OR=10.37 [3.00-35.02], p<.001) and higher neuropsychiatric symptoms (OR=1.19 [1.02-1.39], p=.023) were associated with higher odds of progression to dementia.

CONCLUSIONS: MCI is etiologically heterogeneous. The presence of Alzheimer's pathology defined by elevated plasma p-tau217 in individuals with MCI significantly worsens prognosis. Neuropsychiatric symptoms may contribute to cognitive complaints and risk for progressive decline irrespective of AD pathology. Plasma p-tau217 can inform our understanding of base rates of different MCI phenotypes on a larger scale. As with other AD biomarkers, frequency of elevated plasma p-tau217 and odds of progression to dementia requires careful consideration of recruitment source (clinic- vs. community-based), especially across ethno-racially diverse older adults. Ongoing integration of emerging neurodegenerative disease biomarkers with detailed clinical evaluations will continue to improve treatment specificity and prognosis.}, } @article {pmid39800464, year = {2025}, author = {Naik, RA and Rajpoot, R and Koiri, RK and Bhardwaj, R and Aldairi, AF and Johargy, AK and Faidah, H and Babalghith, AO and Hjazi, A and Alsanie, WF and Alamri, AS and Alhomrani, M and Alsharif, A and Shkodina, A and Singh, SK}, title = {Dietary supplementation and the role of phytochemicals against the Alzheimer's disease: Focus on polyphenolic compounds.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {1}, pages = {100004}, doi = {10.1016/j.tjpad.2024.100004}, pmid = {39800464}, issn = {2426-0266}, mesh = {*Alzheimer Disease/drug therapy/prevention & control ; Humans ; *Phytochemicals/therapeutic use/administration & dosage/pharmacology ; *Polyphenols/therapeutic use/pharmacology/administration & dosage ; *Dietary Supplements ; Oxidative Stress/drug effects ; Animals ; }, abstract = {Alzheimer's disease is a complicated, multifaceted, neurodegenerative illness that places an increasing strain on healthcare systems. Due to increasing malfunction and death of nerve cells, the person suffering from Alzheimer's disease (AD) slowly and steadily loses their memories, cognitive functions and even their personality. Although medications may temporarily enhance memory, there are currently no permanent therapies that can halt or cure this irreversible neurodegenerative process. Nonetheless, fast progress in comprehending the cellular and molecular abnormalities responsible for neuronal degeneration has increased confidence in the development of viable prevention and treatments. All FDA-approved anti-AD medications have merely symptomatic effects and cannot cure the illness. This necessitates the pursuit of alternate treatments. Accumulating data shows that systemic neuroinflammation, oxidative stress and associated mitochondrial dysfunction play crucial roles in the etiology of AD and precede its clinical presentation. Therefore, innovative therapeutic approaches targeting these pathophysiological components of Alzheimer's disease are being explored aggressively in the present scenario. Phytochemicals such as resveratrol, curcumin, quercetin, genistein and catechins are prospective therapies owing to their capacity to alter key AD pathogenetic pathways, such as oxidative stress, neuroinflammation, and mitochondrial dysfunction. The use of new phytochemical delivery strategies would certainly provide the possibility to solve several issues with standard anti-AD medicines. In this review, the roles of phytophenolic compound-based treatment strategies for AD are discussed.}, } @article {pmid39800462, year = {2025}, author = {Farrar, G and Weber, CJ and Rabinovici, GD}, title = {Expert opinion on Centiloid thresholds suitable for initiating anti-amyloid therapy. Summary of discussion at the 2024 spring Alzheimer's Association Research Roundtable.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {1}, pages = {100008}, doi = {10.1016/j.tjpad.2024.100008}, pmid = {39800462}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis ; *Cognitive Dysfunction/drug therapy ; Amyloid beta-Peptides/metabolism ; Positron-Emission Tomography ; Expert Testimony ; }, abstract = {A 24-30 Centiloid (CL) threshold was collectively considered by a group of global dementia experts as a practical and implementable cut-off for anti-amyloid therapy intervention, in Alzheimer's disease patients who have been diagnosed at the mild cognitive impairment or mild dementia stage of their disease. Though additional validation is needed, knowledge of this threshold would be valuable to those involved in diagnosing and treating patients in the new AD care pathways, as well as entry into clinical trials. Therapy monitoring to determine future treatment response and assess amyloid clearance can be accomplished with amyloid PET with some technical details still to be elucidated.}, } @article {pmid39800458, year = {2025}, author = {Siemers, E and Feaster, T and Sethuraman, G and Sundell, K and Skljarevski, V and Cline, EN and Zhang, H and Jerecic, J and Honig, LS and Salloway, S and Sperling, R and Trame, MN and Dodds, MG and Johnson, K}, title = {INTERCEPT-AD, a phase 1 study of intravenous sabirnetug in participants with mild cognitive impairment or mild dementia due to Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {1}, pages = {100005}, doi = {10.1016/j.tjpad.2024.100005}, pmid = {39800458}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Cognitive Dysfunction/drug therapy ; Male ; Aged ; Double-Blind Method ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacokinetics/administration & dosage/adverse effects ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; Dose-Response Relationship, Drug ; }, abstract = {BACKGROUND: Soluble species of multimeric amyloid-beta including globular amyloid-beta oligomers (AβOs) and linear amyloid-beta protofibrils are toxic to neurons. Sabirnetug (ACU193) is a humanized monoclonal antibody, raised against globular species of soluble AβO, that has over 650-fold greater binding affinity for AβOs over monomers and appears to have relatively little binding to amyloid plaque.

OBJECTIVES: To assess safety, pharmacokinetics, and exploratory measures including target engagement, biomarker effects, and clinical efficacy of sabirnetug in participants with early symptomatic Alzheimer's disease (AD; defined as mild cognitive impairment and mild dementia due to AD).

DESIGN: Randomized, double-blind, placebo-controlled, ascending dose first-in-human phase 1 study.

SETTING: Fifteen study centers in the United States.

PARTICIPANTS: Sixty-five participants with early symptomatic AD.

INTERVENTION: Participants received one infusion of sabirnetug 2 mg/kg, 10 mg/kg, 25 mg/kg, 60 mg/kg, or placebo (Part A) or three infusions of sabirnetug 10 mg/kg, 25 mg/kg, 60 mg/kg, or placebo (Part B).

MEASUREMENTS: Safety, tolerability, serum pharmacokinetics, and central target engagement of single and multiple doses of sabirnetug, cerebrospinal fluid (CSF) concentrations of sabirnetug, and amyloid plaque load, as determined by positron emission tomography.

RESULTS: Sabirnetug was generally well tolerated. A larger percentage of participants receiving sabirnetug (56.3%) versus placebo (42.9%) had at least one treatment emergent adverse event, with approximately 29% in each group considered related to study drug. Most events were mild-to-moderate in severity. Of 48 participants given sabirnetug, five developed amyloid related imaging abnormalities - edema/effusion, including one instance that was mildly symptomatic in a participant who had received one dose sabirnetug 60 mg/kg. Notably, none of the six apolipoprotein E Ɛ4 homozygotes who received sabirnetug developed amyloid related imaging abnormalities - edema/effusion or - hemorrhage/hemosiderin deposition. Infusion reactions, such as rash, pain, or erythema, were not frequent (6.3% for sabirnetug versus 0.0% for placebo). Sabirnetug exposure was dose proportional in both serum and CSF. Target engagement, defined as drug bound to AβOs in CSF, was shown to be dose and exposure dependent. Over three months, approximately 25% and 20% reduction in amyloid plaques, respectively, were observed in participants receiving three infusions of sabirnetug 60 mg/kg every four weeks and 25 mg/kg every two weeks.

CONCLUSIONS: The Phase 1 INTERCEPT-AD study provided safety, tolerability, dosing, and target engagement data that supported the design of the ongoing ALTITUDE-AD study (NCT06335173).}, } @article {pmid39800452, year = {2025}, author = {Macfarlane, S and Grimmer, T and Teo, K and O'Brien, TJ and Woodward, M and Grunfeld, J and Mander, A and Brodtmann, A and Brew, BJ and Morris, P and Short, C and Kurrle, S and Lai, R and Bharadwaj, S and Drysdale, P and Sturm, J and Lewis, SJG and Barton, D and Kalafatis, C and Sharif, S and Perry, R and Mannering, N and MacSweeney, JE and Pearson, S and Evans, C and Krishna, V and Thompson, A and Munisamy, M and Bhatt, N and Asher, A and Connell, S and Lynch, J and Rutgers, SM and Dautzenberg, PL and Prins, N and Oschmann, P and Frölich, L and Tacik, P and Peters, O and Wiltfang, J and Henri-Bhargava, A and Smith, E and Pasternak, S and Frank, A and Chertkow, H and Ingram, J and Hsiung, GR and Brittain, R and Tartaglia, C and Cohen, S and Villa, LM and Gordon, E and Jubault, T and Guizard, N and Tucker, A and Kaufmann, WE and Jin, K and Chezem, WR and Missling, CU and Sabbagh, MN}, title = {Blarcamesine for the treatment of Early Alzheimer's Disease: Results from the ANAVEX2-73-AD-004 Phase IIB/III trial.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {1}, pages = {100016}, doi = {10.1016/j.tjpad.2024.100016}, pmid = {39800452}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Double-Blind Method ; Male ; Female ; Aged ; Receptors, sigma ; Sigma-1 Receptor ; Amyloid beta-Peptides ; Middle Aged ; Treatment Outcome ; Aged, 80 and over ; }, abstract = {BACKGROUND: There are no approved oral disease-modifying treatments for Alzheimer's disease (AD).

OBJECTIVES: The objective of this study was to assess efficacy and safety of blarcamesine (ANAVEX®2-73), an orally available small-molecule activator of the sigma-1 receptor (SIGMAR1) in early AD through restoration of cellular homeostasis including autophagy enhancement.

DESIGN: ANAVEX2-73-AD-004 was a randomized, double-blind, placebo-controlled, 48-week Phase IIb/III trial.

SETTING: Multicenter - 52 medical research centers/hospitals in 5 countries.

INTERVENTION: 508 participants with early AD (Stage 3) were randomized to receive either blarcamesine (n = 338) in medium dose group 30 mg or in high dose group 50 mg or placebo (n = 170) oral capsules once daily for 48 weeks. Participants in these groups were offered to enroll into the open-label-extension study ATTENTION-AD, which completed June 2024, ClinicalTrials.gov Identifier NCT04314934.

MEASUREMENTS: The co-primary cognitive and functional outcomes were assessed as change in ADAS-Cog13 and ADCS-ADL from baseline to 48 weeks. The outcomes include the secondary outcome CDR-SB and biomarkers from the A/T/N spectrum, plasma Aβ42/40-ratio and global brain volume changes measured by MRI. All clinical endpoints were analyzed using mixed model for repeated measures (MMRM), plasma biomarker measurements were analyzed by Welch's t-test, and volumetric MRI scans were analyzed by general linear model.

RESULTS: Among 462 randomized participants in the intent-to-treat population (mean age, 73.7 years; 225 [48.7%] women), 338 (73.2%) completed the trial. The co-primary outcome was met under the multiplicity control rule, since the differences in the least-squares mean (LSM) change from baseline to 48 weeks between the prespecified blarcamesine and placebo groups for ADAS-Cog13 was significant at a level of P < 0.025 and for CDR-SB was significant at a level of P < 0.025, while ADCS-ADL did not reach significance at Week 48 (ADAS-Cog13 difference of -2.027 [95% CI -3.522 to -0.533]; P = 0.008; CDR-SB difference of -0.483 [95% CI -0.853 to -0.114]; P = 0.010; ADCS-ADL difference of 0.775 [95%CI -0.874 to 2.423]; P = 0.357). Plasma Aβ42/40-ratio increased significantly with blarcamesine group vs. placebo, (P = 0.048) and whole brain volume loss was significantly decreased (P = 0.002). Participants in the full safety population with ≥1 serious treatment-emergent adverse events (TEAEs) occurred in 56 participants (16.7%) in the blarcamesine and 17 (10.1%) in the placebo group. Common TEAEs included dizziness, which was transient and mostly mild to moderate in severity. One death in the blarcamesine group and 1 in the placebo group were both not considered treatment related.

CONCLUSIONS: Blarcamesine, demonstrating a safety profile with no associated neuroimaging adverse events, significantly slowed clinical progression by 36.3% at 48 weeks with blarcamesine group as well as the individual 30 mg (by 34.6%) and 50 mg (by 38.5%) blarcamesine groups vs. placebo on the prespecified primary cognitive endpoint ADAS-Cog13. The prespecified secondary endpoint CDR-SB, which is used as the sole primary endpoint in recent successful AD drug submissions, is significantly improved at Week 48 with blarcamesine relative to placebo. The findings are supported by biomarkers from the A/T/N spectrum, including plasma Aβ42/40-ratio and reduction of whole brain atrophy. Additionally, the prespecified SIGMAR1 gene variant subgroup analysis confirmed beneficial clinical effect of blarcamesine group through upstream SIGMAR1 activation - subjects with the common SIGMAR1 wild-type gene (excluding carriers of the mutated SIGMAR1 rs1800866 variant) experienced an even greater significant clinical benefit with slowed clinical progression by 49.8% at 48 weeks on the prespecified primary cognitive endpoint ADAS-Cog13. Oral once daily blarcamesine could represent a novel treatment in early AD and be complementary or alternative to anti-beta amyloid drugs.}, } @article {pmid39800193, year = {2025}, author = {Ji, HL and Liu, C and Zhang, JJ and Lin, L and Yang, Q and Yang, Y and Dong, CC and He, YB and Shao, C}, title = {Molecular cloning, expression, and functional analyses of plasmanylethanolamine desaturase gene of Takifugu rubripes.}, journal = {Gene}, volume = {}, number = {}, pages = {149242}, doi = {10.1016/j.gene.2025.149242}, pmid = {39800193}, issn = {1879-0038}, abstract = {The aging population has led to a significant increase in neurodegenerative diseases, particularly Alzheimer's disease (AD), which adversely affects the quality of life and longevity of the elderly. Abnormal plasmalogen metabolism plays a crucial role in the pathogenesis of AD. This study focused ontmem189, a key gene involved in plasmalogen synthesis. We successfully cloned and characterized the open reading frame (ORF) oftmem189, revealing that it encodes a protein consisting of 275 amino acids. Notably,tmem189expression was found to be highest in liver tissues compared to other tissues. We transfected a GFP-fused eukaryotic expression vector into 293 T cells, confirming successful expression oftmem189with increased relative levels. Additionally, liquid chromatography-mass spectrometry (LC-MS) analysis demonstrated thattmem189promotes plasmalogen synthesis in the transfected 293 T cells. Our findings suggest thattmem189could serve as a potential target for the treatment of neurodegenerative diseases, providing new insights into the promotion of plasmalogen synthesis.}, } @article {pmid39799838, year = {2025}, author = {Nair, AC and Kuriakose, BB and Biju, A and Surendran, S and Sudheesh, MS and Lakshmi, PK}, title = {Pharmacological effects of herbal ingredients of Manasamitra vatakam in the treatment of Alzheimer's disease: A review.}, journal = {Journal of Ayurveda and integrative medicine}, volume = {16}, number = {1}, pages = {101041}, pmid = {39799838}, issn = {0975-9476}, abstract = {Multi-targeted drug therapy has received substantial attention for the treatment of diseases of multi-factorial origin, including neurodegenerative and autoimmune diseases. It seems reasonable to argue that the complex pathology of neurodegenerative diseases (ND) cannot be reduced to a single target to modulate a broad range of cellular signaling, associated pathologies, and symptoms. It is this idea that has brought the attention of the scientific world towards phytochemicals and traditional drugs that are notoriously multi-targeted. A systematic study of these formulations and establishing the molecular pathways of individual molecules can lead to a standardized multi-component product that can modulate a broad range of activities on different targets of ND. This could provide an accessible and affordable solution to the significant disease burden of ND. With this idea in mind, a systematic review was carried out on an Ayurvedic product Manasamitra Vatakam (MMV), known to be a neuroprotective formulation and highly effective against Alzheimer's disease. MMV can be a source of phytomolecules for treating neurodegenerative diseases. The multifactorial nature of these diseases makes them suitable candidates for testing phytochemicals due to the inherent multitargeting capabilities of these compounds. The primary objective of this review is to provide a comprehensive understanding of the phytomolecules from MMV that are responsible for its multitargeted effect against neurodegenerative diseases. From the reported literature, it is clear that many phytoconstituents and extracts of the herbal ingredients from MMV have demonstrated their efficacy against AD models. However, the combination of these molecules in AD models has never been tested. Scientific studies should be done to explore the bioactive compounds in the formulation and the druggability of these identified compounds can be evaluated using experimental methods.}, } @article {pmid39799559, year = {2025}, author = {Üremiş, N and Üremiş, MM}, title = {Oxidative/Nitrosative Stress, Apoptosis, and Redox Signaling: Key Players in Neurodegenerative Diseases.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {1}, pages = {e70133}, pmid = {39799559}, issn = {1099-0461}, support = {//This research was supported by the Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (grant number: TUB1)./ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Apoptosis ; *Oxidative Stress ; *Nitrosative Stress ; *Oxidation-Reduction ; Animals ; *Signal Transduction ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases are significant health concerns that have a profound impact on the quality and duration of life for millions of individuals. These diseases are characterized by pathological changes in various brain regions, specific genetic mutations associated with the disease, deposits of abnormal proteins, and the degeneration of neurological cells. As neurodegenerative disorders vary in their epidemiological characteristics and vulnerability of neurons, treatment of these diseases is usually aimed at slowing disease progression. The heterogeneity of genetic and environmental factors involved in the process of neurodegeneration makes current treatment methods inadequate. However, the existence of common molecular mechanisms in the pathogenesis of these diseases may allow the development of new targeted therapeutic strategies. Oxidative and nitrosative stress damages membrane components by accumulating ROS and RNS and disrupting redox balance. This process results in the induction of apoptosis, which is important in the pathogenesis of neurodegenerative diseases through oxidative stress. Studies conducted using postmortem human samples, animal models, and cell cultures have demonstrated that oxidative stress, nitrosative stress, and apoptosis are crucial factors in the development of diseases such as Alzheimer's, Parkinson's, Multiple Sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. The excessive production of reactive oxygen and nitrogen species, elevated levels of free radicals, heightened mitochondrial stress, disturbances in energy metabolism, and the oxidation and nitrosylation of cellular macromolecules are recognized as triggers for neuronal cell death. Challenges in managing and treating neurodegenerative diseases require a better understanding of this field at the molecular level. Therefore, this review elaborates on the molecular mechanisms by which oxidative and nitrosative stress are involved in neuronal apoptosis.}, } @article {pmid39799207, year = {2025}, author = {Shen, D and Agarwal, A and Misra, V and Schelter, B and Shah, D and Shiells, H and Wischik, C}, title = {Obtaining personalized predictions from a randomized controlled trial on Alzheimer's disease.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1671}, pmid = {39799207}, issn = {2045-2322}, mesh = {*Alzheimer Disease/therapy ; Humans ; *Randomized Controlled Trials as Topic ; *Precision Medicine/methods ; Clinical Trials, Phase III as Topic ; }, abstract = {The purpose of this article is to infer patient level outcomes from population level randomized control trials (RCTs). In this pursuit, we utilize the recently proposed synthetic nearest neighbors (SNN) estimator. At its core, SNN leverages information across patients to impute missing data associated with each patient of interest. We focus on two types of missing data: (i) unrecorded outcomes from discontinuing the assigned treatments and (ii) unobserved outcomes associated with unassigned treatments. Data imputation in the former powers and de-biases RCTs, while data imputation in the latter simulates "synthetic RCTs" to predict the outcomes for each patient under every treatment. The SNN estimator is interpretable, transparent, and causally justified under a broad class of missing data scenarios. Relative to several standard methods, we empirically find that SNN performs well for the above two applications using Phase 3 clinical trial data on patients with Alzheimer's Disease. Our findings directly suggest that SNN can tackle a current pain point within the clinical trial workflow on patient dropouts and serve as a new tool towards the development of precision medicine. Building on our insights, we discuss how SNN can further generalize to real-world applications.}, } @article {pmid39798939, year = {2025}, author = {Magavern, EF and Deshmukh, H and Asselin, G and Theusch, E and Trompet, S and Li, X and Noordam, R and Chen, YI and Seeman, TE and Taylor, KD and Post, WS and Tardif, JC and Paul, DS and Benjamin, EJ and Heard-Costa, NL and Vasan, RS and Rotter, JI and Krauss, RM and Jukema, JW and Ridker, PM and Munroe, PB and Caulfield, MJ and Chasman, DI and Dubé, MP and Hitman, GA and Warren, HR and , }, title = {GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study.}, journal = {Pharmacological research}, volume = {212}, number = {}, pages = {107575}, doi = {10.1016/j.phrs.2024.107575}, pmid = {39798939}, issn = {1096-1186}, mesh = {Humans ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use/pharmacology ; *Genome-Wide Association Study ; *Apolipoproteins E/genetics ; *C-Reactive Protein/genetics/metabolism ; Polymorphism, Single Nucleotide ; Female ; Male ; Hepatocyte Nuclear Factor 1-alpha ; }, abstract = {Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response. CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts. Our GWAS identified two genome-wide significant (P < 5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer's and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P < 0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered. The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer's, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment.}, } @article {pmid39798853, year = {2025}, author = {Guan, D and Liang, C and Zheng, D and Liu, S and Luo, J and Cai, Z and Zhang, H and Chen, J}, title = {The role of mitochondrial remodeling in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {183}, number = {}, pages = {105927}, doi = {10.1016/j.neuint.2024.105927}, pmid = {39798853}, issn = {1872-9754}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; Mitochondrial Dynamics/physiology ; Energy Metabolism/physiology ; }, abstract = {Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.}, } @article {pmid39798677, year = {2025}, author = {Meng, X and Zhao, W and Yang, R and Xu, SQ and Wang, SY and Li, MM and Jiang, YK and Hao, ZC and Guan, W and Kuang, HX and Chen, QS and Yao, HY and Yan, JJ and Yang, BY and Liu, Y}, title = {Lignans from Schisandra chinensis (Turcz.) Baill ameliorates cognitive impairment in Alzheimer's disease and alleviates ferroptosis by activating the Nrf2/FPN1 signaling pathway and regulating iron levels.}, journal = {Journal of ethnopharmacology}, volume = {341}, number = {}, pages = {119335}, doi = {10.1016/j.jep.2025.119335}, pmid = {39798677}, issn = {1872-7573}, mesh = {Animals ; *Ferroptosis/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Lignans/pharmacology/therapeutic use/isolation & purification ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; *Schisandra/chemistry ; *Signal Transduction/drug effects ; *Iron/metabolism ; Male ; *Cognitive Dysfunction/drug therapy/metabolism ; Cell Line ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/isolation & purification ; }, abstract = {Schisandra chinensis (Turcz.) Baill (S. chinensis), first recorded in Shennong's Classic of the Materia Medica, is described as a "top grade medicine". As a traditional Chinese medicine of tonifying the kidneys and the brain, S. chinensis is widely used to treat diseases such as amnesia and dementia. Alzheimer's disease (AD) is a neurodegenerative disease, and ferroptosis is one of the essential causes of AD. Although previous studies have suggested that the lignans of S. chinensis (SCL) have neuroprotective effects, it is unclear whether SCL can alleviate AD pathology by inhibiting ferroptosis.

AIM OF THE STUDY: To investigate the effect of SCL on AD caused by ferroptosis and its possible molecular mechanism.

MATERIALS AND METHODS: This study was based on SAMR1/SAMP8 mouse models along with Erastin-induced HT22 cell lines to examine the influence of SCL on ferroptosis in AD. The S. chinensis was extracted via 75% EtOH-H2O and identified by HPLC/UPLC-QTOF-MS. MWM assessed spatial learning, while HE staining, biochemical detection, IHC, and WB analyzed AD pathology and iron metabolism. Mitochondrial changes were evaluated by TEM, and confocal imaging post-SCL treatment analyzed ROS, MMP, and Fe[2+] levels in HT22 cells. IF determined the expression levels and localization of Nrf2 and FPN1. CETSA was deployed to study the interaction between SCL and Nrf2.

RESULTS: Treatment with SCL mitigated cognitive dysfunction and reduced p-Tau as well as neuronal loss in AD model mice. Additionally, the administration of SCL alleviated oxidative stress and maintained relatively intact mitochondrial ridges and membranes, decreased TFR and DMT1 protein expression, and upregulated FTH1. Consistent with the in vivo results, SCL inhibited Erastin-induced ferroptosis in HT22 cells. SCL promoted Nrf2 nuclear translocation and upregulated FPN1, SLC7A11, and GPX4 protein expressions while decreasing FACL4. The improvement of ferroptosis by SCL was associated with the regulation of the Nrf2/FPN1 signaling pathway.

CONCLUSION: The novel discoveries of this study suggest that SCL can suppress ferroptosis in the brains of AD model mice and exerts a partial protective effect against Erastin-induced ferroptosis in HT22 cells, in which the Nrf2/FPN1 signaling pathway plays a crucial role.}, } @article {pmid39798452, year = {2025}, author = {Kumar, V and Jangid, K and Kumar, V and Kumar, N and Mishra, J and Arora, T and Dwivedi, AR and Kumar, P and Bhatti, JS and Parkash, J and Kumar, V}, title = {In vitro and in vivo Investigations of 4-Substituted 2-Phenylquinazoline derivatives as multipotent ligands for the treatment of Alzheimer's disease.}, journal = {Bioorganic chemistry}, volume = {155}, number = {}, pages = {108126}, doi = {10.1016/j.bioorg.2025.108126}, pmid = {39798452}, issn = {1090-2120}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; *Quinazolines/pharmacology/chemistry/chemical synthesis ; *Zebrafish ; Ligands ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; Humans ; *Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Structure-Activity Relationship ; *Acetylcholinesterase/metabolism ; Molecular Structure ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Monoamine Oxidase/metabolism ; Dose-Response Relationship, Drug ; Monoamine Oxidase Inhibitors/pharmacology/chemistry/chemical synthesis ; Peptide Fragments/antagonists & inhibitors/metabolism ; Molecular Docking Simulation ; Reactive Oxygen Species/metabolism ; }, abstract = {The pathology of Alzheimer's disease (AD) is complex due to its multifactorial nature and single targeting drugs proved inefficient. A series of novel 4-N-substituted-2-phenylquinazoline derivatives was designed and synthesized as potential multi-target directed ligands (MTDLs) through dual inhibition of AChE and MAO-B enzymes along with Aβ42 aggregation inhibition for the treatment of AD. Two compounds in the series, VAV-8 and VAV-19 were found to be the most potent inhibitors of both AChE and MAO-B enzymes and moderate inhibitor of Aβ42, with good thermodynamic stability at the binding pocket of the enzymes. Both the ligands showed moderate ROS inhibition and neuroprotection potential and found to be permeable to the blood-brain barrier. Furthermore, VAV-8 was subjected to toxicity evaluation and in vivo investigation using a zebrafish model. In adult zebrafish, VAV-8 (5 μM, and 10 μM) was found to be effective in reducing cognitive deterioration, neurodegeneration, and oxidative stress induced by scopolamine. Thus, these quinazoline derivatives have the potential to be developed as MTDLs for the treatment of Alzheimer's disease.}, } @article {pmid39798400, year = {2025}, author = {Xun, QQ and Zhang, J and Li, YP and Li, Y and Ma, YY and Chen, ZB and Ding, LP and Shi, XL}, title = {Synthesis and biological evaluation of novel pyrrolo[2,3-b]pyridine derivatives as potent GSK-3β inhibitors for treating Alzheimer's disease.}, journal = {European journal of medicinal chemistry}, volume = {285}, number = {}, pages = {117236}, doi = {10.1016/j.ejmech.2025.117236}, pmid = {39798400}, issn = {1768-3254}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Animals ; *Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/metabolism ; *Pyridines/pharmacology/chemical synthesis/chemistry ; *Zebrafish ; Structure-Activity Relationship ; *Pyrroles/pharmacology/chemistry/chemical synthesis ; Mice ; Molecular Structure ; Protein Kinase Inhibitors/pharmacology/chemical synthesis/chemistry ; Dose-Response Relationship, Drug ; Cell Line, Tumor ; }, abstract = {The development of potent glycogen synthase kinase-3β (GSK-3β) inhibitor has been increasingly recognized as the candidate treatment against the multifactorial pathogenic mechanism of Alzheimer's disease (AD). This study prepared various new pyrrolo[2,3-b]pyridine derivatives, evaluated the anti-AD activities and detected the security based on the structure-guided rational design. Our results indicated that many pyrrolo[2,3-b]pyridine derivatives had strong GSK-3β inhibitory activities, particularly compounds 41, 46 and 54, with the half maximal inhibitory concentrations (IC50) of 0.22, 0.26 and 0.24 nM, respectively, and each of them generally possessed GSK-3β selectivity over 24 structurally similar kinases. In addition, further targeting studies at the cellular level revealed that compound 41 increased GSK-3β phosphorylation at Ser9 site dose-dependently for inhibiting GSK-3β activity, therefore inhibiting the hyperphosphorylation of tau protein by decreasing the p-tau-Ser396 abundance. Moreover, 41 up-regulated β-catenin and neurogenesis-related markers (GAP43 and MAP-2), thereby promoting neurite outgrowth of neurons in SH-SY5Y cells. According to the in vitro cells assay, 41 showed the lower cytotoxicity to SH-SY5Y cells with a survival rate of over 70 % at the concentration of 100 μM. In vivo efficacy and acute toxicity experiments showed that, 41 effectively ameliorated the dyskinesia in AlCl3-induced zebrafish AD models and exhibited its low-toxicity nature in C57BL/6 mice. Overall, the pyrrolo[2,3-b]pyridine derivative 41 could serve as a promising GSK-3β inhibitor for treating AD.}, } @article {pmid39797567, year = {2025}, author = {Bhattacharya, K and Bhattacharjee, A and Chakraborty, M and Das, D and Paudel, KR}, title = {From Antipsychotic to Neuroprotective: Computational Repurposing of Fluspirilene as a Potential PDE5 Inhibitor for Alzheimer's Disease.}, journal = {Journal of computational chemistry}, volume = {46}, number = {2}, pages = {e70029}, doi = {10.1002/jcc.70029}, pmid = {39797567}, issn = {1096-987X}, mesh = {*Alzheimer Disease/drug therapy ; *Phosphodiesterase 5 Inhibitors/pharmacology/chemistry ; Humans ; *Neuroprotective Agents/pharmacology/chemistry ; *Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism/chemistry ; *Antipsychotic Agents/pharmacology/chemistry ; *Molecular Docking Simulation ; Molecular Dynamics Simulation ; Drug Repositioning ; Molecular Structure ; }, abstract = {Phosphodiesterase 5 (PDE5) inhibitors have shown great potential in treating Alzheimer's disease by improving memory and cognitive function. In this study, we evaluated fluspirilene, a drug commonly used to treat schizophrenia, as a potential PDE5 inhibitor using computational methods. Molecular docking revealed that fluspirilene binds strongly to PDE5, supported by hydrophobic and aromatic interactions. Molecular dynamics simulations confirmed that the fluspirilene-PDE5 complex is stable and maintains its structural integrity over time. Binding energy calculations further highlighted favorable interactions, indicating that the drug forms a strong and stable bond with PDE5. Additional analyses, including studies of protein dynamics and energy landscape mapping, revealed how the drug interacts dynamically with PDE5, adapting to different conformations and maintaining stability. These findings suggest that fluspirilene may modulate PDE5 activity, potentially offering therapeutic benefits for Alzheimer's disease. This study provides strong evidence for repurposing fluspirilene as a treatment for Alzheimer's and lays the foundation for further experimental and clinical investigations.}, } @article {pmid39796582, year = {2024}, author = {Gentili, V and Schiuma, G and Dilliraj, LN and Beltrami, S and Rizzo, S and Lara, D and Giovannini, PP and Marti, M and Bortolotti, D and Trapella, C and Narducci, M and Rizzo, R}, title = {DAG-MAG-ΒHB: A Novel Ketone Diester Modulates NLRP3 Inflammasome Activation in Microglial Cells in Response to Beta-Amyloid and Low Glucose AD-like Conditions.}, journal = {Nutrients}, volume = {17}, number = {1}, pages = {}, pmid = {39796582}, issn = {2072-6643}, mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Humans ; *Microglia/drug effects/metabolism ; *Inflammasomes/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism ; Cell Line ; Glucose/metabolism ; Ketones/pharmacology ; Cell Survival/drug effects ; Mitochondria/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: A neuroinflammatory disease such as Alzheimer's disease, presents a significant challenge in neurotherapeutics, particularly due to the complex etiology and allostatic factors, referred to as CNS stressors, that accelerate the development and progression of the disease. These CNS stressors include cerebral hypo-glucose metabolism, hyperinsulinemia, mitochondrial dysfunction, oxidative stress, impairment of neuronal autophagy, hypoxic insults and neuroinflammation. This study aims to explore the efficacy and safety of DAG-MAG-ΒHB, a novel ketone diester, in mitigating these risk factors by sustaining therapeutic ketosis, independent of conventional metabolic pathways.

METHODS: We evaluated the intestinal absorption of DAG-MAG-ΒHB and the metabolic impact in human microglial cells. Utilizing the HMC3 human microglia cell line, we examined the compound's effect on cellular viability, Acetyl-CoA and ATP levels, and key metabolic enzymes under hypoglycemia. Additionally, we assessed the impact of DAG-AG-ΒHB on inflammasome activation, mitochondrial activity, ROS levels, inflammation and phagocytic rates.

RESULTS: DAG-MAG-ΒHB showed a high rate of intestinal absorption and no cytotoxic effect. In vitro, DAG-MAG-ΒHB enhanced cell viability, preserved morphological integrity, and maintained elevated Acetyl-CoA and ATP levels under hypoglycemic conditions. DAG-MAG-ΒHB increased the activity of BDH1 and SCOT, indicating ATP production via a ketolytic pathway. DAG-MAG-ΒHB showed remarkable resilience against low glucose condition by inhibiting NLRP3 inflammasome activation.

CONCLUSIONS: In summary, DAG-MAG-ΒHB emerges as a promising treatment for neuroinflammatory conditions. It enhances cellular health under varying metabolic states and exhibits neuroprotective properties against low glucose conditions. These attributes indicate its potential as an effective component in managing neuroinflammatory diseases, addressing their complex progression.}, } @article {pmid39796199, year = {2025}, author = {Zhang, J and Tsui, KC and Lee, HY and Aquili, L and Wong, KH and Kocabicak, E and Temel, Y and Lu, Z and Fung, ML and Kalueff, A and Lim, LW}, title = {Data Mining Approach to Melatonin Treatment in Alzheimer's Disease: New Gene Targets MMP2 and NR3C1.}, journal = {International journal of molecular sciences}, volume = {26}, number = {1}, pages = {}, pmid = {39796199}, issn = {1422-0067}, mesh = {*Alzheimer Disease/drug therapy/genetics/metabolism ; *Melatonin/pharmacology/therapeutic use ; Humans ; *Matrix Metalloproteinase 2/genetics/metabolism ; *Data Mining ; *Protein Interaction Maps ; Gene Regulatory Networks/drug effects ; Gene Ontology ; Signal Transduction/drug effects ; }, abstract = {Melatonin is a hormone released by the pineal gland that regulates the sleep-wake cycle. It has been widely studied for its therapeutic effects on Alzheimer's disease (AD), particularly through the amyloidosis, oxidative stress, and neuroinflammation pathways. Nevertheless, the mechanisms through which it exerts its neuroprotective effects in AD are still largely unknown. Data mining was used to identify potential gene targets that link melatonin's effects to AD pathways, yielding a comprehensive view of the underlying molecular mechanisms. We identified 3397 genes related to AD from DisGeNet and 329 melatonin gene targets from ChEMBL, which revealed 223 overlapping genes and the potential shared pathways. These genes were used to construct a protein-protein interaction (PPI) network comprising 143 nodes and 823 edges, which demonstrated significant PPI enrichment. A cluster analysis highlighted two key clusters centered on MMP2 and NR3C1, with both genes playing crucial roles in steroid hormone signaling, apoptosis, and monoamine neurotransmission. Gene Ontology (GO) enrichment and KEGG pathway analyses further elucidated their involvement in critical pathways, for instance, steroid hormone signaling and apoptosis regulation, significantly influencing AD pathology through mechanisms such as extracellular matrix remodeling, epigenetic modifications, and neuroinflammation. Our findings emphasize MMP2 and NR3C1 as important gene targets for future research on melatonin treatment in AD, paving the way for further investigations into their roles in AD pathophysiology.}, } @article {pmid39796097, year = {2024}, author = {Mohd Murshid, N and Mohd Sahardi, NFN and Makpol, S}, title = {Advancing Alzheimer's Disease Modelling by Developing a Refined Biomimetic Brain Microenvironment for Facilitating High-Throughput Screening of Pharmacological Treatment Strategies.}, journal = {International journal of molecular sciences}, volume = {26}, number = {1}, pages = {}, pmid = {39796097}, issn = {1422-0067}, support = {FRGS/1/2024/SKK10/UKM/01/1//Malaysia Ministry of Higher Education Fundamental Research Grant Scheme/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Brain/metabolism/drug effects/pathology ; *High-Throughput Screening Assays/methods ; Animals ; Biomimetics/methods ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Disease Models, Animal ; Drug Evaluation, Preclinical/methods ; Drug Discovery/methods ; }, abstract = {Alzheimer's disease (AD) poses a significant worldwide health challenge, requiring novel approaches for improved models and treatment development. This comprehensive review emphasises the systematic development and improvement of a biomimetic brain environment to address the shortcomings of existing AD models and enhance the efficiency of screening potential drug treatments. We identify drawbacks in traditional models and emphasise the necessity for more physiologically accurate systems through an in-depth analysis of current literature. This review aims to study the development of an advanced AD model that accurately replicates key AD pathophysiological aspects using cutting-edge biomaterials and microenvironment design. Incorporating biomolecular elements like Tau proteins and beta-amyloid (Aβ) plaques improve the accuracy of illustrating disease mechanisms. The expected results involve creating a solid foundation for high-throughput screening with enhanced scalability, translational significance, and the possibility of speeding up drug discovery. Thus, this review fills the gaps in AD modelling and shows potential for creating precise and efficient drug treatments for AD.}, } @article {pmid39796014, year = {2024}, author = {Ogos, M and Stary, D and Bajda, M}, title = {Recent Advances in the Search for Effective Anti-Alzheimer's Drugs.}, journal = {International journal of molecular sciences}, volume = {26}, number = {1}, pages = {}, pmid = {39796014}, issn = {1422-0067}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Ligands ; Animals ; Plaque, Amyloid/drug therapy/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Drug Design ; }, abstract = {Alzheimer's disease, the most common form of dementia, is characterized by the deposition of amyloid plaques and neurofibrillary tangles in the brain, leading to the loss of neurons and a decline in a person's memory and cognitive function. As a multifactorial disease, Alzheimer's involves multiple pathogenic mechanisms, making its treatment particularly challenging. Current drugs approved for the treatment of Alzheimer's disease only alleviate symptoms but cannot stop the progression. Moreover, these drugs typically target a single pathogenic mechanism, leaving other contributing factors unaddressed. Recent advancements in drug design have led to the development of multi-target-directed ligands (MTDLs), which have gained popularity for their ability to simultaneously target multiple pathogenic mechanisms. This paper focuses on analyzing the activity, mechanism of action, and binding properties of the anti-Alzheimer's MTDLs developed between 2020 and 2024.}, } @article {pmid39795532, year = {2024}, author = {Benredjem, S and Mekhaznia, T and Rawad, A and Turaev, S and Bennour, A and Sofiane, B and Aborujilah, A and Al Sarem, M}, title = {Parkinson's Disease Prediction: An Attention-Based Multimodal Fusion Framework Using Handwriting and Clinical Data.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, pmid = {39795532}, issn = {2075-4418}, abstract = {BACKGROUND: Neurodegenerative diseases (NGD) encompass a range of progressive neurological conditions, such as Alzheimer's disease (AD) and Parkinson's disease (PD), characterised by the gradual deterioration of neuronal structure and function. This degeneration manifests as cognitive decline, movement impairment, and dementia. Our focus in this investigation is on PD, a neurodegenerative disorder characterized by the loss of dopamine-producing neurons in the brain, leading to motor disturbances. Early detection of PD is paramount for enhancing quality of life through timely intervention and tailored treatment. However, the subtle nature of initial symptoms, like slow movements, tremors, muscle rigidity, and psychological changes, often reduce daily task performance and complicate early diagnosis.

METHOD: To assist medical professionals in timely diagnosis of PD, we introduce a cutting-edge Multimodal Diagnosis framework (PMMD). Based on deep learning techniques, the PMMD framework integrates imaging, handwriting, drawing, and clinical data to accurately detect PD. Notably, it incorporates cross-modal attention, a methodology previously unexplored within the area, which facilitates the modelling of interactions between different data modalities.

RESULTS: The proposed method exhibited an accuracy of 96% on the independent tests set. Comparative analysis against state-of-the-art models, along with an in-depth exploration of attention mechanisms, highlights the efficacy of PMMD in PD classification.

CONCLUSIONS: The obtained results highlight exciting new prospects for the use of handwriting as a biomarker, along with other information, for optimal model performance. PMMD's success in integrating diverse data sources through cross-modal attention underscores its potential as a robust diagnostic decision support tool for accurately diagnosing PD.}, } @article {pmid39795159, year = {2024}, author = {Tareen, FK and Catenacci, L and Perteghella, S and Sorrenti, M and Bonferoni, MC}, title = {Carvacrol Essential Oil as a Neuroprotective Agent: A Review of the Study Designs and Recent Advances.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {1}, pages = {}, pmid = {39795159}, issn = {1420-3049}, mesh = {*Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; *Oils, Volatile/therapeutic use/chemistry/pharmacology ; *Cymenes/therapeutic use/pharmacology/chemistry ; Humans ; Animals ; Neurodegenerative Diseases/drug therapy ; }, abstract = {Neurodegenerative diseases were mostly perceived as diseases of ageing populations, but now-a-days, these diseases pose a threat to populations of all age groups despite significant improvements in quality of life. Almost all essential oils (EOs) have been reported to have some neuroprotective abilities and have been used as supplements for good mental health over the centuries. This review highlights the therapeutic potential of one such monoterpene phenolic EO, carvacrol (CV), that has the potential to be used as a main therapeutic intervention for neurodegenerative disorders. Three libraries, Google Scholar, PubMed, and ScienceDirect, were explored for research studies related to the neuroprotective roles of CV. All the research articles from these libraries were sorted out, with the first article tracing back to 2009, and the latest article was published in 2024. The positive effects of CV in the treatment of Alzheimer's and Parkinson's Diseases, multiple sclerosis, ischemia, and behavioural disorders have been supported with evidence. This review not only focused on study designs and the pharmacological pathways taken by CV for neuroprotection but also focused on demographics, illustrating the trend of CV research studies in certain countries and the preferences for the use of in vitro or in vivo models in studies. Our review provides useful evidence about the neuroprotective potential of CV; however, a lack of studies was observed regarding CV encapsulation in proper dosage forms, in particular nanoparticles, which could be further explored for CV delivery to the central nervous system.}, } @article {pmid39794687, year = {2025}, author = {Barisch-Fritz, B and Shah, J and Krafft, J and Geda, YE and Wu, T and Woll, A and Krell-Roesch, J}, title = {Physical activity and the outcome of cognitive trajectory: a machine learning approach.}, journal = {European review of aging and physical activity : official journal of the European Group for Research into Elderly and Physical Activity}, volume = {22}, number = {1}, pages = {1}, pmid = {39794687}, issn = {1813-7253}, abstract = {BACKGROUND: Physical activity (PA) may have an impact on cognitive function. Machine learning (ML) techniques are increasingly used in dementia research, e.g., for diagnosis and risk stratification. Less is known about the value of ML for predicting cognitive decline in people with dementia (PwD). The aim of this study was to use an ML approach to identify variables associated with a multimodal PA intervention that may impact cognitive changes in PwD, i.e., by distinguishing between cognitive decliners and non-decliners.

METHODS: This is a secondary, exploratory analysis using data from a Randomized Controlled Trial that included a 16-week multimodal PA intervention for the intervention group (IG) and treatment as usual for the control group (CG) in nursing homes. Predictors included in the ML models were related to the intervention (e.g., adherence), physical performance (e.g., mobility, balance), and pertinent health-related variables (e.g., health status, dementia form and severity). Primary outcomes were global and domain-specific cognitive performance (i.e., attention/ executive function, language, visuospatial skills, memory) assessed by standardized tests. A Support Vector Machine model was used to perform the classification of each primary outcome into the two classes of decline and non-decline. GridSearchCV with fivefold cross-validation was used for model training, and area under the ROC curve (AUC) and accuracy were calculated to assess model performance.

RESULTS: The study sample consisted of 319 PwD (IG, N = 161; CG, N = 158). The proportion of PwD experiencing cognitive decline, in the different domains measured, ranged from 27-48% in CG, and from 23-49% in IG, with no statistically significant differences and no time*group effects. ML models showed accuracy and AUC values ranging from 40.6-75.6. The strongest predictors of cognitive decline or non-decline were performance of activities of daily living in IG and CG, and adherence and mobility in IG.

CONCLUSIONS: ML models showed moderate performance, suggesting that the selected variables only had limited value for classification, with adherence and performance of activities of daily living appearing to be predictors of cognitive decline. While the study provides preliminary evidence of the potential use of ML approaches, larger studies are needed to confirm our observations and to include other variables in the prediction of cognitive decline, such as emotional health or biomarker abnormalities.}, } @article {pmid39793907, year = {2025}, author = {Zheng, N and Cao, RL and Liu, DY and Liu, P and Zhao, XY and Zhang, SX and Huang, M and Zheng, ZH and Chen, GL and Zou, LB}, title = {OAB-14 alleviates mitochondrial impairment through the SIRT3-dependent mechanism in APP/PS1 transgenic mice and N2a/APP cells.}, journal = {Free radical biology & medicine}, volume = {228}, number = {}, pages = {360-378}, doi = {10.1016/j.freeradbiomed.2025.01.014}, pmid = {39793907}, issn = {1873-4596}, mesh = {Animals ; *Sirtuin 3/metabolism/genetics ; Mice ; *Mitochondria/metabolism/drug effects/pathology ; *Mice, Transgenic ; *Alzheimer Disease/metabolism/drug therapy/pathology/genetics ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Presenilin-1/genetics/metabolism ; Humans ; Hippocampus/metabolism/pathology/drug effects ; Disease Models, Animal ; Mitophagy/drug effects ; DNA, Mitochondrial/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Mitochondrial Dynamics/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive degenerative disease that affects a growing number of elderly individuals worldwide. OAB-14, a novel chemical compound developed by our research group, has been approved by the China Food and Drug Administration (FDA) for clinical trials in patients with AD (approval no. YD-OAB-220210). Previous studies have shown that OAB-14 enhances cognitive function in APP/PS1 transgenic mice and ameliorates abnormal mitochondrial morphology in the hippocampus. Mitochondrial dysfunction is a major risk factor for the development of AD, and maintaining healthy mitochondrial morphology and function is essential for improving the pathological changes and symptoms of AD. However, the protective effects of OAB-14 on mitochondria in AD and the underlying mechanisms remain unclear. This study aimed to investigate the protective effects of OAB-14 on the mitochondria of APP/PS1 transgenic mice and N2a/APP cells. Treatment with OAB-14 restored impaired mitochondrial function, mitochondrial dynamics, mitophagy, and mitochondrial DNA (mtDNA) in APP/PS1 transgenic mice and N2a/APP cells. In APP/PS1 transgenic mice and N2a/APP cells, OAB-14-treated elevated the expression and activity of SIRT3, decreased mitochondrial acetylation, and reduced mitochondrial reactive oxygen species (mtROS) levels. OAB-14 also attenuated mitochondrial acetylation, improved mitochondrial dynamics and mitophagy, and mitigated mtDNA damage in a SIRT3-dependent manner. In addition, OAB-14 suppressed mitochondrial Aβ accumulation in the hippocampus of APP/PS1 transgenic mice. This study provides further clarification on the potential therapeutic mechanisms of OAB-14 in the treatment of AD and lays the groundwork for future drug applications.}, } @article {pmid39793847, year = {2025}, author = {Shinde, U and Balasinor, NH and Ravichandran, V and Kumar, AS and Gunasekaran, VP}, title = {"Extracellular Vesicle DNA: Advances and Applications as a Non-Invasive Biomarker in Disease Diagnosis and Treatment".}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {568}, number = {}, pages = {120125}, doi = {10.1016/j.cca.2025.120125}, pmid = {39793847}, issn = {1873-3492}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers/analysis/metabolism ; *DNA ; Cardiovascular Diseases/diagnosis/metabolism ; Neoplasms/diagnosis/genetics/therapy ; Neurodegenerative Diseases/diagnosis/metabolism ; }, abstract = {Extracellular vesicles (EVs) are nanoscale, membrane-enclosed structures released by cells into the extracellular milieu. These vesicles encapsulate a diverse array of molecular constituents, including nucleic acids, proteins, and lipids, which provide insights into the physiological or pathological conditions of their parent cells. Despite their potential, the study of EV-derived DNA (EV-DNA) has gathered relatively limited attention. This review aims to present a thorough examination of the emerging knowledge surrounding the utility of EV-DNA as a non-invasive biomarker across a spectrum of diseases. The review delves into various mechanisms underlying DNA packaging within EVs and the prevalent methodologies employed for extraction of EV-DNA. The relevance of EV-DNA is assessed across numerous health conditions, notably cancer, cardiovascular diseases, neurodegenerative disorders, infectious diseases, and pregnancy-related complications. The use of EV-DNA for cancer mutation detection has demonstrated remarkable sensitivity and specificity, thereby enhancing both diagnostic accuracy and therapeutic monitoring. In the context of cardiovascular diseases, EV-DNA serves as a predictive marker for events such as myocardial infarctions and shows a correlation with the severity of the disease. With respect to neurodegenerative conditions, including Parkinson's and Alzheimer's, EV-DNA contributes to the understanding of disease mechanisms and progression. Additionally, it plays an essential role in modulating immune tolerance and facilitating communication between maternal and fetal systems. Although there is a pressing need for standardized protocols for EV isolation and DNA analysis to facilitate clinical implementation, the prospect of EV-DNA as a non-invasive biomarker for diagnostic and prognostic purposes across diverse pathological conditions is considerable.}, } @article {pmid39793029, year = {2025}, author = {Tiwari, A and Singh, R and Kumar, S and Sunkaria, A and Jain, A}, title = {From Plant to Pathway: Molecular Mechanisms of Ruscogenin in Preventing Amyloid-Beta Aggregation through Computational and Experimental Approaches.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {3}, pages = {500-512}, doi = {10.1021/acschemneuro.4c00745}, pmid = {39793029}, issn = {1948-7193}, mesh = {*Amyloid beta-Peptides/metabolism ; *Spirostans/pharmacology/chemistry ; Humans ; *Molecular Dynamics Simulation ; *Molecular Docking Simulation ; Alzheimer Disease/metabolism ; Protein Aggregates/drug effects ; Sapogenins/pharmacology/chemistry ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, extracellular amyloid-β (Aβ) plaque accumulation, and intracellular neurofibrillary tangles. Recent efforts to find effective therapies have increased interest in natural compounds with multifaceted effects on AD pathology. This study explores natural compounds for their potential to mitigate AD pathology using molecular docking, ADME screening, and in vitro assays, with ruscogenin─a steroidal sapogenin from Ruscus aculeatus─emerging as a promising candidate. Ruscogenin, known for its antioxidant and anti-inflammatory properties, was investigated for its effects on Aβ aggregation, a critical process in AD progression. In vitro assays demonstrated that ruscogenin inhibits Aβ oligomerization at equimolar and higher molar ratios. Molecular dynamics (MD) simulations further revealed that ruscogenin targets aggregation-prone regions, reducing noncovalent interactions and the solvent-accessible surface area of Aβ aggregates. These effects were concentration-dependent, with higher concentrations yielding optimal inhibition, pointing to a multiphasic behavior in ruscogenin's modulation of Aβ aggregation. This study highlights ruscogenin's potential as a natural therapeutic agent for AD, capable of addressing both oxidative stress and inflammation. The findings lay the groundwork for further exploration of ruscogenin-based interventions and underscore the broader potential of natural compounds in AD treatment strategies.}, } @article {pmid39793012, year = {2025}, author = {Ye, BS and Chang, KW and Kang, S and Jeon, S and Chang, JW}, title = {Repetitive and extensive focused ultrasound-mediated bilateral frontal blood-brain barrier opening for Alzheimer's disease.}, journal = {Journal of neurosurgery}, volume = {}, number = {}, pages = {1-8}, doi = {10.3171/2024.8.JNS24989}, pmid = {39793012}, issn = {1933-0693}, abstract = {OBJECTIVE: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is safe and potentially beneficial in patients with Alzheimer's disease (AD) for the removal of amyloid-beta (Aβ) plaques. However, the optimal BBB opening intervals and number of treatment sessions for clinical improvement remain undefined. Therefore, the aim of this study was to evaluate the safety and benefits of repeated and more extensive BBB opening alone.

METHODS: In this open-label prospective study, 6 patients with AD were enrolled from June 2022 to July 2023. FUS-mediated BBB opening was performed three times at 2-month intervals targeting the bilateral frontal lobes. 18F-florbetaben positron emission tomography (FBB-PET) was performed before the first procedure and after the third procedure. Patients were administered neuropsychological and neuropsychiatric evaluations.

RESULTS: All 6 participants completed the study without any acute treatment-related adverse events. An extensive area of BBB opening (mean 43.1 cm3), more than twice as large as the opening volume (mean 20 cm3) in the authors' previous study, was confirmed by contrast-enhanced MRI. FBB-PET scans demonstrated a 14.9-Centiloid average decrease in Aβ plaques in 4 of the 6 participants (67%), but the Aβ plaques increased in 2 participants after BBB opening, compared with baseline. No significant changes were obser