@article {pmid40026419,
year = {2025},
author = {Marizzoni, M and Tournier, BB and Chevalier, C and Saleri, S and Lathuilière, A and Ceyzériat, K and Paquis, A and Park, R and Troesch, E and Cattaneo, A and Millet, P and Frisoni, GB},
title = {Stools from a human APOEe2 donor reduces amyloid and tau pathology and increases neuroinflammation in a 3xTg AD mouse model.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1539067},
pmid = {40026419},
issn = {1663-4365},
abstract = {BACKGROUND: The mechanisms underlying the protective effect of the e2 variant of the APOE gene (APOEe2) against Alzheimer's disease (AD) have not been elucidated. We altered the microbiota of 3xTgAD mice by fecal microbiota transplantation from a human APOEe2 donor (e2-FMT) and tested the effect of microbiota perturbations on brain AD pathology.

METHODS: FMT of bacteria isolated from stools of untreated 3xTgAD mice (M-FMT) or e2-FMT were transplanted in 15-month-old 3xTgAD mice. FMT was done alone or in combination with antibiotic and proton-pump inhibitor following the Microbiota Transfer Therapy protocol (MTT). The effect of donor (M or e2) and transplantation protocol (FMT or MTT) on hippocampal amyloid, tau pathology and neuroinflammation were assessed at the end of the treatment.

RESULTS: e2-FMT reduced amyloid, and tau pathology as well as increased neuroinflammation as compared with M-FMT. MTT was associated with reduced number of Aβ40+ plaques and tau pathology. Low levels of amyloid were associated with high levels of pro-inflammatory molecules in e2-FMT mice. These associations were partially attenuated by MTT.

CONCLUSION: Bacteria from a human APOEe2 donor reduced AD pathology and increased neuroinflammation in mice suggesting that the gut microbiota may be a mediator of the protective effect of APOEe2.},
}

@article {pmid40025713,
year = {2025},
author = {Bosire, EN and Blackmon, K and Kamau, LW and Udeh-Momoh, C and Sokhi, D and Shah, J and Mbugua, S and Muchungi, K and Meier, I and Narayan, V and Nesic, O and Merali, Z},
title = {Healthcare providers perspectives and perceptions of dementia diagnosis and management at the Aga Khan University Hospital, Nairobi, Kenya.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251320411},
doi = {10.1177/13872877251320411},
pmid = {40025713},
issn = {1875-8908},
abstract = {BACKGROUND: The rising number of older people, including those living with Alzheimer's disease and related dementias (AD/ADRD) in sub-Saharan Africa (SSA) highlights the need for an improved clinical diagnosis and management of the diseases.

OBJECTIVE: To understand and describe healthcare providers' perceptions and practices regarding AD/ADRD diagnosis and care in Kenya, not previously reported.

METHODS: This was an ethnographic study involving observations and semi-structured interviews with healthcare providers working at the Aga Khan University Hospital, Nairobi (AKUHN) Kenya. Twenty-one healthcare providers were purposively recruited and interviewed in English, with the data transcribed verbatim and thematically analysed using Nvivo version 14.

RESULTS: Our findings reveal that AKUHN's dementia diagnostic pathway aligns with universal best practice models and involves multidisciplinary care. Yet, healthcare providers noted that this level of care is not representative of most public hospitals in Kenya, where a lack of diagnostic equipment and trained staff severely limits patient access to timely dementia care. In addition, new medications that can slow AD/ADRD progression, are not readily available in Africa, including Kenya. We also identified barriers to timely diagnosis and care such as: lack of dementia policy and guidelines, limited expertise of healthcare providers, high cost of care, and sociocultural factors, including stigma.

CONCLUSIONS: We emphasize the need for the Kenyan government and relevant stakeholders to develop social and healthcare policies and allocate resources to raise awareness about dementia and combat stigma; train healthcare providers; improve early detection and service delivery through access to diagnostic tools, and establish clear guidelines/protocols for AD/ADRD care.},
}

@article {pmid40024487,
year = {2025},
author = {Roy, H and Maddiboyina, B and Nandi, S and Srungarapati, S and Nayak, BS and Gade, NJ and Anjana, TLNS and Vinayasri, KM and Gummadi, A and Haseena, S},
title = {Enhanced rivastigmine delivery through nanoemulsion and pyridoxine supplementation: An in-vivo study on Alzheimer's disease intervention.},
journal = {Nanomedicine : nanotechnology, biology, and medicine},
volume = {},
number = {},
pages = {102810},
doi = {10.1016/j.nano.2025.102810},
pmid = {40024487},
issn = {1549-9642},
abstract = {Nanoemulsions are nanostructured material and stabilized colloidal in nature evolved as a highly desirable mechanism for the delivery of drugs. Our objective of the study deals with a successful Rivastigmine (RSG) loaded nanoemulsion which can effectively progress the treatment of AD patients. We developed nanoemulsion containing RSG by combining pyridoxine, an essential vitamin supplement for central nervous system development, with linseed oil, which functioned as the lipophilic phase in the nanoemulsion formulation. The optimal formulation having globular size of 202.3 nm was further evaluated by various analytical techniques, including zeta potential analysis, ATR, DSC, and XRD study. The study utilized the Morris Water Maze (MWM) model to assess the cognitive abilities of Long-Evans rats. The current investigation establishes that the utilization of RSG nanoemulsion incorporating blend of linseed oil and pyridoxine which reduced travel distance in animal mode and can be successfully contribute to therapeutic advancements in patients with AD.},
}

@article {pmid40024279,
year = {2025},
author = {López-García, P and Tejero-Ojeda, MM and Morales, MEV and Carrión-Vázquez, M},
title = {Current amyloid inhibitors: therapeutic applications and nanomaterial-based innovations.},
journal = {Progress in neurobiology},
volume = {},
number = {},
pages = {102734},
doi = {10.1016/j.pneurobio.2025.102734},
pmid = {40024279},
issn = {1873-5118},
abstract = {Amyloid proteins have long been in the spotlight for being involved in many degenerative diseases including Alzheimer´s, Parkinson´s or type 2 diabetes, which currently cannot be prevented and for which there is no effective treatment or cure. Here we provide a comprehensive review of inhibitors that act directly on the amyloidogenic pathway (at the monomer, oligomer or fibril level) of key pathological amyloids, focusing on the most representative amyloid-related diseases. We discuss the latest advancements in preclinical and clinical trials, focusing on cutting-edge developments, particularly on nanomaterials-based inhibitors, which offer unprecedented opportunities to address the complexity of protein misfolding disorders and are revolutionizing the landscape of anti-amyloid therapeutics. Notably, nanomaterials are impacting critical areas such as bioavailability, penetrability and functionality of compounds currently used in biomedicine, paving the way for more specific therapeutic solutions tailored to various amyloid-related diseases. Finally, we highlight the window of opportunity that comparative analysis with so-called functional amyloids opens for the development of innovative therapeutic approaches for these devastating diseases.},
}

@article {pmid40024051,
year = {2025},
author = {Periyasamy, TS and Kasivishwanathan, A and Roy, G and Sekar, N and Lakshmanan, H},
title = {Phytocompounds of Senecio candicans as potential acetylcholinesterase inhibitors targeting Alzheimer's disease: A structure-based virtual screening and molecular dynamics simulation study.},
journal = {Computational biology and chemistry},
volume = {117},
number = {},
pages = {108396},
doi = {10.1016/j.compbiolchem.2025.108396},
pmid = {40024051},
issn = {1476-928X},
abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by cognitive decline due to the accumulation of amyloid-beta plaques, neurofibrillary tangles, and decreased acetylcholine levels caused by acetylcholinesterase (AChE) activity. Current treatments using synthetic acetylcholinesterase inhibitors (AChEIs) provide only symptomatic relief and are associated with adverse effects, highlighting the need for safer and more effective alternatives. This study investigates the potential of phytoconstituents from the plant Senecio candicans as natural AChE inhibitors for AD treatment. Using structure-based virtual screening, molecular docking, and molecular dynamics simulations, we evaluated several compounds from Senecio candicans for their binding affinity, stability, and inhibitory activity against AChE. The findings identified compounds such as Estra-135(10)-trien-17β-ol and Vulgarone A, which demonstrated strong binding affinities and stable interactions with AChE, comparable to or surpassing the clinically used drug Donepezil. These phytoconstituents exhibited potential as effective AChEIs with potentially fewer side effects. The results underscore the therapeutic potential of plant-based molecules for drug discovery, offering a promising avenue for developing new treatments for neurodegenerative diseases. Combining phytochemical studies with computational methods provides a powerful approach to identifying novel therapeutic agents. This study suggests that phytoconstituents from Senecio candicans could serve as safer alternatives for managing AD. Further experimental validation and clinical studies are necessary to confirm these compounds' efficacy and safety, paving the way for innovative, plant-derived treatments for Alzheimer's disease.},
}

@article {pmid40023730,
year = {2025},
author = {Cai, Z and Zhong, J and Zhu, G and Zhang, J},
title = {Comparative efficacy and safety of antidiabetic agents in Alzheimer's disease: A network meta-analysis of randomized controlled trials.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100111},
doi = {10.1016/j.tjpad.2025.100111},
pmid = {40023730},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options. Emerging evidence suggests that antidiabetic agents may offer neuroprotective effects by targeting shared pathophysiological mechanisms such as insulin resistance and neuroinflammation. However, the comparative efficacy, and safety of these agents in the treatment of AD remain unclear.

OBJECTIVES: This study aimed to systematically evaluate and compare the efficacy and safety of antidiabetic agents for improving cognitive outcomes, reducing amyloid-β (Aβ) deposition, and managing adverse effects in patients with AD, using a network meta-analysis of randomized controlled trials (RCTs).

METHODS: A comprehensive literature search was conducted across multiple databases to identify RCTs examining the effects of antidiabetic agents in patients with AD. The primary outcomes included cognitive performance (e.g., MMSE scores), Aβ deposition (measured via CSF biomarkers), and safety/adverse effects. A network meta-analysis was performed to integrate direct and indirect evidence, ranking interventions using Surface Under the Cumulative Ranking (SUCRA) probabilities. Risk of bias was assessed using the Cochrane risk-of-bias tool.

RESULTS: A total of 26 studies, involving 7,361 participants, were included in the analysis. The interventions evaluated included insulin detemir (both low-dose and high-dose), liraglutide, exenatide, metformin, and pioglitazone. Both low-dose insulin detemir (mean difference: 2.10, 95 % CI: 1.04 to 3.15), high-dose insulin detemir (mean difference: 1.40, 95 % CI: -0.07 to 2.88), exenatide (mean difference: 1.19, 95 % CI: 0.06 to 2.32), and metformin combined with exenatide (mean difference: 1.06, 95 % CI: -1.68 to 3.80) showed cognitive improvements compared to placebo. Among these, low-dose insulin detemir demonstrated the most significant improvement. In terms of reducing Aβ deposition, metformin ranked highest in effectiveness, with the highest SUCRA score (84.6), followed by high-dose insulin detemir (SUCRA: 54.1). Low-dose insulin detemir (SUCRA: 51.1) also demonstrated moderate efficacy. Low-dose insulin detemir showed some reduction in Aβ deposition (mean difference: -0.31, 95 % CI: -2.82 to 2.20), although statistical significance was limited. Liraglutide exhibited the highest rate of study treatment withdrawal (mean difference: 1.97, 95 % CI: -0.07 to 4.00), while pioglitazone demonstrated the lowest withdrawal rates (mean difference: 0.07, 95 % CI: -0.03 to 0.17).

CONCLUSIONS: This network meta-analysis provides valuable insights into the comparative efficacy and safety of antidiabetic agents in AD. Low-dose insulin detemir demonstrated the most significant cognitive improvement and a moderate effect on reducing Aβ deposition. Metformin emerged as the most effective agent for reducing Aβ levels, though its effects on cognitive function were less pronounced. Safety profiles varied, with liraglutide associated with the highest rate of treatment withdrawals, while pioglitazone demonstrated the lowest incidence of treatment-related discontinuations. These findings support the potential use of antidiabetic agents, particularly insulin detemir, as a therapeutic option for AD, although further studies are needed to confirm their long-term benefits and safety.},
}

@article {pmid40022853,
year = {2025},
author = {Liu, S and Zhang, Z and Gu, Y and Hao, J and Liu, Y and Fu, H and Guo, X and Song, H and Zhang, S and Zhao, Y},
title = {Beyond the eye: A relational model for early dementia detection using retinal OCTA images.},
journal = {Medical image analysis},
volume = {102},
number = {},
pages = {103513},
doi = {10.1016/j.media.2025.103513},
pmid = {40022853},
issn = {1361-8423},
abstract = {Early detection of dementia, such as Alzheimer's disease (AD) or mild cognitive impairment (MCI), is essential to enable timely intervention and potential treatment. Accurate detection of AD/MCI is challenging due to the high complexity, cost, and often invasive nature of current diagnostic techniques, which limit their suitability for large-scale population screening. Given the shared embryological origins and physiological characteristics of the retina and brain, retinal imaging is emerging as a potentially rapid and cost-effective alternative for the identification of individuals with or at high risk of AD. In this paper, we present a novel PolarNet+ that uses retinal optical coherence tomography angiography (OCTA) to discriminate early-onset AD (EOAD) and MCI subjects from controls. Our method first maps OCTA images from Cartesian coordinates to polar coordinates, allowing approximate sub-region calculation to implement the clinician-friendly early treatment of diabetic retinopathy study (ETDRS) grid analysis. We then introduce a multi-view module to serialize and analyze the images along three dimensions for comprehensive, clinically useful information extraction. Finally, we abstract the sequence embedding into a graph, transforming the detection task into a general graph classification problem. A regional relationship module is applied after the multi-view module to explore the relationship between the sub-regions. Such regional relationship analyses validate known eye-brain links and reveal new discriminative patterns. The proposed model is trained, tested, and validated on four retinal OCTA datasets, including 1,671 participants with AD, MCI, and healthy controls. Experimental results demonstrate the performance of our model in detecting AD and MCI with an AUC of 88.69% and 88.02%, respectively. Our results provide evidence that retinal OCTA imaging, coupled with artificial intelligence, may serve as a rapid and non-invasive approach for large-scale screening of AD and MCI. The code is available at https://github.com/iMED-Lab/PolarNet-Plus-PyTorch, and the dataset is also available upon request.},
}

@article {pmid40022313,
year = {2025},
author = {Liu, H and Zhang, Z and Li, X and Zhang, L and Zhao, A and Zheng, Z and Gao, H and You, S and Zhang, J and Sun, J},
title = {Depolymerized peanut skin-derived proanthocyanidins alleviate cognitive dysfunction by inhibiting Aβ42 aggregation in Alzheimer's disease.},
journal = {Food research international (Ottawa, Ont.)},
volume = {203},
number = {},
pages = {115747},
doi = {10.1016/j.foodres.2025.115747},
pmid = {40022313},
issn = {1873-7145},
mesh = {*Proanthocyanidins/pharmacology/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism ; Animals ; *Cognitive Dysfunction/drug therapy ; *Arachis/chemistry ; Rats ; *Peptide Fragments ; Male ; Antioxidants/pharmacology/chemistry ; Rats, Sprague-Dawley ; Disease Models, Animal ; Polymerization ; },
abstract = {Peanut skin proanthocyanidins (PSP) are natural polyphenols with antioxidant properties that mitigate Alzheimer's disease (AD), a complex progressive neurodegenerative disorder whose underlying biological mechanisms includes the aggregation of insoluble amyloid plaques. However, the high degree of polymerization of PSP, extracted using conventional methods, limits its bioavailability. This study established the optimal processes for ultrasound-assisted alkaline depolymerization to produce oligomeric proanthocyanidins (OPSP) from PSP content (2.7 mg/mL), depolymerization temperature (54.8 °C), ultrasonic power (480 W, 28 Hz), ultrasonic duration (28.7 min), and pH (12.1). Under these conditions, the degree of polymerization of the proanthocyanidins decreased from 6.74 to 2.87. Physicochemical characteristics of PSP and OPSP were analyzed. Both PSP and OPSP exhibited shared structural bonding and a repeating 288 Da unit, with Proanthocyanidin A identified as the predominant type. Furthermore, compared with PSP, OPSP demonstrated enhanced stability and antioxidant activity. Using in vitro detection of amyloid-beta (Aβ42) inhibition, this study demonstrated that OPSP exhibited greater inhibition of Aβ42 fibrillogenicity than underpolymerized PSP, and OPSP significantly inhibited Aβ42-induced cytotoxicity. In addition, the effect of OPSP was investigated in a rat model of Alzheimer's disease. The results indicated that OPSP improved the memory performance of AD rats in the water maze and decreased the levels of inflammatory factors IL-6, IL-1β, and TNF-α. Moreover, OPSP ameliorated histopathological changes and reduced Aβ42 plaque deposition in the brains of AD rats. These findings regarding OPSP are anticipated to facilitate high-value utilization of peanut by-products, expand their applications, and provide guidance for the use of OPSP in the development of natural healthcare pharmaceuticals and mitigation and treatment of Alzheimer's disease.},
}

*Proanthocyanidins/pharmacology/chemistry
*Alzheimer Disease/drug therapy/metabolism
*Amyloid beta-Peptides/metabolism
Animals
*Cognitive Dysfunction/drug therapy
*Arachis/chemistry
Rats
*Peptide Fragments
Male
Antioxidants/pharmacology/chemistry
Rats, Sprague-Dawley
Disease Models, Animal
Polymerization

@article {pmid40022172,
year = {2025},
author = {Decaix, T and Bouaziz-Amar, E and Paquet, C and Lilamand, M},
title = {Revisiting ABCB1 polymorphism: a missing piece in Alzheimer's risk and treatment?.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {252},
pmid = {40022172},
issn = {1479-5876},
}

@article {pmid40021385,
year = {2025},
author = {Zeng, J and Zhang, R and Xu, H and Zhang, C and Lu, L},
title = {Integrative single-cell RNA sequencing and mendelian randomization analysis reveal the potential role of synaptic vesicle cycling-related genes in Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100097},
doi = {10.1016/j.tjpad.2025.100097},
pmid = {40021385},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) involves alterations in synaptic vesicle cycling (SVC), which significantly affect neuronal communication and function. Therefore, a thorough investigation into the potential roles of SVC-related genes (SVCRGs) in AD can enhance the identification of critical biomarkers that may influence disease progression and treatment responses.

METHODS: The datasets used in this study were sourced exclusively from public databases. By integrating differential expression analysis with Mendelian randomization (MR), we identified SVCRGs as biomarkers for AD. Functional characterization of these biomarkers was performed, followed by integration into a nomogram. Further investigation of immune infiltration in AD patients and healthy individuals was carried out. Ultimately, the potential cellular mechanisms of AD were explored through single-cell RNA sequencing (scRNA-seq) analysis.

RESULTS: ATP6V1D, ATP6V1G2, CLTB, and NSF were identified as biomarkers, exhibiting a positive correlation with each other and a downregulated expression in AD. These markers were pinpointed as protective factors for AD [odds ratio (OR) < 1, P < 0.05], with potential to reduce the risk of the disease. Integrated into a nomogram, they demonstrated satisfactory diagnostic performance and clinical utility, surpassing the use of single gene. They were collectively enriched in pathways related to "interferon gamma response", "inflammatory response", and "TNFα signaling via NFκB". Additionally, an increase in infiltration of 17 immune cell types in AD was noted, particularly cells associated with neuroinflammation such as activated CD8 T cells and various dendritic cells (DCs), suggesting an inflammatory milieu in AD while also displaying a negative correlation with the biomarkers. The cell types were further annotated, revealing specific expressions of biomarkers and uncovering the heterogeneity of excitatory neurons. A significant reduction in the overall number of excitatory neurons under AD conditions was observed, alongside consistent expression of biomarkers during the developmental stages of excitatory neurons.

CONCLUSION: By using MR, we firstly identified four SVCRGs as protective factors for AD, functioning through pathways associated with mitochondrial dysfunction, chronic inflammation, immune dysregulation, and neuronal damage. These genes had the potential to modulate immune cell infiltration activated in AD patients and exhibited cell-type-specific expression profiles within AD-related cellular contexts. Their findings provide novel insights and valuable references for future research on AD pathogenesis and therapeutic strategies.},
}

@article {pmid40021093,
year = {2025},
author = {Jia, B and Xu, Y and Zhu, X},
title = {Cognitive resilience in Alzheimer's disease: Mechanism and potential clinical intervention.},
journal = {Ageing research reviews},
volume = {106},
number = {},
pages = {102711},
doi = {10.1016/j.arr.2025.102711},
pmid = {40021093},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is a globally recognized neurodegenerative disorder that severely impairs cognitive function and imposes substantial psychological and financial burdens on patients and their families. The hallmark pathological features of AD include progressive neurodegeneration, extracellular beta-amyloid (Aβ) plaque accumulation, and intracellular hyperphosphorylated tau protein tangles. However, recent studies have identified a subset of patients exhibiting cognitive resilience, characterized by a slower cognitive decline or the preservation of high cognitive function despite the presence of AD pathology. Cognitive resilience is influenced by a complex interplay of genetic, environmental, and lifestyle factors. In addition, cognitive resilience contributes to the new perspectives on the diagnosis and personalized treatment of AD. This review aims to provide a comprehensive analysis of current studies on cognitive resilience in AD and to explore future research directions of AD diagnosis and treatment.},
}

@article {pmid40020826,
year = {2025},
author = {Li, Z and Zheng, G and Fang, C and Mei, J and Liang, H and Yang, L},
title = {Comparation of brain-targeting chitosan/sodium tripolyphosphate and ovalbumin/sodium carboxymethylcellulose nanoparticles on dihydromyricetin delivery and cognitive impairment in obesity-related Alzheimer's disease.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {141517},
doi = {10.1016/j.ijbiomac.2025.141517},
pmid = {40020826},
issn = {1879-0003},
abstract = {The brain-gut axis plays an important role in regulating cognitive ability in obesity-related Alzheimer's disease (AD). In this study, we aimed to investigate the correlation between the barrier penetration ability of the DMY nanodelivery system in vivo and the regulation of the gut-brain axis to alleviate cognitive impairment. Brain-targeted peptide (TGN: TGNYKALHPHNG) and DMY loaded chitosan (CS)/sodium tripolyphosphate (TPP) nanoparticles (TGN-DMY-CS/TPP-NPs) and ovalbumin (OVA)/sodium carboxymethylcellulose (CMC) nanoparticles (TGN-DMY-OVA/CMC-NPs) were prepared. TGN-DMY-CS/TPP-NPs demonstrated superior mucus penetration and BBB targeting ability compared to TGN-DMY-OVA/CMC-NPs, while the latter showed notable intestinal accumulation. TGN-DMY-CS/TPP-NPs treatment significantly increased the relative abundance of Alistipes and Rikenellaceae_RC9_gut_group, and TGN-DMY-OVA/CMC-NPs treatment obviously enhanced the relative abundance of Lactobacillus. Furthermore, both nanoparticles alleviated lipid metabolism disorder, oxidative stress, and inflammation in the liver, reduced oxidative stress and neuroinflammation in the brain, inhibited neuronal apoptosis, and enhanced mitochondrial biogenesis and synaptic plasticity in obesity-related AD mice. Despite different mucus penetration and biodistribution, their similar efficacy in improving obesity-related AD is attributed to the gut-brain bidirectional connection.},
}

@article {pmid40020795,
year = {2025},
author = {Li, JQ and Ma, XH and Dai, H and Wang, CC and Zhang, J and Meng, XL},
title = {Isoliensinine ameliorates cognitive dysfunction in AlCl3/D-gal-induced Alzheimer's disease-like mice by inhibiting the calcium signaling pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {119567},
doi = {10.1016/j.jep.2025.119567},
pmid = {40020795},
issn = {1872-7573},
abstract = {The embryos of lotus (Nelumbo nucifera Gaertn.) is a famous traditional Chinese medicine used to treat insomnia, memory decline, and dementia for a long time. However, the underlying material basis and mechanisms of this medicine are still unclear. Isoliensinine (IL) is a major alkaloid derived from lotus embryos. Our previous research has demonstrated that IL can exert strong anti-inflammatory and neuroprotective effects in vitro.

AIM OF THE STUDY: To reveal the underlying therapeutic effect and mechanism of IL on Alzheimer's disease (AD)-like mice induced by AlCl3 and D-galactose (D-gal) in vivo.

MATERIALS AND METHODS: The AD-like mice were modeled by intragastric injection (i.g.) of AlCl3 (20 mg/kg/day) and intraperitoneal injection (i.p.) of D-gal (120 mg/kg/day) for 8 weeks. Starting from the third week, AD-like mice were treated with IL (1, 3, or 10 mg/kg/day; i.p.) for 6 weeks. Cognitive impairment in AD-like mice was evaluated through some behavioral experiments including nest building, open field, novel object recognition, Y maze, and Morris water maze tests. The cortex and hippocampus (DG, CA1, and CA3) regions were analyzed as follows: Neuronal pathological changes and neurofibrillary tangles (NFTs) formation were observed by hematoxylin-eosin (HE) and silver staining, respectively; The production of Aβ plaques and the activation of microglia and astrocytes were detected by immunohistochemistry; The levels of Ca[2+] levels were determined by the ortho-cresolphtalein complexone method. The levels of inflammatory cytokines (TNF-α, IL-6, and IL-1β) were analyzed using the ELISA kits. The expression of CaM, p-CaMKII, Calpain, CDK5, p35/p25, p-Tau, ADAM10, BACE1, PSEN1, APP, Aβ1-42, p-IκBα, and IκBα were evaluated by western blotting.

RESULTS: IL (1, 3, and 10 mg/kg) treatment effectively ameliorated cognitive impairment in AD-like model mice. IL inhibited the decrease of brain index and body weight in AD-like mice and alleviated neuronal damage in the cortex and hippocampus (DG, CA1, and CA3). IL decreased the levels of Ca[2+] and reduce high expression of CaM and Calpain in the cortex and hippocampus of AD-like mice. IL treatment did not affect the expression of CDK5 but inhibited the expression of p-CaMKII and p25/p35, and reduced Tau phosphorylation and NFTs formation. IL also down-regulated the high expression of Aβ1-42 and APP and regulated the expression of APP-cleavage secretase (reducing the expression of BACE1 and PSEN1, while increasing the expression of ADAM10), thereby inhibited the production of Aβ plaques in AD-like mouse brain. Moreover, IL inhibited the phosphorylation and degradation of IκBα, as well as the production of inflammatory cytokines (TNF-α, IL-6, and IL-1β), and prevented the activation of microglia and astrocytes in AD-like mice.

CONCLUSIONS: IL has a significant therapeutic effect on pathological alterations and cognitive impairment in AlCl3 and D-gal-induced AD-like mice, indicating that IL may have the potential to treat AD. The anti-AD activity of IL may be associated with its regulation of the Ca[2+] homeostasis and downstream signaling molecules such as CaM and Calpain.},
}

@article {pmid40020805,
year = {2025},
author = {Wang, C and Hou, T and Shao, X and Wang, C and Wang, X and Guan, P and Wu, Y and Hu, X},
title = {Functionalized carbon dots with guanidine salt ionic liquid regulate oxidative damage and amyloid aggregation.},
journal = {International journal of biological macromolecules},
volume = {306},
number = {Pt 2},
pages = {141531},
doi = {10.1016/j.ijbiomac.2025.141531},
pmid = {40020805},
issn = {1879-0003},
abstract = {An imbalance in the brain microenvironment, involving oxidative stress and β-amyloid (Aβ) accumulation, is thought to be one of the primary characteristics of early Alzheimer's disease (AD). To address the intricate pathophysiology of AD, therapeutic approaches that can concurrently control several diseases in the AD microenvironment are desperately needed. This study created a guanidine salt ionic liquid functionalized carbon dots (CDs@TGM-IL) to mitigate Aβ aggregation-induced cytotoxicity and scavenge reactive oxygen species (ROS) simultaneously. In vitro studies have shown that CDs@TGM-IL can effectively inhibit Aβ42 protein aggregation, disaggregate mature Aβ42 fibrils, and effectively remove ROS. In vivo studies have found that CDs@TGM-IL can cross the blood-brain barrier (BBB) and improve cognitive performance in AD mice. Just as importantly, CDs@TGM-IL has been shown to have unparalleled biocompatibility. This means that CDs@TGM-IL is expected to be a possible treatment for AD.},
}

@article {pmid40019895,
year = {2025},
author = {Park, JM and Tsai, LH},
title = {Innovations in noninvasive sensory stimulation treatments to combat Alzheimer's disease.},
journal = {PLoS biology},
volume = {23},
number = {2},
pages = {e3003046},
pmid = {40019895},
issn = {1545-7885},
mesh = {*Alzheimer Disease/therapy/physiopathology ; Humans ; Animals ; *Brain/physiopathology ; Acoustic Stimulation/methods ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide. There is no known cure for AD, highlighting an urgent need for new, innovative treatments. Recent studies have shed light on a promising, noninvasive approach using sensory stimulation as a potential therapy for AD. Exposing patients to light and sound pulses at a frequency of 40 hertz induces brain rhythms in the gamma frequency range that are important for healthy brain activity. Using this treatment in animal models, we are now beginning to understand the molecular, cellular, and circuit-level changes that underlie improvements in disease pathology, cognition, and behavior. A mechanistic understanding of the basic biology that underlies the 40-hertz treatment will inform ongoing clinical trials that offer a promising avenue of treatment without the side effects and high costs typically associated with pharmacological interventions. Concurrent advancements in neurotechnology that can also noninvasively stimulate healthy brain rhythms are illuminating new possibilities for alternative therapies. Altogether, these noninvasive approaches could herald a new era in treating AD, making them a beacon of hope for patients, families, and caregivers facing the challenges of this debilitating condition.},
}

*Alzheimer Disease/therapy/physiopathology
Humans
Animals
*Brain/physiopathology
Acoustic Stimulation/methods
Disease Models, Animal

@article {pmid40018518,
year = {2025},
author = {Wang, S and Xu, H and Liu, G and Chen, L},
title = {Non-pharmacological treatment of Alzheimer's disease: an update.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1527242},
pmid = {40018518},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impairs memory, cognitive function, and the ability to perform daily tasks. The pathological features of AD include β-amyloid plaques, neurofibrillary tangles, and neuronal loss. Current AD treatments target pathological changes but often fail to noticeably slow disease progression and can cause severe complications, limiting their effectiveness. In addition to therapies targeting the core pathology of AD, a more comprehensive approach may be needed for its treatment. In recent years, non-pharmacological treatments such as physical therapy, exercise therapy, cell therapy, and nanoparticles have shown great potential in mitigating disease progression and alleviating clinical symptoms. This article reviews recent advances in non-pharmacological treatment approaches for AD, highlighting their contributions to AD management and facilitating the exploration of novel therapeutic strategies.},
}

@article {pmid40018516,
year = {2025},
author = {Komaki, S and Amiri, P and Safari, S and Abbasi, E and Ramezani-Aliakbari, F and Golipoor, M and Kourosh-Arami, M and Rashno, M and Komaki, A},
title = {Investigation of protective effects of olanzapine on impaired learning and memory using behavioral tests in a rat model of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1376074},
pmid = {40018516},
issn = {1663-4365},
abstract = {INTRODUCTION: Evidence suggests that oxidative stress plays a critical role in the pathogenesis and progression of Alzheimer's disease (AD). Consequently, antioxidants may mitigate neurotoxicity induced by beta-amyloid (Aβ) and potentially reduce cell death. Previous research has demonstrated that olanzapine (OLZ) possesses antioxidant and neuroprotective properties. In this study, we investigated the protective and therapeutic effects of OLZ on an animal model of AD induced by Aβ using behavioral assessments.

METHODS: Rats were randomly assigned to one of five groups (n = 10 rats per group): a control group, a sham group that received an intracerebrovascular (ICV) injection of phosphate-buffered saline (the solvent for Aβ), an AD group that received an ICV injection of Aβ, an OLZ group that received OLZ via gavage for two months, and an AD + OLZ group that received OLZ for one month before and one month after AD induction.

RESULTS: We used the Elevated Plus Maze (EPM), Novel Object Recognition Test (NORT), Barnes Maze (BM), Passive Avoidance Test (PAT), and Morris Water Maze (MWM) to assess behavioral performance in the experimental rats. Aβ administration impaired cognition and increased anxiety-like behavior. Treatment with OLZ improved cognitive decline and reduced anxiety-like behavior in Aβ-infused rats.

CONCLUSION: Our findings suggest that OLZ can restore cognitive performance and alleviate anxiety-like behavior following Aβ injection. Thus, OLZ may have both preventive and therapeutic potential for AD and could be considered a viable pharmacological option.},
}

@article {pmid40018325,
year = {2025},
author = {Abughofah, Y and Deardorff, R and Vosmeier, A and Hottle, S and Dage, JL and Dempsey, D and Apostolova, LG and Brosch, J and Clark, D and Farlow, M and Foroud, T and Gao, S and Wang, S and Zetterberg, H and Blennow, K and Saykin, AJ and Risacher, SL},
title = {Association between BrainAGE and Alzheimer's disease biomarkers.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {1},
pages = {e70094},
pmid = {40018325},
issn = {2352-8729},
abstract = {INTRODUCTION: The brain age gap estimation (BrainAGE) method uses a machine learning model to generate an age estimate from structural magnetic resonance imaging (MRI) scans. The goal was to study the association of brain age with Alzheimer's disease (AD) imaging and plasma biomarkers.

METHODS: One hundred twenty-three individuals from the Indiana Memory and Aging Study underwent structural MRI, amyloid and tau positron emission tomography (PET), and plasma sampling. The MRI scans were processed using the software program BrainAgeR to receive a "brain age" estimate. Plasma biomarker concentrations were measured, and partial Pearson correlation models were used to evaluate their relationship with brain age gap (BAG) estimation (BrainAGE = chronological age - MRI estimated brain age).

RESULTS: Significant associations between BAG and amyloid and tau levels on PET and in plasma were observed depending on diagnostic categories.

DISCUSSION: These findings suggest that BAG is potentially a biomarker of pathology in AD which can be applied to routine brain imaging.

HIGHLIGHTS: Novel research that uses an artificial intelligence learning tool to estimate brain age.Findings suggest that brain age gap is associated with plasma and positron emission tomography Alzheimer's disease (AD) biomarkers.Differential relationships are seen in different stages of disease (preclinical vs. clinical).Results could play a role in early AD diagnosis and treatment.},
}

@article {pmid40018263,
year = {2024},
author = {Kaser, AN and Mikula, CM and Kiselica, AM},
title = {Technology Assistance in Dementia (Tech-AiD): A Framework for Care in the Digital Age.},
journal = {Journal of health service psychology},
volume = {50},
number = {1},
pages = {37-46},
pmid = {40018263},
issn = {2662-2653},
support = {R01 AG082783/AG/NIA NIH HHS/United States ; U54 AG063546/AG/NIA NIH HHS/United States ; },
abstract = {Recent advances in digital technologies hold promise for supporting aging adults and their care partners as they navigate changes in cognitive and daily functioning associated with Alzheimer's disease and related dementias (ADRD). Commonly owned digital technologies, like smartphones, include features that could help maintain independence and reduce caregiver burden. However, we lack models for successful integration of technologies into treatment of persons with ADRD. We propose the Technology Assistance in Dementia (Tech-AiD) framework for aiding persons with ADRD and their care partners with using digital technologies to reach individualized goals. We discuss how technology use is impacted by a multitude of factors, including severity of cognitive impairment, technology proficiency, and barriers to adequate and equitable care, all of which are further complicated by health disparities. Further, we explore the potential benefits of technology use among patients with ADRD and their care partners, highlighting pertinent clinical and ethical challenges and drawing from evidence-based strategies to promote practical recommendations.},
}

@article {pmid40017464,
year = {2025},
author = {Nguyen, TN and Shalaby, RA and Lee, E and Kim, SS and Ro Kim, Y and Kim, S and Je, HS and Kwon, HS and Chung, E},
title = {Ultrafast optical imaging techniques for exploring rapid neuronal dynamics.},
journal = {Neurophotonics},
volume = {12},
number = {Suppl 1},
pages = {S14608},
pmid = {40017464},
issn = {2329-423X},
abstract = {Optical neuroimaging has significantly advanced our understanding of brain function, particularly through techniques such as two-photon microscopy, which captures three-dimensional brain structures with sub-cellular resolution. However, traditional methods struggle to record fast, complex neuronal interactions in real time, which are crucial for understanding brain networks and developing treatments for neurological diseases such as Alzheimer's, Parkinson's, and chronic pain. Recent advancements in ultrafast imaging technologies, including kilohertz two-photon microscopy, light field microscopy, and event-based imaging, are pushing the boundaries of temporal resolution in neuroimaging. These techniques enable the capture of rapid neural events with unprecedented speed and detail. This review examines the principles, applications, and limitations of these technologies, highlighting their potential to revolutionize neuroimaging and improve the diagnose and treatment of neurological disorders. Despite challenges such as photodamage risks and spatial resolution trade-offs, integrating these approaches promises to enhance our understanding of brain function and drive future breakthroughs in neuroscience and medicine. Continued interdisciplinary collaboration is essential to fully leverage these innovations for advancements in both basic and clinical neuroscience.},
}

@article {pmid40016632,
year = {2025},
author = {Hitt, EM},
title = {Brexpiprazole: A Balance of Risks and Benefits.},
journal = {The Senior care pharmacist},
volume = {40},
number = {3},
pages = {115-122},
doi = {10.4140/TCP.n.2025.115},
pmid = {40016632},
issn = {2639-9636},
mesh = {Humans ; *Quinolones/therapeutic use/adverse effects ; *Thiophenes/therapeutic use/adverse effects/pharmacology ; *Antipsychotic Agents/therapeutic use/adverse effects ; *Alzheimer Disease/drug therapy ; Psychomotor Agitation/drug therapy/etiology ; Risk Assessment ; Aged ; },
abstract = {Alzheimer's disease is the most common cause of dementia. Behavioral and psychological symptoms in dementia (BPSD) are neuropsychiatric signs accompanying dementia that carry a significant impact on prognosis and management. Management of BPSD is challenging because of its complex and multifactorial nature. Historically, no medications were specifically approved for the treatment of BPSD, and any pharmacological use was considered off-label. In May 2023, brexpiprazole was the first and only atypical antipsychotic agent to receive US Food and Drug Administration approval for the treatment of agitation associated with dementia because of Alzheimer's disease. The purposes of this article are to discuss the clinical characteristics of brexpiprazole with a focus on safety and efficacy in older adults, to review the studies that led to the approval for agitation associated with dementia, and to examine its potential place in therapy and impact on patient care. Brexpiprazole is a second-generation antipsychotic with affinity for multiple monoaminergic receptors. Efficacy, safety, and tolerability of brexpiprazole for the treatment of agitation associated with dementia because of Alzheimer's disease was evaluated in two Phase III studies with results suggesting that brexpiprazole has potential to be a safe, effective, and well-tolerated treatment for this indication. Given the individualized and complicated nature of BPSD, brexpiprazole is another option in the treatment landscape that may improve symptoms of agitation but requires careful assessment to ensure benefits outweigh any risks.},
}

Humans
*Quinolones/therapeutic use/adverse effects
*Thiophenes/therapeutic use/adverse effects/pharmacology
*Antipsychotic Agents/therapeutic use/adverse effects
*Alzheimer Disease/drug therapy
Psychomotor Agitation/drug therapy/etiology
Risk Assessment
Aged

@article {pmid40015759,
year = {2025},
author = {Perez-Arce, F and Burke, J and Rabinovich, L and Zhang, Q and Monfared, AAT and Mattke, S},
title = {American's overall and equity-based societal valuation of a disease-modifying Alzheimer's treatment: Results from a discrete choice experiment.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {12},
number = {3},
pages = {100036},
doi = {10.1016/j.tjpad.2024.100036},
pmid = {40015759},
issn = {2426-0266},
mesh = {Humans ; *Alzheimer Disease/economics ; United States ; Male ; Female ; Aged ; Middle Aged ; Choice Behavior ; Ethnic and Racial Minorities ; Health Services Accessibility/economics ; Social Class ; },
abstract = {OBJECTIVES: To estimate Americans' willingness-to-pay (WTP) for universal access to a disease-modifying Alzheimer's disease (AD) treatment with a discrete choice experiment in a nationally representative sample. As part of this experiment, we examined whether providing information about the higher disease burden among minorities and persons of lower socioeconomic status (SES) changes WTP.

METHODS: We conducted an information experiment using the nationally representative Understanding America Study (UAS) panel. Participants were provided with general information about AD and a hypothetical treatment that reduces disease progression by 30 %. Two-thirds of the sample were randomized to receive additional information about the higher prevalence of Alzheimer's among either lower SES groups or racial/ethnic minorities. We measured participants' WTP for making the treatment nationally available as a fixed annual fee and income-proportionate fee. Differences in WTP between those exposed to the additional information and those who were not provide the societal valuation of the equity-enhancing effects of the AD treatment.

RESULTS: Average valuations were $252, $260 and $247 per year, and 0.59 %, 0.59 % and 0.61 % of earned income, for the control, race/ethnicity and SES frames, respectively-all statistically indistinguishable. These average results imply that Americans would be willing to pay $33.7 billion based on the fixed fee and $51.4 billion based on the income-related charge for universal access to an AD treatment annually, but their valuation does not further increase when informed about equity considerations.

CONCLUSIONS: While Americans value universal access to an AD treatment highly, health equity considerations did not significantly alter respondents' WTP.},
}

Humans
*Alzheimer Disease/economics
United States
Male
Female
Aged
Middle Aged
Choice Behavior
Ethnic and Racial Minorities
Health Services Accessibility/economics
Social Class

@article {pmid40015753,
year = {2025},
author = {Ozawa, T and Selzler, KJ and Ball, DE and Deckert, A and MacLeod, T and Corrêa Dos Santos Filho, O and Govia, I and Robinson, JN and Kowa, H and Lopez-Ortega, M and McKean, A and Chambers, W and Smith, SR and Baksh, M and Willis, DR and Fowler, NR and Mattke, S and , },
title = {Effects of the Davos Alzheimer's Collaborative early detection of cognitive impairment program on clinician attitudes, engagement, and confidence.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {12},
number = {3},
pages = {100038},
doi = {10.1016/j.tjpad.2024.100038},
pmid = {40015753},
issn = {2426-0266},
mesh = {Humans ; *Early Diagnosis ; *Attitude of Health Personnel ; *Cognitive Dysfunction/diagnosis ; Male ; Female ; Alzheimer Disease/diagnosis ; Primary Health Care ; United States ; Japan ; Brazil ; Health Personnel/psychology ; Mexico ; Scotland ; },
abstract = {BACKGROUND: The number of people with dementia is expected to grow substantially across the world due to population aging, but cognitive impairment remains undetected and undiagnosed, especially in early stages. Newly available diagnostic tools such as digital cognitive assessments and blood biomarker tests may be well suited to increase the rates of early detection of dementia in primary care.

OBJECTIVES: The objective of the Davos Alzheimer's Collaborative Healthcare System Preparedness (DAC-SP) Early Detection Flagship Program was to improve the rate of early detection of cognitive impairment in primary care and non-specialty settings. We aimed to understand the program's impact on clinician attitudes, engagement, and confidence in diagnosing and managing cognitive impairment.

DESIGN: Survey of participating healthcare professionals before and after the intervention.

SETTING: The DAC Healthcare System Preparedness Early Detection Flagship Program was implemented in seven sites across six countries: Brazil, Jamaica, Japan, Mexico, Scotland, and the United States (2 sites).

PARTICIPANTS: 110 healthcare professionals, including, primary care physicians, specialists (neurologists and psychologists), nurses, nurse practitioners, physician assistants, social workers, and healthcare support workers completed the pre-intervention survey. 68 healthcare professionals completed the post-intervention survey.

INTERVENTION: Participating sites implemented a digital cognitive assessment tool and a blood biomarker test for the Alzheimer's pathology and were trained in the administration of the digital cognitive assessment tool. The intervention was adapted to each site for cultural relevance and operational feasibility.

MEASUREMENTS: Participants completed the General Practitioners Attitude and Confidence Scale for Dementia (GPACS-D), a 15-item scale with three subscales: Attitude to Care (six items), Confidence in Clinical Abilities (six items), and Engagement (three items). In addition to the subscale scores, the total GPACS-D score was reported.

RESULTS: Across all sites, there was a significant increase in the Confidence in Clinical Abilities score from 2.98 (SD = 0.77) pre-intervention to 3.27 (SD = 0.72) post-intervention (p = 0.01), and in the total GPACS-D score from 3.48 (SD = 0.48) to 3.65 (SD = 0.39) (p = 0.01). There were non-significant increases in the Attitude to Care and Engagement scores across all sites.

CONCLUSIONS: The implementation of digital cognitive assessment tools and a blood biomarker test was associated with an increase in healthcare professionals' confidence in diagnosing and managing patients with cognitive impairment in primary care and non-specialty settings. Digital cognitive assessments and blood biomarker tests are promising tools that could be utilized in primary care to increase clinicians' confidence in detecting dementia and lead to timely clinical evaluation, treatment, and referral to supportive resources.},
}

Humans
*Early Diagnosis
*Attitude of Health Personnel
*Cognitive Dysfunction/diagnosis
Male
Female
Alzheimer Disease/diagnosis
Primary Health Care
United States
Japan
Brazil
Health Personnel/psychology
Mexico
Scotland

@article {pmid40015468,
year = {2025},
author = {Gupta, A and Choudhary, P and Ranjan, S and Singh, S},
title = {Exploring the therapeutic potential of Diosgenin as a Semaphorin-4D antagonist against neurodegenerative disorders.},
journal = {Archives of biochemistry and biophysics},
volume = {},
number = {},
pages = {110356},
doi = {10.1016/j.abb.2025.110356},
pmid = {40015468},
issn = {1096-0384},
abstract = {Neurodegenerative disorders represent a significant health challenge for the population, with their mechanisms of action being poorly understood. The development of inhibitory pharmaceuticals has encountered several obstacles, resulting in therapies that lacks the necessary efficacy. Neurodegenerative disorders are marked by a gradual deterioration of neurons, leading to a decline in various functions directed by central nervous system (CNS) including motor and non-motor symptoms. Recent focus has turned towards targeting Sema4D as a potential target for mitigating neuroinflammation and inhibiting demyelination, prevalent in various neurodegenerative disorders like Alzheimer's, Parkinson's, Huntington's, multiple sclerosis, etc. But despite the efforts the treatment options developed poses a major hinderance in terms of side effects. An effective answer to this is Ayurvedic phytochemicals. Phytochemicals of the Piperaceae family have been known to reverse the adversities caused by neurodegeneration. In pursuit of effective interventions, this study has conducted In-silico and In-vitro studies to evaluate the efficacy of Piper nigrum and Piper betle bioactive phytochemicals as antagonists against Sema4D. Among these, Diosgenin has emerged with notable promise, demonstrating a remarkable binding affinity of -8.84 kcal/mol with Sema4D. Molecular dynamics simulations (RMSF, RMSD, PCA, SASA, FEL, etc.) have further underscored its stability, exhibiting a consistent complex structure over 100 ns. In addition to its favourable binding properties, Diosgenin has exhibited compelling effects In-vitro. It's not only enhanced cellular viability and proliferation but also exerts protective effects against oxidative stress-induced injury in PC12 cells. These findings suggest Diosgenin's potential as a therapeutic agent against Sema4D, offering a promising avenue in the battle against neurodegenerative diseases. However, further studies are required to elucidate its precise molecular mechanisms, assess its bioavailability and toxicity in vivo, and validate its therapeutic efficacy in animal models and clinical settings.},
}

@article {pmid40015072,
year = {2025},
author = {Daksh, R and Mathew, MS and Bosco, AM and Sojan, C and Tom, AA and Bojja, SL and Nampoothiri, M},
title = {The role of exosomes in diagnosis, pathophysiology, and management of Alzheimer's Disease.},
journal = {Biochemical and biophysical research communications},
volume = {754},
number = {},
pages = {151526},
doi = {10.1016/j.bbrc.2025.151526},
pmid = {40015072},
issn = {1090-2104},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder associated with impaired cognitive function and memory loss. Currently, available therapeutics can effectively alleviate the symptoms of AD, but there is a lack of treatment to halt the progression of the disease. In recent years, exosomes have gained much attention due to their involvement in various neurological disorders. Exosomes are small extracellular vesicles comprising lipids, proteins, DNA, non-coding RNA, and mRNAs, can carry various therapeutic molecules, and are potential drug delivery vehicles. Exosomes are known as a double-edged sword due to their involvement in both the pathogenesis and management of AD. This review explores the function of exosomes in the pathophysiology, treatment, and diagnosis of AD, also emphasizing their potential as a targeted drug delivery carrier to the brain. This review seeks to provide novel perspectives to understand better the onset, targeted treatment, and diagnosis of AD using exosomes.},
}

@article {pmid40014257,
year = {2025},
author = {Uvarajan, D and Gnanarajan, R and Karuppusamy, PA and Ravichandran, N and Govindasamy, C and Vellingiri, B and Narayanaswamy, A and Wang, W},
title = {Neuroprotective Effects of Berberine Chloride Against the Aluminium Chloride-Induced Alzheimer's Disease in Zebra Fish Larvae.},
journal = {Molecular biotechnology},
volume = {},
number = {},
pages = {},
pmid = {40014257},
issn = {1559-0305},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease distinguished by cognitive and memory deficits. A lack of memory, cognition, and other forms of cognitive dissonance characterizes AD, which affects approximately 50 million people worldwide. This study aimed to identify the neuroprotective effects of berberine chloride (BC) against aluminium chloride (AlCl3)-induced AD in zebrafish larvae by inhibiting oxidative stress and neuroinflammation. BC toxicity was assessed by evaluating survival rates, malformations, and heart rates in zebrafish larvae following treatment with varying concentrations of BC. This study elucidates the mechanisms of BC through an extensive range of biochemical assays, behavioral testing, and molecular docking analysis. The developmental toxicity assessment of BC indicated that doses up to 40 μM did not cause any developmental abnormalities until 96 h post fertilization. The LC50 value of BC in zebrafish larvae was found to be 50.16 μM. The biochemical and behavioral changes induced by AlCl3 in zebrafish larvae were significantly mitigated by BC treatment. Our findings demonstrate that BC can reduce total cholesterol and triglyceride levels in AlCl3-induced AD zebrafish larvae. Our molecular docking results indicated that BC significantly interacted with the ABCA1 protein, suggesting that BC may act as an ABCA1 agonist. Based on our results, it can be concluded that BC may serve as an effective therapeutic agent for mitigating oxidative stress by altering cholesterol metabolism in AlCl3-induced AD.},
}

@article {pmid40014129,
year = {2025},
author = {Rathi, KM and Undale, VR and Wavhale, RD and Mohammed, FS and Karwa, PN and Patil, H},
title = {From computational screening to zebrafish testing: repurposing of doxazosin, donepezil, and dolutegravir for neuroprotective potential in Alzheimer's disease.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {40014129},
issn = {1432-1912},
abstract = {Amyloid-beta (Aß) plaques and neurofibrillary tangles are distinctive features of Alzheimer's disease (AD), a progressive disorder that results in considerable memory loss and decline in cognitive function. Presently available therapies, such as donepezil and other medications that inhibit acetylcholinesterase, mainly provide relief from symptoms but do not change the course of the disease. This research article intends to investigate the possible reuse of two FDA-approved medications, doxazosin and dolutegravir, discovered through computerized screening using shape similarity, docking energy, and molecular dynamics stability, for the purpose of targeting human acetylcholinesterase (AChE) in the development of disease-altering treatments. In order to mimic neurotoxicity similar to Alzheimer's disease, zebrafish (Danio rerio) were treated with aluminum chloride (AlCl3). Various behavioral assessments, such as the open field test, mirror biting test, novel tank test, social preference test, and dark-light preference test, were carried out to assess cognitive function, movement, and anxiety-related behaviors. The results indicated that doxazosin, a drug that blocks alpha-1 adrenergic receptors, successfully decreased neuroinflammation and improved cognitive abilities. Additionally, dolutegravir, which is mainly used as an antiviral medication, showed notable benefits in protecting the nervous system. This study highlights the possibility of using doxazosin and dolutegravir as effective alternative treatments for Alzheimer's disease. Upcoming preclinical and clinical research is necessary to confirm the safety and effectiveness of AD treatment, paving the way for new opportunities in therapeutic intervention.},
}

@article {pmid40013817,
year = {2025},
author = {Fu, J and Zhu, M and Zhang, L and Li, C and Liang, T and Li, Z and Liu, Z},
title = {Visualization of Oxidative Stress in the Early Stage of Alzheimer's Disease with a NIR-IIb Probe.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.4c05780},
pmid = {40013817},
issn = {1520-6882},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, is associated with the complete loss of cognition, and its pathogenesis has been suggested to be closely linked to oxidative stress in the early stage. However, there is currently a lack of effective methods to provide direct evidence for dynamic development of the oxidative stress status during AD progression. Herein, through manipulating the multiple energy transfer between 4f electronic levels of lanthanide ions (Ln[3+]), we proposed an energy interception strategy to construct activatable NIR-IIb nanoprobe for visualizing oxidative stress level. By utilizing an organic molecule, A1094 that absorbs light at wavelength matching the emission of Nd[3+] and Yb[3+], NIR-IIb emission from Er[3+] can be modulated upon the response of A1094 to oxidative species. This nanoprobe can not only clearly outline and distinguish oxidative stress regions in AD brains with adjacent age but also provide fast feedback on the efficacy of early interventional treatment for AD.},
}

@article {pmid40013172,
year = {2025},
author = {Namrouti, A and Desamour, P and Marquez, A and Lorenzen, C and Cervantes, O and Hodges, TB and Alvarez, G and Chandra, S},
title = {Atypical Early Onset Alzheimer's Disease in a Young Female: A Case Report.},
journal = {Cureus},
volume = {17},
number = {1},
pages = {e78082},
pmid = {40013172},
issn = {2168-8184},
abstract = {Early-onset Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the development of amyloid plaques and neurofibrillary tangles at an earlier age. It affects multiple cognitive domains, including memory, executive function, and motor abilities. Here, we present a case of atypical early-onset AD. A 33-year-old woman with no significant medical history experienced a two-year decline in cognitive function, resulting in job loss and incidents such as cooking-related fires. Neurological examination revealed impaired attention, myoclonus, hyperreflexia, and a dystaxic gait. Imaging and tests showed minor abnormalities, with normal cerebrospinal fluid (CSF), genetic, autoimmune, and metabolic workups. Brain magnetic resonance imaging (MRI) and positron emission tomography (PET) fluorodeoxyglucose (FDG) scans indicated cortical atrophy and parietal hypometabolism. The patient was referred to a memory center for further evaluation and potential treatment with lecanemab. This case highlights the challenges in diagnosing early-onset neurodegenerative disorders, which can present atypically and mimic other conditions. The extensive diagnostic workup emphasizes the difficulty of diagnosing these disorders, particularly in the absence of specific biomarkers. Early diagnosis of neurodegenerative disorders in young adults requires heightened clinical suspicion and a comprehensive diagnostic workup, including advanced brain imaging, such as MRI and PET scans, to ensure timely diagnosis and referral to specialized centers.},
}

@article {pmid40012567,
year = {2025},
author = {Chen, S and Wang, H and Zhang, L and Xi, Y and Lu, Y and Yu, K and Zhu, Y and Regina, I and Bi, Y and Tong, F},
title = {Glymphatic system: a self-purification circulation in brain.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1528995},
pmid = {40012567},
issn = {1662-5102},
abstract = {The glymphatic system theory introduces a new perspective on fluid flow and homeostasis in the brain. Here, cerebrospinal fluid and interstitial fluid (CSF-ISF) moves from the perivascular spaces (PVS) of arteries to those of veins for drainage. Aquaporin-4 (AQP4) plays a crucial role in driving fluid within the PVS. The impairment to AQP4 is closely linked to the dysfunction of the glymphatic system. The function of the glymphatic system is less active during waking but enhanced during sleep. The efficiency of the glymphatic system decreases with aging. Damage to the glymphatic system will give rise to the development and progression of many brain diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), chronic traumatic encephalopathy (CTE), and vascular dementia (VaD). Here, we reviewed previous research associated with the glymphatic system, including its concepts, principles, and influencing factors. We hypothesize that AQP4 could be a target for the prevention and treatment of certain brain diseases through the regulation on the glymphatic system.},
}

@article {pmid40012393,
year = {2025},
author = {Gulin, W and Oziemblewska, M and Zając-Lamparska, L},
title = {Use of Virtual Reality to Improve Spatial Orientation in Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050374807250224044204},
pmid = {40012393},
issn = {1875-5828},
abstract = {BACKGROUND: Alzheimer's disease is a chronic, neurodegenerative condition that leads to a significant cognitive decline. One of the symptoms that greatly reduces the quality of daily functioning is the deterioration of spatial orientation abilities. A non-pharmacological treatment option for Alzheimer's disease, which is also employed to improve the cognitive functioning of individuals with mild cognitive impairment, is virtual reality training.

OBJECTIVE: To the best of the authors' knowledge, there is no existing systematic review on the use of virtual reality training to enhance spatial orientation in individuals with Alzheimer's disease or mild cognitive impairment. The review was therefore conducted to fill this gap. The findings of this review may support the efficacy of virtual reality in enhancing spatial orientation.

METHODS: Five databases were searched. The primary inclusion criteria were study participants aged over 60 years with a diagnosis of Alzheimer's disease or mild cognitive impairment and the use of virtual reality for improving spatial orientation. Six studies meeting these criteria were ultimately included in the review.

RESULTS: All included studies demonstrated an improvement in the spatial orientation of individuals with Alzheimer's disease or mild cognitive impairment following virtual reality training. This indicates the effectiveness of virtual reality technology in cognitive rehabilitation.

CONCLUSION: As virtual reality cognitive training has proven effective, its use should be more widely adopted. Further research on the application of virtual reality for enhancing spatial orientation in individuals with dementia is recommended.},
}

@article {pmid40012390,
year = {2025},
author = {Singh, NK and Bhushan, B},
title = {Biochanin-A: A Potential Candidate for the Treatment of Alzheimer's Disease.},
journal = {Current pharmaceutical biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892010362795250223160707},
pmid = {40012390},
issn = {1873-4316},
abstract = {Alzheimer's disease (AD), the most common form of dementia, is a multifactorial neurological condition characterized by progressive loss of memory and learning, uncontrollable movement, difficulty processing visual images, and impairment of reasoning and/or judgment skills. Although the exact cause of AD is still unknown, recent evidence suggests that environmental, lifestyle, and genetic factors are common contributors to the disease's progression. Pathophysiological features of AD include amyloid beta (Aβ) accumulation, abnormal deposition of neuritic plaques and neurofibrile tangles, cholinergic dysfunction, neuroinflammation, and oxidative stress burden along with mitochondrial dysfunction. There are currently no pharmaceutical methods or medications that can stop the progression of a disease. More attention is now being paid to natural products, herbal medicines, and different bioactive phytoconstituents, particularly flavonoids, as alternative therapies and useful resources for finding new drug candidates for the treatment of AD-like symptoms. A dietary isoflavone, biochanin-A, which is isolated from the leaves and stems of Trifolium pretense L. (family: Leguminosae), possesses remarkable anti-inflammatory and antioxidant properties along with cognitive-enhancing effects. Biochanin-A exhibits notable neuroprotective effects by reducing Aβ deposition, decreasing apoptosis, and preventing the production of pro-inflammatory mediators, including TNF-α, IL- 1β, and NO. Various preclinical reports explore the pharmacological role of biochanin-A against experimentally-induced AD and highlight that it can alter numerous signaling pathways, including Nrf2, NF-κB, JNK, MAPK, and Bcl-2/Bax. The present review article summarizes the numerous research studies that have evaluated the role of biochanin-A for dementia associated with AD. As part of a comprehensive program, biochanin-A has very exceptional potential to prevent and treat AD-related cognitive impairment. It is envisaged that these potential chemical moieties can be employed in the drug discovery process to identify efficacious and safe therapy for the treatments for AD-like manifestation.},
}

@article {pmid40012182,
year = {2025},
author = {Shan, G and Zhang, Y and Lu, X and Li, Y and Lu, M and Li, Z},
title = {Sample size determination for a study with variable follow-up time.},
journal = {Journal of biopharmaceutical statistics},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/10543406.2025.2469879},
pmid = {40012182},
issn = {1520-5711},
abstract = {For a study to detect the outcome change at the follow-up visit from baseline, the pre-test and post-test design is commonly used to assess the treatment-control difference. Several existing methods were developed for sample size calculation including the subtraction method, analysis of covariance (ANCOVA), and linear mixed model. The first two methods can be used when the follow-up time is the same as scheduled. Although the linear mixed model can analyze the repeated measures by including the actual visit time to account for the variability of the follow-up time, it often assumes a constant treatment-control difference at any follow-up time which may not be correct in practice. We propose to develop a new statistical model to compare the treatment-control difference at the planned follow-up time while controlling for the follow-up time variation. The spline functions are used to estimate the trajectories of the treatment arm and the control arm. We compared the performance of these methods with regards to type I error rate, statistical power, and sample size under various conditions. These four methods all control for the type I error rate. The new method and the ANCOVA method are often more powerful than the other two methods, and they have similar statistical power when a linear disease progression is satisfied. For a study with non-linear disease progression, the new method can be more powerful than the ANCOVA method. We used data from a completed Alzheimer's disease trial to illustrate the application of the proposed method.},
}

@article {pmid40011826,
year = {2025},
author = {Liu, J and Yu, X and Fukuyama, H and Murai, T and Wu, J and Li, Q and Zhang, Z},
title = {CSEPC: a deep learning framework for classifying small-sample multimodal medical image data in Alzheimer's disease.},
journal = {BMC geriatrics},
volume = {25},
number = {1},
pages = {130},
pmid = {40011826},
issn = {1471-2318},
support = {62103404//National Natural Science Foundation of China/ ; 62103404//National Natural Science Foundation of China/ ; 62103404//National Natural Science Foundation of China/ ; 62103404//National Natural Science Foundation of China/ ; 62103404//National Natural Science Foundation of China/ ; KQTD20180413181834876//Shenzhen Overseas Innovation Team Project/ ; KQTD20180413181834876//Shenzhen Overseas Innovation Team Project/ ; KQTD20180413181834876//Shenzhen Overseas Innovation Team Project/ ; KQTD20180413181834876//Shenzhen Overseas Innovation Team Project/ ; KQTD20180413181834876//Shenzhen Overseas Innovation Team Project/ ; JCYJ20210324101402008//Shenzhen Basic Research Program/ ; JCYJ20210324101402008//Shenzhen Basic Research Program/ ; JCYJ20210324101402008//Shenzhen Basic Research Program/ ; JCYJ20210324101402008//Shenzhen Basic Research Program/ ; JCYJ20210324101402008//Shenzhen Basic Research Program/ ; GJHZ20210705141405016//Shenzhen Science and Technology Program/ ; GJHZ20210705141405016//Shenzhen Science and Technology Program/ ; GJHZ20210705141405016//Shenzhen Science and Technology Program/ ; GJHZ20210705141405016//Shenzhen Science and Technology Program/ ; GJHZ20210705141405016//Shenzhen Science and Technology Program/ ; 21K15614//Japan Society for the Promotion of Science/ ; 21K15614//Japan Society for the Promotion of Science/ ; 21K15614//Japan Society for the Promotion of Science/ ; 21K15614//Japan Society for the Promotion of Science/ ; 21K15614//Japan Society for the Promotion of Science/ ; 21K15614//Japan Society for the Promotion of Science/ ; 2023A1515012929//Guang Dong Basic and Applied Basic Research Foundation/ ; 2023A1515012929//Guang Dong Basic and Applied Basic Research Foundation/ ; 2023A1515012929//Guang Dong Basic and Applied Basic Research Foundation/ ; 2023A1515012929//Guang Dong Basic and Applied Basic Research Foundation/ ; 2023A0505050162//International Cooperation Projects of Science and Technology of Guangdong Province/ ; 2023A0505050162//International Cooperation Projects of Science and Technology of Guangdong Province/ ; 2023A0505050162//International Cooperation Projects of Science and Technology of Guangdong Province/ ; 2023A0505050162//International Cooperation Projects of Science and Technology of Guangdong Province/ ; },
mesh = {*Alzheimer Disease/classification/diagnostic imaging ; Humans ; *Deep Learning ; *Magnetic Resonance Imaging/methods ; Aged ; *Multimodal Imaging/methods ; Female ; Male ; Neuroimaging/methods ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impacts health care worldwide, particularly among the elderly population. The accurate classification of AD stages is essential for slowing disease progression and guiding effective interventions. However, limited sample sizes continue to present a significant challenge in classifying the stages of AD progression. Addressing this obstacle is crucial for improving diagnostic accuracy and optimizing treatment strategies for those affected by AD.

METHODS: In this study, we proposed cross-scale equilibrium pyramid coupling (CSEPC), which is a novel diagnostic algorithm designed for small-sample multimodal medical imaging data. CSEPC leverages scale equilibrium theory and modal coupling properties to integrate semantic features from different imaging modalities and across multiple scales within each modality. The architecture first extracts balanced multiscale features from structural MRI (sMRI) data and functional MRI (fMRI) data using a cross-scale pyramid module. These features are then combined through a contrastive learning-based cosine similarity coupling mechanism to capture intermodality associations effectively. This approach enhances the representation of both inter- and intramodal features while significantly reducing the number of learning parameters, making it highly suitable for small sample environments. We validated the effectiveness of the CSEPC model through experiments on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset and demonstrated its superior performance in diagnosing and staging AD.

RESULTS: Our experimental results demonstrate that the proposed model matches or exceeds the performance of models used in previous studies in AD classification. Specifically, the model achieved an accuracy of 85.67% and an area under the curve (AUC) of 0.98 in classifying the progression from mild cognitive impairment (MCI) to AD. To further validate its effectiveness, we used our method to diagnose different stages of AD. In both classification tasks, our approach delivered superior performance.

CONCLUSIONS: In conclusion, the performance of our model in various tasks has demonstrated its significant potential in the field of small-sample multimodal medical imaging classification, particularly AD classification. This advancement could significantly assist clinicians in effectively managing and intervening in the disease progression of patients with early-stage AD.},
}

*Alzheimer Disease/classification/diagnostic imaging
Humans
*Deep Learning
*Magnetic Resonance Imaging/methods
Aged
*Multimodal Imaging/methods
Female
Male
Neuroimaging/methods

@article {pmid40011745,
year = {2025},
author = {Rödström, KEJ and Eymsh, B and Proks, P and Hayre, MS and Cordeiro, S and Mendez-Otalvaro, E and Madry, C and Rowland, A and Kopec, W and Newstead, S and Baukrowitz, T and Schewe, M and Tucker, SJ},
title = {Cryo-EM structure of the human THIK-1 K2P K[+] channel reveals a lower Y gate regulated by lipids and anesthetics.},
journal = {Nature structural & molecular biology},
volume = {},
number = {},
pages = {},
pmid = {40011745},
issn = {1545-9985},
abstract = {THIK-1 (KCNK13) is a halothane-inhibited and anionic-lipid-activated two-pore domain (K2P) K[+] channel implicated in microglial activation and neuroinflammation, and a current target for the treatment of neurodegenerative disorders, for example Alzheimer's disease and amyothropic lateral sclerosis (ALS). However, compared to other K2P channels, little is known about the structural and functional properties of THIK-1. Here we present a 3.16-Å-resolution cryo-EM structure of human THIK-1 that reveals several distinct features, in particular, a tyrosine in M4 that contributes to a lower 'Y gate' that opens upon activation by physiologically relevant G-protein-coupled receptor and lipid signaling pathways. We demonstrate that linoleic acid bound within a modulatory pocket adjacent to the filter influences channel activity, and that halothane inhibition involves a binding site within the inner cavity, both resulting in conformational changes to the Y gate. Finally, the extracellular cap domain contains positively charged residues that line the ion exit pathway and contribute to the distinct biophysical properties of this channel. Overall, our results provide structural insights into THIK-1 function and identify distinct regulatory sites that expand its potential as a drug target for the modulation of microglial function.},
}

@article {pmid40011632,
year = {2025},
author = {Zhong, M and Xu, QQ and Huang, MQ and Zhan, RT and Huang, XQ and Yang, W and Lin, ZX and Xian, YF},
title = {Rhynchophylline alleviates cognitive deficits in multiple transgenic mouse models of Alzheimer's disease via modulating neuropathology and gut microbiota.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {40011632},
issn = {1745-7254},
abstract = {Amyloid-beta (Aβ) aggregation, phosphorylated tau accumulation and neuroinflammation are considered as three hallmarks of Alzheimer's disease (AD). Rhynchophylline (RN), the major alkaloid of a Chinese medicinal plant Uncaria rhynchophylla, has been shown to possess potent anti-AD effects. This study explored the effects of RN on Aβ pathology, tauopathy, and neuroinflammation using three AD mouse models, including TgCRND8, 3×Tg-AD, and 5×FAD, with RN treatment lasting for 4, 6, and 6 months, respectively, followed by behavioral tests and biological assays. In addition, BV2 cells were employed to further evaluate the biological effects of RN. RN treatment improved cognitive functions by reducing anxiety-like behaviors, enhancing recognition ability, and ameliorating learning impairments. It modulated Aβ processing through reducing the Aβ-producing enzyme activities and enhancing degradation enzyme activities, thereby diminishing Aβ accumulation. RN also decreased hyperphosphorylated tau proteins at Thr181, Thr205, Ser396, and Ser404 sites. Moreover, RN diminished neuroinflammation by reducing microglia and astrocyte activation and lowering the release of inflammatory cytokines. Furthermore, RN treatment could restore gut microbiota dysbiosis in 5×FAD mice. In BV2 cells, knockdown of p53, HDAC2, and Galectin-3 markedly enhanced the anti-inflammatory effects of RN. Overall, the anti-AD properties of RN were attributed to its regulation of multiple biological pathways, including regulation of the p53/PINK1 signaling pathway, inhibition of the HDAC2/AMPK signaling pathway, suppression of the Galectin-3/C/EBPβ/AEP signaling pathway, and modulation of gut microflora dysbiosis. This pioneering study unambiguously revealed the effects of RN on cognitive impairments, APP processing, tauopathy, and neuroinflammation in different transgenic mouse models with differing AD burdens, highlighting its potential as an anti-AD therapeutic agent and enhancing the scientific basis for its clinical use in treating AD.},
}

@article {pmid40011292,
year = {2025},
author = {Li, Q and Han, X and Dong, M and Bai, L and Zhang, W and Liu, W and Wang, F and Zhu, X},
title = {FDA-Approved Secukinumab Alleviates Glial Activation and Immune Cell Infiltration in MPTP-Induced Mouse Model of Parkinson's Disease.},
journal = {Inflammation},
volume = {},
number = {},
pages = {},
pmid = {40011292},
issn = {1573-2576},
support = {82471276//National Natural Science Foundation of China/ ; TJYXZDXK-060B//Tianjin Key Medical Discipline (Specialty) Construction Projec/ ; },
abstract = {Interleukin-17A (IL-17A) has been implicated in the progression of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, the effect of the FDA-approved Secukinumab (SEC), an IL-17A inhibitor, on PD remains unclear. This study aimed to investigate the neuroprotective effect of SEC and its potential mechanisms in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Male C57BL/6 J mice were mainly assigned to three groups: Sham, MPTP, and MPTP + SEC. Motor coordination was assessed using the climbing rod and rotarod tests. Dopaminergic neurons (TH +) and glial cells (Iba-1 + , GFAP +) in the substantia nigra were evaluated using immunohistochemistry and immunofluorescence. Flow cytometry was used to analyze immune cell populations in the brain and spleen. Inflammatory cytokines and chemokines were quantified using RT-PCR. SEC treatment significantly alleviated the loss of dopaminergic neurons and improved motor coordination in MPTP mice. It also reduced the infiltration of peripheral immune cells, including CD4 + T cells, NK cells, and monocyte-macrophages into the brain. SEC attenuated glial activation (Iba-1 + , GFAP +) and decreased the expression of pro-inflammatory cytokines and chemokines (CCL2, CXCL9), which recruit immune cells into the brain. These results suggest that Secukinumab protects dopaminergic neurons and attenuates neuroinflammation in MPTP-induced model. SEC treatment in PD might be an effective therapeutic approach for clinical application in the future. HIGHLIGHTS: • Secukinumab reduces the loss of dopaminergic neurons and axons in MPTP mice. • Secukinumab inhibits the infiltration of peripheral immune cells into the brain in MPTP mice. • Secukinumab inhibits the activation of glial cells and reduces neuroinflammation in MPTP mice.},
}

@article {pmid40011174,
year = {2025},
author = {Rosen, J and Jessen, F},
title = {Patient eligibility for amyloid-targeting immunotherapies in Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100102},
doi = {10.1016/j.tjpad.2025.100102},
pmid = {40011174},
issn = {2426-0266},
abstract = {BACKGROUND: Amyloid beta (Aβ) targeting immunotherapies have evolved as promising treatment options for patients with early symptomatic Alzheimer's disease (AD). Understanding how eligibilty criteria impact on the number of patients potentially qualifying for treatment is of high relevance for designing diagnostic workflows in clinical practice and for estimating required ressources and costs.

OBJECTIVES: We aimed at estimating the number of potentially eligible patients for treatment with the Aβ targeting antibodies aducanumab, lecanemab and donanemab in a specialized center real-world sample by the applying the phase 3 clinical trial and the appropriate use recommendations (AUR) inclusion and exclusion criteria to the data set. The post-mortem report was used for defining amyloid positivity and the presence of AD pathology in this study.

DESIGN: Retrospective, descriptive study.

SETTING: The multicenter National Alzheimer's Coordinating Center-Uniform Data Set (NACC-UDS) and Neuropathology Data Set (NACCNP).

PARTICIPANTS: We included all 3,343 participants of the NACC dataset with available post-mortem pathology reports.

MEASUREMENTS/RESULTS: 887 participants were potential candidates for anti-Aβ immunotherapy as they presented with amnestic mild cognitive impairment or mild dementia and the clinical diagnosis of AD (amnestic AD syndrome). Applying the criterion of amyloid positivity (post mortem report) and the clinical trial inclusion and exclusion criteria to this sample resulted in 83 (9 %), 275 (31 %), and 172 (19 %) participants eligible for treatment with aducanumab, lecanemab, and donanemab, respectively. Applying the criteria of the AUR resulted in 242 (27 %) and 266 (30 %) participants eligible for treatment with aducanumab or lecanemab, respectively. The eligible participant groups for each antibody showed partial, but not full overlap. Co-pathologies were common.

CONCLUSIONS: The number of eligible participants varies between the different antibodies and the selected groups only partly overlap, indicating partly different groups of eligible participants for each antibody. Since not all inclusion and exclusion criteria can be extracted from the NACC-UDS dataset, the real number of eligible patients will be smaller.},
}

@article {pmid40011173,
year = {2025},
author = {Villain, N and Planche, V and Lilamand, M and Cordonnier, C and Soto-Martin, M and Mollion, H and Bombois, S and Delrieu, J and , },
title = {Lecanemab for early Alzheimer's disease: Appropriate use recommendations from the French federation of memory clinics.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100094},
doi = {10.1016/j.tjpad.2025.100094},
pmid = {40011173},
issn = {2426-0266},
abstract = {Lecanemab, a monoclonal antibody targeting β-amyloid protofibrils, has shown promising results in a Phase III clinical trial for the treatment of early stages of Alzheimer's disease (AD) and has been approved by the European Medicines Agency. An Early Market Authorization could be submitted to the French regulatory agencies, potentially allowing for the drug's use in clinical practice in France in 2025. To guide French clinicians in administering lecanemab in a standardized way, the French Federation of Memory Clinics has developed appropriate use recommendations for lecanemab that highlight relevant questions established to ensure an optimal risk-benefit ratio. The recommendations emphasize that lecanemab treatment requires a comprehensive individualized evaluation of the risk-benefit ratio, which should occur in multidisciplinary meetings. When approved, the guidelines support the use of blood biomarkers, proposing specific cutoffs for patients eligible for lecanemab under restricted conditions. In addition to the European Medicines Agency restrictions in patients on anticoagulants, and APOE4 homozygotes, the guidelines recommend against lecanemab treatment for patients with high amyloid-related hemorrhagic risk such as probable cerebral amyloid angiopathy (Boston criteria v1.5) until further data become available. Additionally, we recommend that MRI monitoring be started before the third infusion to account for early Amyloid Related Imaging Abnormalities (ARIA) occurring on lecanemab. It is recommended to establish a specific clinical care pathway with protocols for patients with ARIA, with trained physicians and radiologists with expertise in neurological emergency and intensive care. Finally, a discontinuation protocol based on dementia severity assessment after 18 months of lecanemab treatment is suggested. Access to lecanemab requires a personalized biological and genetic diagnosis of AD, which is currently not necessary in most cases. Therefore, the healthcare system must rapidly adjust to new diagnostic procedures and treatment delivery to ensure equal access for all individuals.},
}

@article {pmid40010509,
year = {2025},
author = {Kaur, V and Sunkaria, A},
title = {Unlocking the Therapeutic Promise of miRNAs in Promoting Amyloid-β Clearance for Alzheimer's Disease.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {115505},
doi = {10.1016/j.bbr.2025.115505},
pmid = {40010509},
issn = {1872-7549},
abstract = {Alzheimer's disease (AD) is a neurological disorder that affects cognition and behavior, accounting for 60-70% of dementia cases. Its mechanisms involve amyloid aggregates, hyperphosphorylated tau tangles, and loss of neural connections. Current treatments have limited efficacy due to a lack of specific targets. Recently, microRNAs (miRNAs) have emerged as key modulators in AD, regulating gene expression through interactions with mRNA. Dysregulation of specific miRNAs contributes to disease progression by disrupting clearance pathways. Antisense oligonucleotide (ASO)-based therapies show promise for AD treatment, particularly when combined with miRNA mimics or antagonists, targeting complex regulatory networks. However, miRNAs can interact with each other, complicating cellular processes and potentially leading to side effects. Our review emphasizes the role of miRNAs in regulating amyloid-beta (Aβ) clearance and highlights their potential as therapeutic targets and early biomarkers for AD, underscoring the need for further research to enhance their efficacy and safety.},
}

@article {pmid40010154,
year = {2025},
author = {Millar, CL and Iloputaife, I and Baldyga, K and Norling, AM and Boulougoura, A and Vichos, T and Tchkonia, T and Deisinger, A and Pirtskhalava, T and Kirkland, JL and Travison, TG and Lipsitz, LA},
title = {A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease.},
journal = {EBioMedicine},
volume = {113},
number = {},
pages = {105612},
doi = {10.1016/j.ebiom.2025.105612},
pmid = {40010154},
issn = {2352-3964},
abstract = {BACKGROUND: This single-arm study evaluates the feasibility, safety, and preliminary effects of two senolytic agents, Dasatinib and Quercetin (DQ), in older adults at risk of Alzheimer's disease.

METHODS: Participants took 100 mg of Dasatinib and 1250 mg of Quercetin for two days every two weeks over 12 weeks. Recruitment rate, adverse events, absolute changes in functional outcomes, and percent changes in biomarkers were calculated. Spearman correlations between functional and biomarker outcomes were performed.

FINDINGS: Approximately 10% of telephone-screened individuals completed the intervention (n = 12). There were no serious adverse events related to the intervention. Mean Montreal Cognitive Assessment (MoCA) scores non-significantly increased following DQ by 1.0 point (95% CI: -0.7, 2.7), but increased significantly by 2.0 points (95% CI: 0.1, 4.0) in those with lowest baseline MoCA scores. Mean percent change in tumour necrosis factor-alpha (TNF-α), a key product of the senescence-associated secretory phenotype (SASP), non-significantly decreased following DQ by -3.0% (95% CI: -13.0, 7.1). Changes in TNF-α were significantly and inversely correlated with changes in MoCA scores (r = -0.65, p = 0.02), such that reductions in TNF- α were correlated with increases in MoCA scores.

INTERPRETATION: This study suggests that intermittent DQ treatment is feasible and safe; data hint at potential functional benefits in older adults at risk of Alzheimer's disease. The observed reduction in TNF-α and its correlation with increases in MoCA scores suggests that DQ may improve cognition by modulating the SASP. However, there was not an appropriate control group. Data are preliminary and must be interpreted cautiously.

FUNDING: National Institute on Ageing grants R21AG073886 and R33AG061456 funded this research.},
}

@article {pmid40010133,
year = {2025},
author = {Almatary, AM and Al-Sanea, MM and Nasr, EE and Haikal, A and Thompson, GS and Abood, A and Ibrahim, MAA and Elgazar, AA and Hamdi, A},
title = {"Triazole-linked thiazolidinedione-Benzothiazole hybrids: Design and biological evaluation as AChE inhibitors".},
journal = {Bioorganic chemistry},
volume = {157},
number = {},
pages = {108295},
doi = {10.1016/j.bioorg.2025.108295},
pmid = {40010133},
issn = {1090-2120},
abstract = {Novel 2,4-thiazolidinedione-benzothiazole-triazole hybrids (7a-7l) were designed and synthesized as therapeutic agents with pleotropic activity for Alzheimer's disease (AD). These compounds were evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities. Compound 7k, exhibited exceptional AChE inhibition (IC50 = 0.083 μM), while compound 7d, showed potent activity (IC50 = 0.119 μM). Kinetic studies revealed that 7k was able to exert its action through mixed types of inhibition. Also, the anti-inflammatory potential of these lead compounds was assessed in LPS-stimulated RAW 264.7 macrophages. Both compounds demonstrated significant dose-dependent inhibition of key inflammatory mediators, including NO, TNF-α, IL-6, and IL-1β at non-cytotoxic concentrations (≤10 μM). Notably, compound 7k exhibited superior anti-inflammatory activity, achieving 92 % NO inhibition, 65 % TNF-α reduction, and 61.1 % IL-1β suppression at 10 μM. Moreover, compound 7k exerted neuroprotective activity against H2O2 induced neurotoxicity in SH-Sy5y cell line leading to reduction in LDH, ROS levels and improving cell survival. Finally, compound 7k was able to prevent Aβ aggregation at IC50 = 5 μM. Molecular docking studies provided structural insights into the possible binding interactions of compounds 7d and 7k within the AChE active site. The stability and binding energies of compounds 7d and 7k complexed with AChE were assessed over 100 ns molecular dynamics simulations and compared with Donepezil. The MM/GBSA binding energy calculations indicated that compound 7k exhibited a higher affinity for AChE in comparison with compound 7d and Donepezil, with ΔGbinding values of -46.1, -42.6, and - 24.0 kcal/mol, respectively. These findings suggest that these novel hybrid molecules represent promising multi-target therapeutic candidates for AD treatment, effectively addressing both cholinergic dysfunction and neuroinflammation.},
}

@article {pmid40009384,
year = {2025},
author = {Matt, E and Mitterwallner, M and Radjenovic, S and Grigoryeva, D and Weber, A and Stögmann, E and Domitner, A and Zettl, A and Osou, S and Beisteiner, R},
title = {Ultrasound Neuromodulation With Transcranial Pulse Stimulation in Alzheimer Disease: A Randomized Clinical Trial.},
journal = {JAMA network open},
volume = {8},
number = {2},
pages = {e2459170},
doi = {10.1001/jamanetworkopen.2024.59170},
pmid = {40009384},
issn = {2574-3805},
mesh = {Humans ; *Alzheimer Disease/therapy ; Female ; Male ; Aged ; Double-Blind Method ; *Transcranial Direct Current Stimulation/methods ; Cross-Over Studies ; Treatment Outcome ; Aged, 80 and over ; Middle Aged ; Neuropsychological Tests/statistics & numerical data ; },
abstract = {IMPORTANCE: Given the increasing prevalence of dementia and the limited treatment options available, ultrasound neuromodulation could serve as a novel add-on therapy to standard treatments for Alzheimer disease (AD). As ultrasound neuromodulation is still in its early stages, further research is essential to fully explore its potential in treating brain disorders.

OBJECTIVE: To evaluate clinical and functional imaging effects of transcranial pulse stimulation (TPS) in patients with AD.

A randomized, double-blind, sham-controlled, crossover clinical trial was conducted at the Medical University of Vienna between January 1, 2017, and July 27, 2022. Sixty patients with clinically diagnosed AD receiving state-of-the-art treatment were randomly allocated to treatment sequence groups verum-sham (first cycle verum, second cycle sham, n = 30) and sham-verum (n = 30). Data analysis was performed from July 28, 2022, to September 5, 2024.

INTERVENTION: Each participant received 6 verum and 6 sham TPS sessions (6000 pulses, 0.20 mJ/mm2, 5 Hz) to frontoparietal brain areas.

MAIN OUTCOMES AND MEASURES: Neuropsychological tests, including the primary outcome Consortium to Establish a Registry for Alzheimer's Disease (CERAD) corrected total score (CTS), were performed at baseline and 1 week, 1 month, and 3 months following the stimulations in each cycle. Primary and secondary outcomes, including functional magnetic resonance imaging and Beck Depression Inventory-II, were analyzed by intention-to-treat analysis and, for sensitivity, by per protocol analysis.

RESULTS: For the intention-to-treat analysis, 60 patients between ages 51 and 82 years (mean [SD], 70.65 [8.16] years; 30 females; 30 males) were included. The CERAD CTS increased by a mean (SD) of 2.22 (6.87) points in the verum condition from 70.93 (14.27) points at baseline to 73.15 (14.90) 3 months after stimulation, while the mean (SD) score in the sham condition increased by 1.00 (6.82) point vs baseline from 71.68 (13.62] at baseline to 72.68 (14.48) 3 months after stimulation. Primary data analysis of the condition × session interaction was not significant (P = .68; partial η2 [ηp2] = 0.01), but its interaction with age was P = .003; ηp2 = 0.08, followed by post hoc analyses of age subsamples. Although several patients older than 70 years benefited from verum TPS, only the younger subgroup (≤70 years) showed significantly higher CTS increases for verum in all poststimulation sessions (condition × session: P = .005; ηp2 = 0.16). At 3 months after stimulation, for example, a mean (SD) 3.91 (7.86)-point increase was found for verum TPS in the younger patients, but a mean (SD) CTS decrease of 1.83 (5.80) was observed for sham. Memory-associated brain activation was significantly higher after verum TPS in the precuneus, visual, and frontal areas, while resting state functional connectivity was significantly upregulated in the dorsal attention network. In the per protocol sample, a significant reduction of the Beck Depression Inventory-II scores 3 months following verum TPS was found (verum baseline: 7.27 [5.87]; verum 3 months after stimulation: 5.27 [5.27]; sham baseline: 6.70 [5.65]; sham 3 months after stimulation: 6.22 [4.40]; P = .008; ηp2 = 0.23). During both verum and sham conditions, the most common observed adverse symptom was depression; no major neuropathologic change was detected in the patients by detailed neuroradiologic assessments.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of TPS in patients with AD, a 2-week verum treatment improved cognitive scores in the younger subgroup, ameliorated depressive symptoms, and induced upregulation of functional brain activation and connectivity. These findings suggest TPS may be a safe and promising add-on therapy for patients with AD receiving state-of-the-art treatment.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03770182.},
}

Humans
*Alzheimer Disease/therapy
Female
Male
Aged
Double-Blind Method
*Transcranial Direct Current Stimulation/methods
Cross-Over Studies
Treatment Outcome
Aged, 80 and over
Middle Aged
Neuropsychological Tests/statistics & numerical data

@article {pmid40009301,
year = {2025},
author = {Ramakrishan, P and Rajangam, J and Mahinoor, SS and Bisht, S and Mekala, S and Upadhyay, DK and Solomon, VR and Sabarees, G and Pelluri, R},
title = {Unveiling the mTOR pathway modulation by SGLT2 inhibitors: a novel approach to Alzheimer's disease in type 2 diabetes.},
journal = {Metabolic brain disease},
volume = {40},
number = {3},
pages = {132},
pmid = {40009301},
issn = {1573-7365},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Diabetes Mellitus, Type 2/drug therapy/metabolism ; *TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; Animals ; },
abstract = {Alzheimer's disease (AD) is a neurological condition causing cognitive deterioration, leading to severe consequences. As the global prevalence of AD increases, new treatment approaches are needed to supplement current conventional therapies, as traditional treatments are not meeting the increasing demand for alternative treatments. It is increasingly evident that treating metabolic disorders like diabetes mellitus, obesity, and AD by blocking mechanistic target of rapamycin (mTOR) signalling is advantageous. Chronic mTOR activation may cause AD's metabolic, lysosomal, and mitochondrial dysfunction, tau hyperphosphorylation, amyloid plaque development, and disruption of the blood-brain barrier through endothelial cell malfunction. Chronic glucose loss through sodium-glucose transporter 2 (SGLT2) inhibitions can restore mTOR cycling, potentially halting or slowing AD pathogenesis. Chronic activation of mTOR is implicated in pathophysiological aspects of AD, such as metabolic dysfunction, tau hyperphosphorylation, amyloid plaque formation, and disruption of the blood-brain barrier. SGLT-2 inhibitors, commonly used in treating Type 2 Diabetes, have been shown to reduce mTOR activation and restore circadian regularity, a new finding in cognitive decline and metabolic disorders. Conversely, SGLT2 inhibitors decrease oxidative damage, inflammation, insulin signaling pathways, and proliferation of endothelial cells to enhance vascular tone, flexibility, and contractility. Along with reducing the formation of plaque containing amyloid and improving brain function, neural plasticity, acetylcholinesterase (AChE) activity, damage to the brain, and cognitive decline, they also regulate the mTOR pathway in the brain. Thus, repurposing SGLT-2 inhibitors, primarily used in diabetes treatment, presents a promising avenue for changing the way that AD is managed. The purpose of this review was to focus on the mTOR signalling cascade of SGLT 2 inhibitors to AD management in Type 2 Diabetes mellitus.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Diabetes Mellitus, Type 2/drug therapy/metabolism
*TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors
*Sodium-Glucose Transporter 2 Inhibitors/pharmacology/therapeutic use
*Signal Transduction/drug effects
Animals

@article {pmid40009144,
year = {2025},
author = {Milani, SA and Westra, J and Kuo, YF and Downer, B and Raji, MA},
title = {Dementia Medications and Their Association with Pain Medication Use in Medicare Beneficiaries with Alzheimer's Disease/Alzheimer's Disease-Related Dementias and Chronic Pain.},
journal = {Drugs & aging},
volume = {},
number = {},
pages = {},
pmid = {40009144},
issn = {1179-1969},
support = {K01-AG075254)/AG/NIA NIH HHS/United States ; P30-AG024832/AG/NIA NIH HHS/United States ; P30-AG059301/AG/NIA NIH HHS/United States ; R01-DA039192/DA/NIDA NIH HHS/United States ; },
abstract = {INTRODUCTION: Chronic pain is prevalent among older adults with Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD). Memantine and acetylcholinesterase inhibitors (ACHEI; donepezil, rivastigmine, and galantamine) are approved for the treatment of dementia symptoms and may also have analgesic properties. However, findings on the clinical utility of these dementia medications for chronic pain treatment are mixed, and little is known about differences in the use of pain medication according to whether an older adult with AD/ADRD is using dementia medications.

METHODS: We selected a 20% national sample of Medicare enrollees with a diagnosis of AD/ADRD and chronic pain in 2020. We calculated the odds of having any pain management prescription (opioids, serotonin and norepinephrine reuptake, gapapentinoids, or non-steroidal anti-inflammatory drugs), having an opioid prescription, and having a long-term (≥ 90 days) opioid prescription, by dementia medication (none, memantine, ACHEI, or memantine and ACHEI).

RESULTS: Among 103,564 patients, 5.5% received a memantine prescription, 14.4% received an ACHEI prescription, and 8.6% received a prescription for both. Over 70% of all patients had a pain management prescription. The percentage of patients who had an opioid prescription ranged from 54.5% for those without a dementia medication prescription to 44.0% for those with a prescription for both memantine and ACHEI. Similarly, the percentage of patients who had a long-term opioid prescription was highest for those without a dementia medication prescription (12.2%) and lowest for those with a prescription for both memantine and ACHEI (8.8%). Having a prescription for memantine only was associated with lower odds of any pain management prescription (odds ratio [OR]: 0.94; 95% confidence interval [CI]: 0.88-1.00; p < 0.05). Having a prescription for either memantine (OR: 0.79; 95% CI 0.75-0.84), ACHEI (OR: 0.85; 95% CI 0.82-0.89), or both (OR: 0.75; 95% CI 0.72-0.79) was associated with lower odds of having an opioid prescription (p < 0.05). Lastly, having a prescription for either memantine (OR: 0.85; 95% CI 0.77-0.94), ACHEI (OR: 0.92; 95% CI 0.86-0.98), or both (OR: 0.83; 95% CI 0.77-0.90) was associated with lower odds of having a long-term opioid prescription.

DISCUSSION: Older adults with co-occurring AD/ADRD and chronic pain who were on dementia medications had lower odds of being prescribed opioid analgesics. Memantine and ACHEIs should be explored as potential opioid-sparing medications for older adults with AD/ADRD, given their relatively safe profiles. Future studies are needed to examine repurposing dementia medications for pain treatment.},
}

@article {pmid40008891,
year = {2025},
author = {Habibatni, S and Maiuolo, J and Davì, F and Samir, Z and Lyas, B and Cacciola, F and Laganà Vinci, R and Mondello, L and Taviano, MF and Miceli, N},
title = {Characterization of the phenolic profile, antioxidant and neuroprotective activity of leaf hydroalcoholic extracts of Euphorbia bupleuroides subsp. luteola (Kralik) maire growing wild in Algeria.},
journal = {International journal of environmental health research},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/09603123.2025.2461098},
pmid = {40008891},
issn = {1369-1619},
abstract = {The objective of this research was to investigate the phenolic profile and some biological properties of the leaves of Euphorbia bupleuroides subsp. luteola grown wild in Algeria, still unexplored. The leaves were subjected to extraction with 80% MeOH using simple maceration (SM) and ultrasound-assisted maceration (UM) to establish the most efficient conditions for the recovery of phenolic compounds. The study of antioxidant potential suggested that SM and UM extracts displayed a superimposable activity both in the DPPH test and in the reducing power assay. On the other hand, in the Fe2+ chelating activity assay, SM was more active than UM. SM extract prevented damage induced by β-amyloid protein (Aβ) being more effective against ROS generated after treatment with Aβ. In addition, SM exhibited later protection against malondialdehyde. In conclusion, it is possible to state that simple maceration represents an effective technique for the recovery of compounds with antioxidant and neuroprotective properties from E. bupleuroides subsp. luteola leaves.},
}

@article {pmid40008329,
year = {2025},
author = {Scheijbeler, EP and de Haan, W and Coomans, EM and den Braber, A and Tomassen, J and Ten Kate, M and Konijnenberg, E and Collij, LE and van de Giessen, E and Barkhof, F and Visser, PJ and Stam, CJ and Gouw, AA},
title = {Amyloid-β deposition predicts oscillatory slowing of magnetoencephalography signals and a reduction of functional connectivity over time in cognitively unimpaired adults.},
journal = {Brain communications},
volume = {7},
number = {1},
pages = {fcaf018},
pmid = {40008329},
issn = {2632-1297},
abstract = {With the ongoing developments in the field of anti-amyloid therapy for Alzheimer's disease, it is crucial to better understand the longitudinal associations between amyloid-β deposition and altered network activity in the living human brain. We included 110 cognitively unimpaired individuals (67.9 ± 5.7 years), who underwent [[18]F]flutemetamol (amyloid-β)-PET imaging and resting-state magnetoencephalography (MEG) recording at baseline and 4-year follow-up. We tested associations between baseline amyloid-β deposition and MEG measures (oscillatory power and functional connectivity). Next, we examined the relationship between baseline amyloid-β deposition and longitudinal MEG measures, as well as between baseline MEG measures and longitudinal amyloid-β deposition. Finally, we assessed associations between longitudinal changes in both amyloid-β deposition and MEG measures. Analyses were performed using linear mixed models corrected for age, sex and family. At baseline, amyloid-β deposition in orbitofrontal-posterior cingulate regions (i.e. early Alzheimer's disease regions) was associated with higher theta (4-8 Hz) power (β = 0.17, P < 0.01) in- and lower functional connectivity [inverted Joint Permutation Entropy (JPEinv) theta, β = -0.24, P < 0.001] of these regions, lower whole-brain beta (13-30 Hz) power (β = -0.13, P < 0.05) and lower whole-brain functional connectivity (JPEinv theta, β = -0.18, P < 0.001). Whole-brain amyloid-β deposition was associated with higher whole-brain theta power (β = 0.17, P < 0.05), lower whole-brain beta power (β = -0.13, P < 0.05) and lower whole-brain functional connectivity (JPEinv theta, β = -0.21, P < 0.001). Baseline amyloid-β deposition in early Alzheimer's disease regions also predicted future oscillatory slowing, reflected by increased theta power over time in early Alzheimer's disease regions and across the whole brain (β = 0.11, β = 0.08, P < 0.001), as well as decreased whole-brain beta power over time (β = -0.04, P < 0.05). Baseline amyloid-β deposition in early Alzheimer's disease regions also predicted a reduction in functional connectivity between these regions and the rest of the brain over time (JPEinv theta, β = -0.07, P < 0.05). Baseline whole-brain amyloid-β deposition was associated with increased whole-brain theta power over time (β = 0.08, P < 0.01). Baseline MEG measures were not associated with longitudinal amyloid-β deposition. Longitudinal changes in amyloid-β deposition in early Alzheimer's disease regions were associated with longitudinal changes in functional connectivity of early Alzheimer's disease regions (JPEinv theta, β = -0.19, P < 0.05) and the whole brain [corrected amplitude envelope correlations alpha (8-13 Hz), β = -0.22, P < 0.05]. Finally, longitudinal changes in whole-brain amyloid-β deposition were associated with longitudinal changes in whole-brain relative theta power (β = 0.21, P < 0.05). Disruptions of oscillatory power and functional connectivity appear to represent early functional consequences of emerging amyloid-β deposition in cognitively unimpaired individuals. These findings suggest a role for neurophysiology in monitoring disease progression and potential treatment effects in pre-clinical Alzheimer's disease.},
}

@article {pmid40007468,
year = {2025},
author = {Feigin, A and Evans, EE and Fisher, TL and Zauderer, M},
title = {Pepinemab: a SEMA4D antagonist for treatment of Huntington's and other neurodegenerative diseases.},
journal = {Expert opinion on investigational drugs},
volume = {},
number = {},
pages = {},
doi = {10.1080/13543784.2025.2473055},
pmid = {40007468},
issn = {1744-7658},
abstract = {INTRODUCTION: Huntington's Disease (HD) is a progressive fatal neurodegenerative disease with an unmet need for disease-modifying therapies. Neuroinflammation, particularly astrogliosis, plays a crucial role in the pathogenesis of HD and modulation of this damaging activity and its downstream effects presents a promising therapeutic avenue. Pepinemab, a semaphorin4D (SEMA4D) blocking antibody, has the potential to serve this purpose.

AREAS COVERED: We review the proposed mechanisms of action of pepinemab, published safety and efficacy results from the 'SIGNAL' Phase 2 trial in HD and supporting data from a Phase 1 trial in multiple sclerosis (MS).

EXPERT OPINION: Pepinemab's potential to reduce reactive gliosis and inflammation is a novel mechanism of action (MOA) that may be effective as a standalone therapy as well as one that may complement other strategies to reduce toxic disease associated processes. Pepinemab has demonstrated a favorable safety profile and treatment benefits in fluid biomarkers, imaging endpoints, and measures of cognitive function that encourage continued development in HD and other neurodegenerative diseases.},
}

@article {pmid40006083,
year = {2025},
author = {Rao, IY and Hanson, LR and Frey Ii, WH},
title = {Brain Glucose Hypometabolism and Brain Iron Accumulation as Therapeutic Targets for Alzheimer's Disease and Other CNS Disorders.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {2},
pages = {},
doi = {10.3390/ph18020271},
pmid = {40006083},
issn = {1424-8247},
abstract = {Two common mechanisms contributing to multiple neurological disorders, including Alzheimer's disease, are brain glucose hypometabolism (BGHM) and brain iron accumulation (BIA). Currently, BGHM and BIA are both widely acknowledged as biomarkers that aid in diagnosing CNS disorders, distinguishing between disorders with similar symptoms, and tracking disease progression. Therapeutics targeting BGHM and BIA in Alzheimer's disease can be beneficial in treating neurocognitive symptoms. This review addresses the evidence for the therapeutic potential of targeting BGHM and BIA in multiple CNS disorders. Intranasal insulin, which is anti-inflammatory and increases brain cell energy, and intranasal deferoxamine, which reduces oxidative damage and inflammation, represent promising treatments targeting these mechanisms. Both BGHM and BIA are promising therapeutic targets for AD and other CNS disorders.},
}

@article {pmid40005231,
year = {2025},
author = {Thawabteh, AM and Ghanem, AW and AbuMadi, S and Thaher, D and Jaghama, W and Karaman, D and Karaman, R},
title = {Promising Natural Remedies for Alzheimer's Disease Therapy.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {4},
pages = {},
doi = {10.3390/molecules30040922},
pmid = {40005231},
issn = {1420-3049},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Plant Extracts/chemistry/therapeutic use/pharmacology ; Biological Products/therapeutic use/chemistry/pharmacology ; Animals ; Phytotherapy/methods ; Phytochemicals/therapeutic use/chemistry/pharmacology ; Plants, Medicinal/chemistry ; Blood-Brain Barrier/drug effects/metabolism ; },
abstract = {This study examines the intricacies of Alzheimer's disease (AD), its origins, and the potential advantages of various herbal extracts and natural compounds for enhancing memory and cognitive performance. Future studies into AD treatments are encouraged by the review's demonstration of the effectiveness of phytoconstituents that were extracted from a number of plants. In addition to having many beneficial effects, such as improved cholinergic and cognitive function, herbal medicines are also much less harmful, more readily available, and easier to use than other treatments. They also pass without difficulty through the blood-brain barrier (BBB). This study focused on natural substances and their effects on AD by using academic databases to identify peer-reviewed studies published between 2015 and 2024. According to the literature review, 66 phytoconstituents that were isolated from 21 distinct plants have shown efficacy, which could be encouraging for future research on AD therapies. Since most clinical trials produce contradictory results, the study suggests that larger-scale studies with longer treatment durations are necessary to validate or refute the therapeutic efficacy of herbal AD treatments.},
}

*Alzheimer Disease/drug therapy
Humans
*Plant Extracts/chemistry/therapeutic use/pharmacology
Biological Products/therapeutic use/chemistry/pharmacology
Animals
Phytotherapy/methods
Phytochemicals/therapeutic use/chemistry/pharmacology
Plants, Medicinal/chemistry
Blood-Brain Barrier/drug effects/metabolism

@article {pmid40005187,
year = {2025},
author = {Capó, T and Rebassa, JB and Raïch, I and Lillo, J and Badia, P and Navarro, G and Reyes-Resina, I},
title = {Future Perspectives of NMDAR in CNS Disorders.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {4},
pages = {},
doi = {10.3390/molecules30040877},
pmid = {40005187},
issn = {1420-3049},
support = {PID2020-113430RB-I00//Spanish Ministry of Economy and Innovation/ ; #2021 SGR 00304//Regional Catalonian Government/ ; },
mesh = {*Receptors, N-Methyl-D-Aspartate/metabolism ; Humans ; Animals ; *Central Nervous System Diseases/metabolism/drug therapy ; Neurodegenerative Diseases/metabolism/drug therapy ; },
abstract = {Neurodegenerative diseases such as Alzheimer's and Parkinson's diseases are among the leading causes of physical and cognitive disability across the globe. Fifty million people worldwide suffer these diseases, and that number is expected to rise as the population ages. Ictus is another pathology that also courses with neurodegeneration and is a leading cause of mortality and long-term disability in developed countries. Schizophrenia is not as common as other mental disorders, affecting approximately 24 million people worldwide. All these disorders have in common that still there is not an effective pharmacological treatment to cure them. The N-methyl-D-aspartate (NMDA) receptor (NMDAR) has attracted attention as a potential therapeutic target due to its important role in learning and memory and also due to its implication in excitotoxicity processes. Some drugs targeting NMDARs are already being used to treat symptoms of disorders affecting the central nervous system (CNS). Here, we aim to review the implications of NMDAR in these CNS pathologies, its role as a potential therapeutic target, and the future perspectives for developing new treatments focused on these receptors.},
}

*Receptors, N-Methyl-D-Aspartate/metabolism
Humans
Animals
*Central Nervous System Diseases/metabolism/drug therapy
Neurodegenerative Diseases/metabolism/drug therapy

@article {pmid40005082,
year = {2025},
author = {Wang, X and Yi, Z and Zhang, Y and Zhang, J and Li, X and Qi, D and Wang, Q and Chai, X and Liu, H and Wang, G and Pan, Y and Liu, Y and Yu, G},
title = {Identification and Therapeutic Potential of Polymethoxylated Flavones in Citri Reticulatae Pericarpium for Alzheimer's Disease: Targeting Neuroinflammation.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {4},
pages = {},
doi = {10.3390/molecules30040771},
pmid = {40005082},
issn = {1420-3049},
support = {CI2021A00511//China Academy of Chinese Medical Sciences (CACMS) Innovation Fund/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Flavones/pharmacology/chemistry/therapeutic use ; Animals ; *Citrus/chemistry ; Mice ; Disease Models, Animal ; Neuroinflammatory Diseases/drug therapy/metabolism ; Flavonoids/chemistry/pharmacology/therapeutic use ; Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use ; Male ; Plant Extracts/chemistry/pharmacology ; },
abstract = {Neuroinflammation is a significant driving force in the pathogenesis and progression of central nervous system (CNS) disorders. Polymethoxylated flavones (PMFs), the key lipid-soluble constituents in Citri Reticulatae Pericarpium (CRP), exhibit excellent blood-brain barrier permeability and anti-inflammatory properties, holding therapeutic potential for CNS disorders. However, the specific bioactive components and therapeutic effects of PMFs in treating CNS disorders are not well understood. This study employed a comprehensive sequential metabolism approach to elucidate the dynamic biotransformation of PMFs in vivo and identified seven brain-targeting components. Subsequently, network pharmacology and experimental validation were utilized to explore the potential mechanisms of PMFs. The results suggested that PMFs have potential therapeutic value for Alzheimer's disease (AD)-like mice, with the inhibition of neuroinflammation likely being a key mechanism of their anti-AD effects. Notably, sinensetin, tangeretin, nobiletin, and 3,5,6,7,8,3',4'-heptamethoxyflavone were identified as potent neuroinflammatory inhibitors. This research elucidated the chemical and therapeutic foundations of PMFs, indicating their potential as treatments or nutritional supplements for AD prevention and treatment. Moreover, the integrated triad approach of sequential metabolism, network pharmacology, and experimental validation may serve as a promising strategy for screening bioactive compounds in herbs or functional foods, as well as for elucidating their therapeutic mechanisms.},
}

*Alzheimer Disease/drug therapy/metabolism
*Flavones/pharmacology/chemistry/therapeutic use
Animals
*Citrus/chemistry
Mice
Disease Models, Animal
Neuroinflammatory Diseases/drug therapy/metabolism
Flavonoids/chemistry/pharmacology/therapeutic use
Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use
Male
Plant Extracts/chemistry/pharmacology

@article {pmid40004604,
year = {2025},
author = {Sin, MK and Dage, JL and Nho, K and Dowling, NM and Seyfried, NT and Bennett, DA and Levey, AI and Ahmed, A},
title = {Plasma Biomarkers for Cerebral Amyloid Angiopathy and Implications for Amyloid-Related Imaging Abnormalities: A Comprehensive Review.},
journal = {Journal of clinical medicine},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/jcm14041070},
pmid = {40004604},
issn = {2077-0383},
abstract = {Anti-amyloid therapies (AATs) are increasingly being recognized as promising treatment options for Alzheimer's disease (AD). Amyloid-related imaging abnormalities (ARIAs), small areas of edema and microbleeds in the brain presenting as abnormal signals in MRIs of the brain for patients with AD, are the most common side effects of AATs. While most ARIAs are asymptomatic, they can be associated with symptoms like nausea, headache, confusion, and gait instability and, less commonly, with more serious complications such as seizures and death. Cerebral amyloid angiopathy (CAA) has been found to be a major risk for ARIA development. The identification of sensitive and reliable non-invasive biomarkers for CAA has been an area of AD research over the years, but with the approval of AATs, this area has taken on a new urgency. This comprehensive review highlights several potential biomarkers, such as Aβ40, Aβ40/42, phosphorylated-tau217, neurofilament light chain, glial fibrillary acidic protein, secreted phosphoprotein 1, placental growth factor, triggering receptor expressed on myeloid cells 2, cluster of differentiation 163, proteomics, and microRNA. Identifying and staging CAA even before its consequences can be detected via neuroimaging are critical to allow clinicians to judiciously select appropriate candidates for AATs, stratify monitoring, properly manage therapeutic regimens for those experiencing symptomatic ARIAs, and optimize the treatment to achieve the best outcomes. Future studies can test potential plasma biomarkers in human beings and evaluate predictive values of individual markers for CAA severity.},
}

@article {pmid40004175,
year = {2025},
author = {Sadiq, AH and Alam, MJ and Begum, F and Hasan, M and Kristof, J and Mamun, MA and Maniruzzaman, M and Shimizu, K and Kanazawa, T and Kahyo, T and Setou, M and Shimizu, K},
title = {Enhancing Galantamine Distribution in Rat Brain Using Microplasma-Assisted Nose-to-Brain Drug Delivery.},
journal = {International journal of molecular sciences},
volume = {26},
number = {4},
pages = {},
doi = {10.3390/ijms26041710},
pmid = {40004175},
issn = {1422-0067},
support = {JP23K17473, and JP24H00794//Japan Society for the Promotion of Science (JSPS) under the KAKENHI program/ ; },
mesh = {*Galantamine/pharmacokinetics/administration & dosage ; Animals ; Rats ; *Brain/metabolism ; *Drug Delivery Systems/methods ; *Administration, Intranasal ; Male ; Nasal Mucosa/metabolism ; Blood-Brain Barrier/metabolism ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Plasma Gases ; Rats, Sprague-Dawley ; Tissue Distribution ; },
abstract = {Nose-to-brain (N2B) drug delivery is a promising technique for the treatment of brain diseases. It allows a drug to enter the brain without passing through the blood-brain barrier. However, the nasal cavity and nasal mucosa can restrict the amount of drug absorbed. Recent studies of non-thermal plasma (NTP) have shown improvement in in vitro drug delivery to cells and tissues. However, whether NTP treatments can enhance the in vivo delivery of drugs for neurodegenerative disease like Alzheimer's disease (AD) into the brain via the N2B technique remains unclear. The drug used in this study was galantamine hydrobromide. Galantamine is used to treat patients with mild to moderate AD. Based on the principle of NTP, a type of dielectric barrier discharge (DBD) plasma, which we called spiral DBD microplasma, was designed. It was inserted into the nose of a rat to a depth of 2 mm. The spiral DBD microplasma was driven by a sinusoidal voltage for 4 min, followed by the immediate administration of galantamine. The effect of the microplasma treatment on the distribution of galantamine in the brain was evaluated using matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS). The results showed a high distribution of galantamine in the left and right brain hemispheres of the rat treated with plasma discharge compared to a control treated without plasma discharge. The spiral DBD microplasma is a novel contribution to DBD plasma designs. In addition, this technique for drug delivery has also created a novel approach with potential for becoming a non-invasive method of enhancing drug distribution in the brain for the treatment of neurological disorders.},
}

*Galantamine/pharmacokinetics/administration & dosage
Animals
Rats
*Brain/metabolism
*Drug Delivery Systems/methods
*Administration, Intranasal
Male
Nasal Mucosa/metabolism
Blood-Brain Barrier/metabolism
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Plasma Gases
Rats, Sprague-Dawley
Tissue Distribution

@article {pmid40003952,
year = {2025},
author = {Wang, Y and Zhao, J and Zhao, L},
title = {L-Lactate Administration Improved Synaptic Plasticity and Cognition in Early 3xTg-AD Mice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {4},
pages = {},
doi = {10.3390/ijms26041486},
pmid = {40003952},
issn = {1422-0067},
support = {2022YFC3600201//National Key Research and Development Program of China/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; *Neuronal Plasticity/drug effects ; *Hippocampus/metabolism/drug effects ; *Lactic Acid/pharmacology/metabolism ; *Cognition/drug effects ; *Long-Term Potentiation/drug effects ; *Mice, Transgenic ; *Disease Models, Animal ; Male ; Synapses/drug effects/metabolism ; Synaptophysin/metabolism/genetics ; },
abstract = {Synaptic plasticity impairment and behavioral deficits constitute classical pathological hallmarks in early-stage Alzheimer's disease (AD). Emerging evidence suggests these synaptic dysfunctions may stem from metabolic dysregulation, particularly impaired aerobic glycolysis. As a key product of astrocyte-mediated aerobic glycolysis, lactate serves dual roles as both an energy substrate and a signaling molecule, playing a critical regulatory role in synaptic plasticity and long-term memory formation. This study investigated whether exogenous L-lactate supplementation could ameliorate synaptic dysfunction and cognitive deficits in early-stage AD models. Our findings reveal significant reductions in hippocampal lactate levels in experimental AD mice. Systemic administration of L-lactate (200 mg/kg) effectively restored physiological lactate concentrations in both hippocampal tissue and cerebrospinal fluid (CSF). Chronic L-lactate treatment significantly improved spatial learning and memory performance in behavioral assessments. Electrophysiological recordings demonstrated that either acute bath application of L-lactate (2 mM) to hippocampal slices or chronic intraperitoneal administration enhanced high-frequency stimulation (HFS)-induced long-term potentiation (LTP) magnitude in 3xTg-AD mice. Ultrastructural analysis revealed that L-lactate treatment enhanced synaptic density and improved morphological features of hippocampal synapses. At the molecular level, L-lactate administration upregulated synaptic marker synaptophysin (SYP) expression while downregulating activity-regulated cytoskeletal-associated protein (ARC) levels in AD mice. These multimodal findings demonstrate that exogenous L-lactate supplementation effectively restores synaptic plasticity and cognitive function in early-stage 3xTg-AD mice through concurrent improvements at behavioral, structural, and molecular levels.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism
Mice
*Neuronal Plasticity/drug effects
*Hippocampus/metabolism/drug effects
*Lactic Acid/pharmacology/metabolism
*Cognition/drug effects
*Long-Term Potentiation/drug effects
*Mice, Transgenic
*Disease Models, Animal
Male
Synapses/drug effects/metabolism
Synaptophysin/metabolism/genetics

@article {pmid40002882,
year = {2025},
author = {Shirvani, A and Shirvani, P and Jonah, U and Moore, BE and Holick, MF},
title = {Suspected Mitochondrial Dysfunction and Complex Pathophysiology in Fatal Hypermobile Ehlers-Danlos Syndrome: Insights from a Case Report and Post-Mortem Findings.},
journal = {Biomedicines},
volume = {13},
number = {2},
pages = {},
doi = {10.3390/biomedicines13020469},
pmid = {40002882},
issn = {2227-9059},
abstract = {Background/Objectives: Hypermobile Ehlers-Danlos Syndrome (hEDS) is a complex connective tissue disorder with multi-systemic manifestations that significantly impact quality of life. This case report investigates the clinical course and molecular mechanisms of advanced hEDS through an in-depth case study and post-mortem findings. Methods: The clinical history of a 24-year-old patient with advanced hEDS was analyzed, focusing on progressive complications across multiple systems. Post-mortem examination and genetic analysis were performed to elucidate the underlying pathophysiology. Results: The patient's clinical course was marked by gastrointestinal, neurological, and immune complications requiring numerous surgical interventions. Post-mortem findings revealed severe gastrointestinal dysmotility and Alzheimer's Type II astrocytes. Genetic analysis identified variants in mtDNA genes ATP6, CYB, and ND, suggesting a potential role of impaired mitochondrial function in hEDS pathogenesis but requiring further validation through functional studies. Conclusions: This case report provides valuable insights into the potential role of mitochondrial dysfunction in advanced hEDS and highlights the need for further research in this area. Future studies should include comprehensive functional assays, longitudinal tissue sampling, family genetic analyses, and muscle biopsies to better understand the complex interplay between genetic factors, mitochondrial function, and clinical manifestations in hEDS. Establishing genetic bases and developing targeted therapies addressing both structural and metabolic aspects are crucial. The patient's legacy offers invaluable information that could significantly contribute to enhancing diagnostic accuracy and developing personalized treatment strategies for this challenging disorder, potentially leading to better care for individuals living with hEDS.},
}

@article {pmid40002846,
year = {2025},
author = {Vuic, B and Milos, T and Kvak, E and Konjevod, M and Tudor, L and Farkas, S and Nedic Erjavec, G and Nikolac Perkovic, M and Zelena, D and Svob Strac, D},
title = {Neuroprotective Effects of Dehydroepiandrosterone Sulphate Against Aβ Toxicity and Accumulation in Cellular and Animal Model of Alzheimer's Disease.},
journal = {Biomedicines},
volume = {13},
number = {2},
pages = {},
doi = {10.3390/biomedicines13020432},
pmid = {40002846},
issn = {2227-9059},
support = {IP-2019-04-6100//Croatian Science Foundation/ ; },
abstract = {Background/Objectives: Beneficial effects of neurosteroid dehydroepiandrosterone sulphate (DHEAS) on cognition, emotions and behavior have been previously reported, suggesting its potential in the prevention and treatment of various neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). This study aimed to investigate the potential neuroprotective actions of DHEAS against Aβ toxicity in both cellular and animal models of AD. Methods: After optimizing the AD model in vitro, we investigated the DHEAS effects on the viability and death of primary mouse neurons exposed to toxic Aβ42 oligomers for 24 h. In order to extend our research to an in vivo study, we further tested the acute effects of intraperitoneal DHEAS administration on the Aβ plaque density in different brain regions of 3xTg-AD mice, an animal model of AD. Results: In cell culture, DHEAS hampered the decrease in the neuronal viability caused by toxic Aβ oligomers, primarily by influencing mitochondrial function and apoptosis. DHEAS also counteracted the increase in the mRNA expression of selected genes (PI3K, Akt, Bcl2, Bax), induced in neuronal culture by treatment with Aβ42 oligomers. Obtained data suggested the involvement of mitochondria, caspases 3 and 7, as well as the PI3K/Akt and Bcl2 signaling network in the antiapoptotic properties of DHEAS in neurons. Forty-eight hours after DHEAS treatment, a significantly lower number of Aβ plaques was observed in the motor cortex but not in other brain areas of 3xTg-AD mice. Conclusions: Results indicated potential neuroprotective effects of DHEAS against Aβ toxicity and accumulation, suggesting that DHEAS supplementation should be further studied as a novel option for AD prevention and/or treatment.},
}

@article {pmid40002740,
year = {2025},
author = {Meng, K and Jia, H and Hou, X and Zhu, Z and Lu, Y and Feng, Y and Feng, J and Xia, Y and Tan, R and Cui, F and Yuan, J},
title = {Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies.},
journal = {Biomedicines},
volume = {13},
number = {2},
pages = {},
doi = {10.3390/biomedicines13020327},
pmid = {40002740},
issn = {2227-9059},
support = {600791001//the Research Start-up Fund of Jining Medical University/ ; JYHL2021MS13//Research Fund for Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University/ ; 81700055//the National Natural Science Foundation of China/ ; Grant No. D2016021//Outstanding Talent Research Funding of Xuzhou Medical University/ ; BK20160229//Natural Science Foundation of Jiangsu Province/ ; tsqn201909147//Taishan Scholars Program of Shandong Province/ ; G2Y-kJS-SD-2023-097//Co-construction of Science and Technology Projects by the Science and Technology Department of the State Administration of Traditional Chinese Medicine/ ; },
abstract = {Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Recent studies have shown that mitochondria play a broad role in cell signaling, immune response, and metabolic regulation. For example, mitochondrial dysfunction is closely associated with the onset and progression of a variety of diseases, including ND, cardiovascular diseases, diabetes, and cancer. The dysfunction of energy metabolism, imbalance of mitochondrial dynamics, or abnormal mitophagy can lead to the imbalance of mitochondrial homeostasis, which can induce pathological reactions such as oxidative stress, apoptosis, and inflammation, damage the nervous system, and participate in the occurrence and development of degenerative nervous system diseases such as AD, PD, and ALS. In this paper, the latest research progress of this subject is detailed. The mechanisms of oxidative stress, mitochondrial homeostasis, and mitophagy-mediated ND are reviewed from the perspectives of β-amyloid (Aβ) accumulation, dopamine neuron damage, and superoxide dismutase 1 (SOD1) mutation. Based on the mechanism research, new ideas and methods for the treatment and prevention of ND are proposed.},
}

@article {pmid40002697,
year = {2025},
author = {Kaštelan, S and Gverović Antunica, A and Puzović, V and Didović Pavičić, A and Čanović, S and Kovačević, P and Vučemilović, PAF and Konjevoda, S},
title = {Non-Invasive Retinal Biomarkers for Early Diagnosis of Alzheimer's Disease.},
journal = {Biomedicines},
volume = {13},
number = {2},
pages = {},
doi = {10.3390/biomedicines13020283},
pmid = {40002697},
issn = {2227-9059},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the brain associated with ageing and is the most prevalent form of dementia, affecting an estimated 55 million people worldwide, with projections suggesting this number will exceed 150 million by 2050. With its increasing prevalence, AD represents a significant global health challenge with potentially serious social and economic consequences. Diagnosing AD is particularly challenging as it requires timely recognition. Currently, there is no effective therapy for AD; however, certain medications may help slow its progression. Existing diagnostic methods such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and biomarker analysis in cerebrospinal fluid tend to be expensive and invasive, making them impractical for widespread use. Consequently, research into non-invasive biomarkers that enable early detection and screening for AD is a crucial area of contemporary clinical investigation. One promising approach for the early diagnosis of AD may be retinal imaging. As an extension of the central nervous system, the retina offers a distinctive opportunity for non-invasive brain structure and function assessment. Considering their shared embryological origins and the vascular and immunological similarities between the eye and brain, alterations in the retina may indicate pathological changes in the brain, including those specifically related to AD. Studies suggest that structural and vascular changes in the retina, particularly within the neuronal network and blood vessels, may act as markers of cerebral changes caused by AD. These retinal alterations have the potential to act as biomarkers for early diagnosis. Since AD is typically diagnosed only after a significant neuronal loss has occurred, identifying early diagnostic markers could enable timely intervention and help prevent disease progression. Non-invasive retinal imaging techniques, such as optical coherence tomography (OCT) and OCT angiography, provide accessible methods for the early detection of changes linked to AD. This review article focuses on the potential of retinal imaging as a non-invasive biomarker for early diagnosis of AD. Investigating the ageing of the retina and its connections to neurodegenerative processes could significantly enhance the diagnosis, monitoring, and treatment of AD, paving the way for new diagnostic and therapeutic approaches.},
}

@article {pmid40002692,
year = {2025},
author = {Dias, D and Socodato, R},
title = {Beyond Amyloid and Tau: The Critical Role of Microglia in Alzheimer's Disease Therapeutics.},
journal = {Biomedicines},
volume = {13},
number = {2},
pages = {},
doi = {10.3390/biomedicines13020279},
pmid = {40002692},
issn = {2227-9059},
abstract = {Alzheimer's disease (AD) is traditionally viewed through the lens of the amyloid cascade hypothesis, implicating amyloid-beta and tau protein aggregates as the main pathological culprits. However, burgeoning research points to the brain's resident immune cells, microglia, as critical players in AD pathogenesis, progression, and potential therapeutic interventions. This review examines the dynamic roles of microglia within the intricate framework of AD. We detail the involvement of these immune cells in neuroinflammation, explaining how their activation and response fluctuations may influence the disease trajectory. We further elucidate the complex relationship between microglia and amyloid-beta pathology. This study highlights the dual nature of these cells, which contribute to both aggregation and clearance of the amyloid-beta protein. Moreover, an in-depth analysis of the interplay between microglia and tau unveils the significant, yet often overlooked, impact of this interaction on neurodegeneration in AD. Shifting from the conventional therapeutic approaches, we assess the current AD treatments primarily targeting amyloid and tau and introduce novel strategies that involve manipulating microglial functions. These innovative methods herald a potential paradigm shift in the management of AD. Finally, we explore the burgeoning field of precision diagnosis and the pursuit of robust AD biomarkers. We underline how a more profound comprehension of microglial biology could enrich these essential areas, potentially paving the way for more accurate diagnostic tools and tailored treatment strategies. In conclusion, this review expands on the conventional perspective of AD pathology and treatment, drawing attention to the multifaceted roles of microglia. As we continue to enhance our understanding of these cells, microglial-focused therapeutic interventions emerge as a promising frontier to bolster our arsenal to fight against AD.},
}

@article {pmid40002547,
year = {2025},
author = {ALNasser, MN and Alboraiy, GM and Alsowig, EM and Alqattan, FM},
title = {Cholinesterase Inhibitors from Plants and Their Potential in Alzheimer's Treatment: Systematic Review.},
journal = {Brain sciences},
volume = {15},
number = {2},
pages = {},
doi = {10.3390/brainsci15020215},
pmid = {40002547},
issn = {2076-3425},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline, primarily due to dysfunction of acetylcholine caused by acetylcholinesterase and butyrylcholinesterase. While synthetic cholinesterase inhibitors like donepezil, rivastigmine, and galantamine are commonly used, they have notable side effects, prompting interest in natural alternatives. Medicinal plants, rich in bioactive compounds like flavonoids and alkaloids, have shown potential as cholinesterase inhibitors with additional antioxidants and anti-inflammatory benefits. This study aimed to evaluate the cholinesterase-inhibiting effects of various plant species and their compounds to identify new therapeutic candidates and reduce side effects.

METHOD: A PRISMA-compliant review was conducted, screening studies from multiple databases, with a final inclusion of 64 in vivo studies.

RESULTS: These studies highlighted plant extracts such as Ferula ammoniacum, Elaeagnus umbellata, Bacopa monnieri, and Centella asiatica, which improved memory, reduced oxidative stress, and provided neuroprotection. Some extracts also reduced amyloid plaques, enhanced neuronal integrity, and restored cholinesterase activity, indicating their potential as therapeutic agents for AD and other neurodegenerative diseases.

CONCLUSIONS: The findings underscore the promise of plant-based compounds in treating cognitive decline and cholinergic dysfunction in AD, advocating for further research into their therapeutic potential.},
}

@article {pmid40002497,
year = {2025},
author = {Lomelí Martínez, SM and Pacheco Moisés, FP and Bitzer-Quintero, OK and Ramírez-Jirano, J and Delgado-Lara, DLC and Cortés Trujillo, I and Torres Jasso, JH and Salazar-Flores, J and Torres-Sánchez, ED},
title = {Effect of N-Acetyl Cysteine as an Adjuvant Treatment in Alzheimer's Disease.},
journal = {Brain sciences},
volume = {15},
number = {2},
pages = {},
doi = {10.3390/brainsci15020164},
pmid = {40002497},
issn = {2076-3425},
abstract = {Oxidative stress levels are exacerbated in Alzheimer's disease (AD). This phenomenon feeds back into the overactivation of oxidase enzymes, mitochondrial dysfunction, and the formation of advanced glycation end-products (AGEs), with the stimulation of their receptors (RAGE). These factors stimulate Aβ peptide aggregation and tau hyperphosphorylation through multiple pathways, which are addressed in this paper. The aim of this study was to evaluate the regulatory effect of N-acetyl cysteine (NAC) on oxidant/antioxidant balance as an adjuvant treatment in patients with AD. The results obtained showed that NAC supplementation produced improved cognitive performance, decreased levels of oxidative stress markers, lowered activities of oxidase enzymes, increased antioxidant responses, and attenuated inflammatory and apoptotic markers. Moreover, NAC reversed mitochondrial dysfunction, lowered AGEs-RAGE formation, attenuated Aβ peptide oligomerization, and reduced phosphorylation of tau, thereby halting the formation of neurofibrillary tangles and the progression of AD.},
}

@article {pmid40002310,
year = {2025},
author = {Zhou, Q and Wu, XN and Luo, WH and Huang, QH and Feng, LL and Wu, Y and Zhang, C},
title = {Discovery of Effective Inhibitors Against Phosphodiesterase 9, a Potential Therapeutic Target of Alzheimer's Disease with Antioxidant Capacities.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {2},
pages = {},
doi = {10.3390/antiox14020123},
pmid = {40002310},
issn = {2076-3921},
support = {22370192, 21977127, and 82003652//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is a widely recognized type of dementia that leads to progressive cognitive decline and memory loss, affecting a significant number of people and their families worldwide. Given the multifactorial nature of AD, multitarget-directed ligands (MTDLs) hold promise in developing effective drugs for AD. Phosphodiesterase-9 (PDE9) is emerging as a promising target for AD therapy. In this study, by combining a PDE9 inhibitor C33 with the antioxidant melatonin, we designed and discovered a series of pyrazolopyrimidinone derivatives that simultaneously inhibit PDE9 and possess antioxidant activities. Molecular docking, together with dynamics simulations, were applied to accelerate compound design and reduce synthetic work. Four out of the 14 compounds were validated as effective PDE9 inhibitors with comparable antioxidant activity. Notably, compounds 17b and 17d demonstrated IC50 values of 91 and 89 nM against PDE9, respectively, with good antioxidant activities (ORAC (Trolox) of 2.00 and 2.60). This work provides a new approach for designing MTDLs for the treatment of AD and offers insights for further structural modifications of PDE9 inhibitors with antioxidant capacities.},
}

@article {pmid40001529,
year = {2025},
author = {Onu, CJ and Adu, M and Chakkour, M and Kumar, V and Greenberg, ML},
title = {Inositol Phosphates and Synthesizing Enzymes: Implications in Neurodegenerative Disorders.},
journal = {Biomolecules},
volume = {15},
number = {2},
pages = {},
doi = {10.3390/biom15020225},
pmid = {40001529},
issn = {2218-273X},
support = {GM125082/GF/NIH HHS/United States ; GM149271/GF/NIH HHS/United States ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Inositol Phosphates/metabolism ; Animals ; Parkinson Disease/metabolism ; Alzheimer Disease/metabolism ; Signal Transduction ; Inositol/metabolism ; },
abstract = {Inositol is a vital sugar molecule involved in numerous signaling pathways required for cellular homeostasis and cell survival. Myo-inositol and its phospho-derivatives, inositol phosphates (IPs), are the most prevalent forms of inositol found in living cells. They are involved in regulating ion channels, metabolic flux, stress response, and other key biological processes. While emerging research has highlighted the significant roles of inositol phosphates in immunity, cancer, and metabolic diseases, there is a lack of comprehensive reviews on their roles in psychiatric and neurological disorders. This review aims to fill that gap by analyzing the existing literature on the importance of inositol phosphates in severe psychiatric and neurological conditions such as Parkinson's disease, Alzheimer's disease, bipolar disorder, amyotrophic lateral sclerosis, schizophrenia, and Huntington's disease, underscoring the potential to pave the way for new treatment regimens for these debilitating disorders targeting inositol pathways.},
}

Humans
*Neurodegenerative Diseases/metabolism
*Inositol Phosphates/metabolism
Animals
Parkinson Disease/metabolism
Alzheimer Disease/metabolism
Signal Transduction
Inositol/metabolism

@article {pmid40001482,
year = {2025},
author = {Kim, KS and Lee, R and Park, I and Hwang, SH and Kim, Y and Jang, JW and Kim, HS and Choi, SM and Kim, SJ and Cho, HJ and Cho, IH and Kim, JH and Kim, DG and Nah, SY},
title = {Gintonin Binds to Reduced LPA4 Receptor Subtype in Human Cortical Neurons in Alzheimer's Disease Brains.},
journal = {Biomolecules},
volume = {15},
number = {2},
pages = {},
doi = {10.3390/biom15020179},
pmid = {40001482},
issn = {2218-273X},
support = {2023R1A2C1003481//National Research Foundation of Korea/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Neurons/metabolism ; *Receptors, Lysophosphatidic Acid/metabolism ; *Cerebral Cortex/metabolism/pathology ; Male ; Female ; Aged ; Plant Extracts/pharmacology/chemistry ; Protein Binding ; },
abstract = {Ginseng, a traditional herbal medicine with a long history of use, is known to support human health, particularly by influencing brain function. Recent studies have identified gintonin, a lysophosphatidic acid (LPA) receptor ligand derived from ginseng, as a key bioactive. However, the specific LPA receptor subtypes targeted by gintonin in the human brain to exert its anti-Alzheimer's (AD) effects remain unclear. This study aimed to elucidate the LPA receptor subtype targeted by gintonin in the human cortex. Using a fluorescent gintonin conjugate, we investigated receptor binding in cortical samples from healthy individuals (n = 4) and AD patients (n = 4). Our results demonstrated that fluorescent gintonin selectively binds to human cortical neurons rather than glial cells and that gintonin-binding sites are co-localized with the LPA4 receptor subtype. Furthermore, the expression of LPA4 receptors was significantly reduced in the cortical neurons of AD patients. These results suggest that the LPA4 receptor may serve as a novel histopathological marker for AD and represent a promising therapeutic target for gintonin-based prevention and treatment strategies.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Neurons/metabolism
*Receptors, Lysophosphatidic Acid/metabolism
*Cerebral Cortex/metabolism/pathology
Male
Female
Aged
Plant Extracts/pharmacology/chemistry
Protein Binding

@article {pmid40001197,
year = {2025},
author = {Choi, H and Kim, HJ and Lee, SE and Song, HH and Kim, J and Han, J and Jeong, JH and Lee, DY and Chang, S and Mook-Jung, I},
title = {25-Hydroxycholesterol modulates microglial function and exacerbates Alzheimer's disease pathology: mechanistic insights and therapeutic potential of cholesterol esterification inhibition.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {50},
pmid = {40001197},
issn = {1742-2094},
support = {RS-2023-00274420//National Research Foundation of Korea/ ; RS-2020-KH106747//Korea Dementia Research Center/ ; },
mesh = {*Hydroxycholesterols/pharmacology/metabolism ; Animals ; *Alzheimer Disease/metabolism/pathology/drug therapy ; Mice ; *Microglia/drug effects/metabolism/pathology ; *Mice, Transgenic ; Esterification ; Phagocytosis/drug effects ; Humans ; Cholesterol/metabolism ; Sulfonamides/pharmacology ; Mice, Inbred C57BL ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Cells, Cultured ; Acetamides ; },
abstract = {This study investigates the role of 25-hydroxycholesterol (25HC), a metabolite produced by cholesterol hydroxylase encoded by the Ch25h gene, in modulating microglial function and its potential implications in Alzheimer's disease (AD) pathology. We demonstrated that 25HC impairs microglial surveillance, reduces phagocytic capacity, and increases the production of pro-inflammatory cytokines. In vivo two-photon microscopy revealed that 25HC administration diminishes microglial response to brain lesions, while flow cytometry confirmed reduced phagocytosis in both in vivo and in vitro models. Additionally, amyloid-beta (Aβ) was shown to upregulate Ch25h expression and elevate 25HC levels in microglia, exacerbating these functional impairments. Mechanistically, 25HC was found to enhance cholesterol esterification, disrupt cell membrane dynamics, and further reduce microglial mobility and phagocytosis. Treatment with Avasimibe, a cholesterol esterification inhibitor, restored membrane dynamics and microglial function, leading to attenuated AD pathology in a 5XFAD mouse model. These findings suggest that 25HC-induced changes in microglial function contribute to AD progression, and targeting cholesterol metabolism could offer therapeutic potential.},
}

*Hydroxycholesterols/pharmacology/metabolism
Animals
*Alzheimer Disease/metabolism/pathology/drug therapy
Mice
*Microglia/drug effects/metabolism/pathology
*Mice, Transgenic
Esterification
Phagocytosis/drug effects
Humans
Cholesterol/metabolism
Sulfonamides/pharmacology
Mice, Inbred C57BL
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Cells, Cultured
Acetamides

@article {pmid40000636,
year = {2025},
author = {Grandke, F and Fehlmann, T and Kern, F and Gate, DM and Wolff, TW and Leventhal, O and Channappa, D and Hirsch, P and Wilson, EN and Meese, E and Liu, C and Shi, Q and Flotho, M and Li, Y and Chen, C and Yu, Y and Xu, J and Junkin, M and Wang, Z and Wu, T and Liu, L and Hou, Y and Andreasson, KI and Gansen, JS and Mass, E and Poston, K and Wyss-Coray, T and Keller, A},
title = {A single-cell atlas to map sex-specific gene-expression changes in blood upon neurodegeneration.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {1965},
pmid = {40000636},
issn = {2041-1723},
support = {14446, 17047 (subc. 125491594)//Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)/ ; MJFF-021418//Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)/ ; 466168626//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; },
mesh = {Humans ; Female ; Male ; *Parkinson Disease/genetics/blood ; *Alzheimer Disease/genetics/blood ; *Single-Cell Analysis/methods ; Aged ; *Leukocytes, Mononuclear/metabolism ; *Cognitive Dysfunction/genetics/blood ; *Gene Expression Profiling/methods ; Middle Aged ; Transcriptome ; Neurodegenerative Diseases/genetics/blood ; Sex Factors ; Aged, 80 and over ; },
abstract = {The clinical course and treatment of neurodegenerative disease are complicated by immune-system interference and chronic inflammatory processes, which remain incompletely understood. Mapping immune signatures in larger human cohorts through single-cell gene expression profiling supports our understanding of observed peripheral changes in neurodegeneration. Here, we employ single-cell gene expression profiling of over 909k peripheral blood mononuclear cells (PBMCs) from 121 healthy individuals, 48 patients with mild cognitive impairment (MCI), 46 with Parkinson's disease (PD), 27 with Alzheimer's disease (AD), and 15 with both PD and MCI. The dataset is interactively accessible through a freely available website (https://www.ccb.uni-saarland.de/adrcsc). In this work, we identify disease-associated changes in blood cell type composition and the gene expression in a sex-specific manner, offering insights into peripheral and solid tissue signatures in AD and PD.},
}

Humans
Female
Male
*Parkinson Disease/genetics/blood
*Alzheimer Disease/genetics/blood
*Single-Cell Analysis/methods
Aged
*Leukocytes, Mononuclear/metabolism
*Cognitive Dysfunction/genetics/blood
*Gene Expression Profiling/methods
Middle Aged
Transcriptome
Neurodegenerative Diseases/genetics/blood
Sex Factors
Aged, 80 and over

@article {pmid40000573,
year = {2025},
author = {Ackley, SF and Wang, J and Chen, R and Hill-Jarrett, TG and Rojas-Saunero, LP and Stokes, A and Shah, SJ and Glymour, MM and , },
title = {Methods to crosswalk between cognitive test scores using data from the Alzheimer's Disease Neuroimaging Cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {2},
pages = {e14597},
doi = {10.1002/alz.14597},
pmid = {40000573},
issn = {1552-5279},
support = {U01 AG024904/AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; P01AG082653//NIH/NIA/ ; F99AG083306//NIH/NIA/ ; T32AG078115//NIH/NIA/ ; K00AG068431//NIH/NIA/ ; R01AG057869//NIH/NIA/ ; K99AG073454//NIH/NIA/ ; R00AG073454//NIH/NIA/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/diagnosis ; *Neuroimaging/methods ; *Mental Status and Dementia Tests/statistics & numerical data ; Aged ; Cohort Studies ; *Neuropsychological Tests/statistics & numerical data ; Male ; Female ; tau Proteins/blood ; Aged, 80 and over ; Cognition/physiology ; },
abstract = {INTRODUCTION: Studies use multiple different instruments to measure dementia-related outcomes, making head-to-head comparisons of interventions difficult.

METHODS: To address this gap, we developed two methods to crosswalk estimated treatment effects on cognitive outcomes that are flexible, broadly applicable, and do not rely on strong distributional assumptions.

RESULTS: We present two methods to crosswalk effect estimates using one measure to estimates using another measure, illustrated with global cognitive measures from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Specifically, we develop crosswalks for the following measures and associated change scores over time: the clinical dementia rating scale sum of box (CDR-SB), Montreal Cognitive Assessment (MoCA), and Mini-Mental State Examination (MMSE) scores. Finally, a setting in which crosswalking is not appropriate is illustrated with plasma phosphorylated tau (p-tau) concentration and global cognitive measures.

DISCUSSION: Given the inconsistent collection and reporting of dementia and cognitive outcomes across studies, these crosswalking methods offer a valuable approach to harmonizing and comparing results reported on different scales.

HIGHLIGHTS: Developed methods to crosswalk from one cognitive outcome to another in studies of dementia interventions. Methods illustrated using combinations of global cognitive tests: the CDR-SB, MoCA, and MMSE. Illustrates scenarios where crosswalking may not be appropriate for certain combinations of measures. Crosswalking methods support comparison of interventions with accurate error propagation. Facilitates inclusion of more studies in meta-analyses by increasing data comparability.},
}

Humans
*Alzheimer Disease/diagnostic imaging/diagnosis
*Neuroimaging/methods
*Mental Status and Dementia Tests/statistics & numerical data
Aged
Cohort Studies
*Neuropsychological Tests/statistics & numerical data
Male
Female
tau Proteins/blood
Aged, 80 and over
Cognition/physiology

@article {pmid40000385,
year = {2025},
author = {Chen, Y and Zhang, D and Chen, T and Zhao, L and Wen, L and Hou, R},
title = {Traditional Chinese Medicine for Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {The American journal of Chinese medicine},
volume = {53},
number = {1},
pages = {1-15},
doi = {10.1142/S0192415X25500016},
pmid = {40000385},
issn = {1793-6853},
mesh = {*Alzheimer Disease/therapy/drug therapy ; Humans ; *Medicine, Chinese Traditional/methods ; *Drugs, Chinese Herbal/therapeutic use ; *Cognition/drug effects ; Phytotherapy ; Activities of Daily Living ; Treatment Outcome ; },
abstract = {The treatment of Alzheimer's Disease (AD) remains a challenge for modern medicine due to its complex pathogenesis. Traditional Chinese Medicine (TCM) has demonstrated significant success in the prevention and treatment of variable medical conditions. For AD pharmacological management, TCM could provide promising approaches. This study aimed to systematically evaluate the current evidence of the effects of TCM therapies on AD. A systematic search of the literature was performed on electronic databases including PubMed, the Cochrane Library, the Chinese National Knowledge Infrastructure (CNKI), and Web of Science. Thirteen studies were included in this review, subject to inclusion and exclusion criteria. Screening, data extraction, and quality assessment were undertaken following the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Our results show that TCM offered a significant improvement in cognitive functioning compared to the control group, measured on both MMSE and ADAS-CoG scales, suggesting its potential utility in slowing cognitive decline and improving cognitive function as compared to conventional drug treatments and placebos. No significant difference was found for scores of neuropsychiatric symptoms (NPI) or ability to perform daily living activities (ADCS-ADL). These findings highlight TCM as a potential adjuvant therapy, in combination with conventional medicine, to improve the effectiveness and reduce the limitations of conventional AD drug regimes. Studies with larger sample sizes, rigorous study designs, accurate long-term reporting, and correlation to neuropathological markers are needed in the future to enhance the evidence base for the use of TCM in AD patients, and to further confirm its efficacy.},
}

*Alzheimer Disease/therapy/drug therapy
Humans
*Medicine, Chinese Traditional/methods
*Drugs, Chinese Herbal/therapeutic use
*Cognition/drug effects
Phytotherapy
Activities of Daily Living
Treatment Outcome

@article {pmid40000032,
year = {2025},
author = {Ng, S and Hornblass, A and Habibi, P and Ikramuddin, S and Chen, J and Feng, W and Cai, D},
title = {Updates on vascular dementia.},
journal = {Stroke and vascular neurology},
volume = {},
number = {},
pages = {},
doi = {10.1136/svn-2025-004048},
pmid = {40000032},
issn = {2059-8696},
abstract = {Vascular dementia (VaD) is the second leading cause of dementia after Alzheimer's disease (AD). In comparison to AD, there is a decline in the incidence of VaD due to recent improvements in cardiovascular risk factors. Brain hypoperfusion and hypoxia due to vascular pathologies have been postulated as the primary disease mechanism of VaD. However, other factors such as neuroinflammation may also contribute to the development of VaD. Non-modifiable and modifiable risk factors have been attributed to VaD. The clinical features overlapping between AD and VaD create significant challenges for physicians. Newly developed biomarkers may potentially help differentiate VaD from other forms of dementia. Unlike AD, there is no Food and Drug Administration-approved drug or device for treating VaD. Current treatment options mainly target symptoms rather than slowing the development or progression of VaD. There are ongoing research studies testing the efficacy of various therapeutic strategies for VaD. In this narrative review, we will summarise current findings on epidemiology, attributed risk factors and disease mechanisms, as well as emphasise the importance of optimising lifestyle modifications and comorbid condition management in preventing or slowing down the development of VaD. Finally, current therapies and ongoing research studies of novel therapeutic interventions such as stem-cell therapy and neuromodulation are highlighted.},
}

@article {pmid39999928,
year = {2025},
author = {Vollhardt, A and Frölich, L and Stockbauer, AC and Danek, A and Schmitz, C and Wahl, AS},
title = {Towards a better diagnosis and treatment of dementia: Identifying common and distinct neuropathological mechanisms in Alzheimer's and vascular dementia.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {106845},
doi = {10.1016/j.nbd.2025.106845},
pmid = {39999928},
issn = {1095-953X},
abstract = {Alzheimer's disease (AD) and vascular dementia (VaD) together contribute to almost 90 % of all dementia cases leading to major health challenges of our time with a substantial global socioeconomic burden. While in AD, the improved understanding of Amyloid beta (Aß) mismetabolism and tau hyperphosphorylation as pathophysiological hallmarks has led to significant clinical breakthroughs, similar advances in VaD are lacking. After comparing the clinical presentation, including risk factors, disease patterns, course of diseases and further diagnostic parameters for both forms of dementia, we highlight the importance of shared pathomechanisms found in AD and VaD: Endothelial damage, blood brain barrier (BBB) breakdown and hypoperfusion inducing oxidative stress and inflammation and thus trophic uncoupling in the neurovascular unit. A dysfunctional endothelium and BBB lead to the accumulation of neurotoxic molecules and Aß through impaired clearance, which in turn leads to neurodegeneration. In this context we discuss possible neuropathological parameters, which might serve as biomarkers and thus improve diagnostic accuracy or reveal targets for novel therapeutic strategies for both forms of dementia.},
}

@article {pmid39999809,
year = {2025},
author = {Umoh, I and Xia, X and Winblad, B and Aye, S and Aho, E and Rhodius-Meester, HFM and Jönsson, L},
title = {Deciphering Perspectives: A European survey on clinical decision support tools for dementia and Alzheimer's disease.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1-17},
doi = {10.1159/000544801},
pmid = {39999809},
issn = {1421-9824},
abstract = {INTRODUCTION: Technological advancements like digital monitoring tools, disease modifying therapies and artificial intelligence have been shown to improve the clinical management of neurocognitive diseases like Alzheimer's disease (AD). To enhance implementation in daily practice, users' input is essential in the technology development process. This study aimed to determine clinician's perspective of clinical decision support systems (CDSS) in the management of dementia and AD.

METHOD: A survey was conducted targeting clinicians practicing in the field of dementia across Europe. A sixty-five-item digital questionnaire was administered, and opinions were enquired across the domains of diagnosis, disease modifying therapy and prognosis, including factors that affect tool implementation and utilization.

RESULTS: Eighty-four clinicians (including specialist physicians, psychologists and nurses) responded to this survey, and more than 50% had no knowledge or experience with CDSS. Most of the respondents reported the ability to predict the likelihood of AD as the most important diagnostic function. It was surprising to find the middling responses for the ability to predict amyloid positivity. The majority indicated assessment of treatment eligibility for disease-modifying therapy as vital, and the ability to predict cognitive and functional decline as the most important prognostic functions. Data accuracy and ease of use were noted as most necessary to facilitate CDSS adoption and implementation.

CONCLUSION: Findings from this study contribute to the future development of CDSS in this field, especially regarding the approval and imminent use of disease modifying therapies, a comprehensive tool that is precise and user friendly would improve clinical decisions and efficiency.},
}

@article {pmid39999645,
year = {2025},
author = {Djebari, S and Jiménez-Herrera, R and Iborra-Lázaro, G and Jiménez-Díaz, L and Navarro-López, JD},
title = {Social and contextual memory impairments induced by Amyloid-β oligomers are rescued by Sigma-1 receptor activation.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {184},
number = {},
pages = {117914},
doi = {10.1016/j.biopha.2025.117914},
pmid = {39999645},
issn = {1950-6007},
abstract = {Sigma-1 receptors (S1Rs) are widely expressed throughout the central nervous system and modulate neuron intracellular calcium levels, leading to changes in neurotransmitter release and neuronal activity. They also interact with various proteins and signaling pathways, playing a key role in regulating synaptic plasticity in brain areas such as the hippocampus, thereby influencing learning and memory processes. This opens a research avenue to explore S1R modulation as a potential therapeutic target in diseases involving hippocampal synaptic alterations and compromised cognitive processes, such as Alzheimer's disease (AD). Here, we hypothesize that pharmacological activation of S1R could counteract synaptic plasticity deficits and hippocampal-dependent cognitive alterations in an early-stage amyloidosis model of Alzheimer's disease, induced by intracerebroventricular (icv) administration of Aβ1-42 oligomers (oAβ1-42). For that purpose, we investigate ex vivo CA3-CA1 synaptic plasticity, while in vivo, we performed open field habituation and social recognition tasks to assess contextual and social memory, respectively. Our data show that pharmacological activation of S1Rs with the selective agonist PRE-084 counteract oAβ1-42 deleterious effects on CA3-CA1 long-term synaptic plasticity (LTP), and hippocampal-dependent contextual and social memory, without alterations of spontaneous behaviors. Together, these results provide further evidence for the role of S1Rs in ameliorating hippocampal synaptic and contextual memory dysfunctions and introduce novel insight into their involvement in early amyloid-induced social memory deficits, highlighting their potential for developing comprehensive treatments for early AD. Also, the absence of adverse behavioral outcomes associated with PRE-084 treatment suggests a favorable safety profile in preclinical models, supporting its potential as a therapeutic option.},
}

@article {pmid39998958,
year = {2025},
author = {Huang, C and Wei, Z and Zheng, N and Yan, J and Zhang, J and Ye, X and Zhao, W},
title = {The interaction between dysfunction of vasculature and tauopathy in Alzheimer's disease and related dementias.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {2},
pages = {e14618},
doi = {10.1002/alz.14618},
pmid = {39998958},
issn = {1552-5279},
support = {81973919//the National Natural Science Foundation of China/ ; 2019A1515011299//Natural Science Foundation of Guangdong Province/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/physiopathology ; Tauopathies/pathology/metabolism/physiopathology ; Blood-Brain Barrier/pathology ; Animals ; tau Proteins/metabolism ; Dementia/pathology/physiopathology ; Risk Factors ; },
abstract = {Tauopathy is one of the pathological features of Alzheimer's disease and related dementias (ADRD). At present, there have been many studies on the formation, deposition, and intercellular transmission of tau in neurons and immune cells. The vasculature is an important component of the central nervous system. This review discusses the interaction between vasculature and tau in detail from three aspects. (1) The vascular risk factors (VRFs) discussed in this review include diabetes mellitus (DM), abnormal blood pressure (BP), and hypercholesterolemia. (2) In ADRD pathology, the hyperphosphorylation and deposition of tau interact with disrupted vasculature, such as different cells (endothelial cells, smooth muscular cells, and pericytes), the blood-brain barrier (BBB), and the cerebral lymphatic system. (3) The functions of vasculature are regulated by various signaling transductions. Endothelial nitric oxide synthase/nitric oxide, calcium signaling, Rho/Rho-associated coiled-coil containing Kinase, and receptors for advanced glycation end products are discussed in this review. Our findings indicate that the prevention and treatment of vascular health may be a potential target for ADRD combination therapy. HIGHLIGHTS: Persistent VRFs increase early disruption of vascular mechanisms and are strongly associated with tau pathology in ADRD. Cell dysfunction in the vasculature causes BBB leakage and drainage incapacity of the cerebral lymphatic system, which interacts with tau pathology. Signaling molecules in the vasculature regulate vasodilation and contraction, angiogenesis, and CBF. Abnormal signaling transduction is related to tau hyperphosphorylation and deposition.},
}

Humans
*Alzheimer Disease/pathology/metabolism/physiopathology
Tauopathies/pathology/metabolism/physiopathology
Blood-Brain Barrier/pathology
Animals
tau Proteins/metabolism
Dementia/pathology/physiopathology
Risk Factors

@article {pmid39998175,
year = {2025},
author = {Yao, K and Wang, S and Xu, Z and Fan, Z and Chen, Z and Jia, P and Tu, S and Liu, Y and Lin, X and Xu, Y and Fang, Y and Dou, B and Guo, Y},
title = {Mechanisms of comorbidity between Alzheimer's disease and pain.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {2},
pages = {e14605},
doi = {10.1002/alz.14605},
pmid = {39998175},
issn = {1552-5279},
support = {82030125//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology ; *Pain/epidemiology ; *Comorbidity ; Pain Management ; Neuroinflammatory Diseases/epidemiology ; Brain/pathology ; },
abstract = {Clinical studies have revealed a significant correlation between pain and neurodegenerative diseases, particularly Alzheimer's disease (AD). However, due to cognitive and speech impairments, AD patients, especially those in moderate to severe stages, are often overlooked in pain management. The challenges in obtaining pain-related information from this population exacerbate the issue. Although recent clinical research has increasingly recognized the comorbidity of AD and pain, the pathological alterations and interactive mechanisms underlying this relationship remain inadequately explored. This review provides a comprehensive analysis of the clinical features and pathological mechanisms of AD with and without pain comorbidity. It examines underlying processes, including neuroinflammation, peripheral-central immune interactions, and neurotransmitter dynamics. Furthermore, it highlights current pain assessment and management strategies in AD patients. By offering a theoretical framework, this review aims to support the development of effective pain management approaches and serve as a reference for clinical interventions targeting AD-associated pain. HIGHLIGHTS: The comorbidity between AD and CP encompasses multiple interrelated biological pathways, such as neurodegeneration and inflammatory responses. The damage to neurons and synapses in AD patients influences the brain regions responsible for processing pain, thereby reducing the pain response. Neuroinflammation plays a vital role in the development of both AD and CP. Enhanced inflammatory responses have an impact on the CNS and promote sensitization. Common neurotransmitter alterations exist in the comorbidity of AD and CP, influencing cognition, emotion, and pain perception.},
}

Humans
*Alzheimer Disease/epidemiology
*Pain/epidemiology
*Comorbidity
Pain Management
Neuroinflammatory Diseases/epidemiology
Brain/pathology

@article {pmid39998021,
year = {2025},
author = {Khartabil, N and Awaness, A},
title = {Targeting Amyloid Pathology in Early Alzheimer's: The Promise of Donanemab-Azbt.},
journal = {Pharmacy (Basel, Switzerland)},
volume = {13},
number = {1},
pages = {},
doi = {10.3390/pharmacy13010023},
pmid = {39998021},
issn = {2226-4787},
abstract = {OBJECTIVE: The purpose of this review is to examine the potential role of donanemab-azbt in the treatment and management of early-stage Alzheimer's disease (AD), with a focus on its efficacy, safety, and clinical relevance based on data from key clinical trials.

DATA SOURCES: A comprehensive literature search of PubMed was conducted using relevant keywords such as "donanemab", "Alzheimer's disease", "Kisunla", "TRAILBLAZER clinical trials", and "amyloid-related imaging abnormalities (ARIA)". Additional data were extracted from clinical trial records (clinicaltrials.gov), conference abstracts, and product monographs.

Only English-language studies conducted in human populations were included. Clinical trials and peer-reviewed studies detailing the efficacy, safety, and mechanistic insights of donanemab-azbt were prioritized.

DATA SYNTHESIS: Key findings from the TRAILBLAZER series of clinical trials highlighted the potential of donanemab-azbt in slowing cognitive and functional decline in early-stage AD: (1) TRAILBLAZER-ALZ (Phase 2): This trial focused on participants with intermediate levels of tau protein. Results demonstrated a statistically significant slowing of cognitive and functional decline. (2) TRAILBLAZER-ALZ 2 (Phase 3): A large-scale, randomized, double-blind, placebo-controlled study confirmed the efficacy of donanemab-azbt in reducing amyloid plaque accumulation and cognitive decline. Key results included a 35% slowing of decline on the Integrated Alzheimer's Disease Rating Scale (iADRS) and a 36% slowing on the Clinical Dementia Rating-Sum of Boxes (CDR-SB). Additional secondary outcomes showed improvements in activities of daily living and reduced risk of disease progression. (3) TRAILBLAZER-ALZ 3: This ongoing trial is evaluating donanemab's potential in delaying or preventing Alois Alzheimer in cognitively normal individuals with amyloid plaques, broadening the scope of early intervention strategies. (4) TRAILBLAZER-ALZ 4: A head-to-head comparison with aducanumab revealed superior amyloid plaque clearance with donanemab. (5) TRAILBLAZER-ALZ 5: Currently recruiting, this trial aims to evaluate safety and efficacy across diverse populations with varying tau levels and comorbidities. (6) TRAILBLAZER-ALZ 6 (Phase 3b): This trial investigates modified dosing regimens to reduce ARIA while maintaining efficacy, particularly in populations with genetic risk factors like ApoE ε4 homozygotes.

Donanemab-azbt represents a promising treatment option for patients with early-stage AD. It specifically targets and reduces amyloid beta plaques, a hallmark of the disease, potentially slowing progression and preserving cognitive function. However, its administration requires careful patient selection, including genetic testing for ApoE ε4 status, to mitigate risks of ARIA. Furthermore, the findings emphasize the importance of close monitoring during treatment.

CONCLUSIONS: Donanemab-azbt offers a new avenue for managing early-stage AD, showing promise in reducing amyloid burden and slowing cognitive decline. While its efficacy and safety have been demonstrated in clinical trials, further research is essential to validate long-term outcomes, assess effectiveness across diverse populations, and refine dosing strategies to minimize side effects. With continued investigation, donanemab-azbt could significantly impact the clinical landscape of AD treatment.},
}

@article {pmid39997718,
year = {2025},
author = {Niu, H and Zhang, M and Zhang, K and Aishan, S and Li, H and Wu, W},
title = {In-Depth Investigation on Potential Mechanism of Forest-Grown Ginseng Alleviating Alzheimer's Disease via UHPLC-MS-Based Metabolomics.},
journal = {Metabolites},
volume = {15},
number = {2},
pages = {},
doi = {10.3390/metabo15020093},
pmid = {39997718},
issn = {2218-1989},
support = {202410199035//National College Students' innovation and entrepreneurship training program/ ; 20240101334JC//Jilin Province Science and technology plan project/ ; },
abstract = {BACKGROUND: Alzheimer's disease is a central nervous system degenerative disease closely related to age with a complex pathogenesis. As a natural medicinal plant, forest-grown ginseng (GSF) contains abundant ginsenosides and offers significant neuroprotective effects.

METHODS: In this study, we comprehensively investigated the effect of GSF on the cell viability of PC12 cells in an AD model alongside metabolic changes in the serum and brains of mice, combined with an efficacy evaluation of PC12 cells in vitro and UHPLC-MS-based metabolomics in vivo. The goal of this study is to clarify the potential mechanism of GSF in treating AD.

RESULTS: The PC12 cell results showed that GSF can promote the proliferation of PC12 cells, reduce the content of IL-8, increase the activity of SOD, and alleviate the inflammation and oxidative stress induced by Aβ25~35. The immunohistochemical results for the mouse brain tissue also showed that GSF could reduce the inflammatory response of mouse brain tissue by reducing the overexpression of IBa1. AD was alleviated by reducing Aβ protein deposition in the mouse brain tissue. An untargeted metabolomics analysis was performed using UHPLC-Q-Exactive MS and principal component analysis (PCA) to identify the differentially expressed metabolites in the serum and brain tissue of AD mice after treatment. Twenty and seventeen different metabolites were identified in the serum and brain tissue, respectively. The pathway enrichment analysis of differential metabolites showed that GSF could treat AD by up-regulating succinic acid semialdehyde, carbamoyl phosphate, Sphingosine 1-phosphate, L-cystathionine, 2-ketobutyric acid, Vanillylmandelic acid, and D-Ribose to regulate sphingomyelin metabolism, the synthesis and metabolism of neurotransmitters and precursors, and energy metabolism.

CONCLUSIONS: GSF can reduce neuroinflammation and alleviate Alzheimer's disease by regulating the metabolic disorders of amino acids, sphingolipids, unsaturated fatty acids, and arachidonic acid in mice serum and brain tissue metabolites. These results suggest a link between metabolite imbalance and AD, and reveal the basis for the mechanism of ginsenosides in AD treatment.},
}

@article {pmid39997520,
year = {2025},
author = {Benson, GS and Bartels, C and Stamatis, F and Belz, M and Esselmann, H and Frölich, L and Hausner, L},
title = {The Use and Understanding of Mild Cognitive Impairment in Routine Specialist Care: A Survey Among German Memory Clinics.},
journal = {Geriatrics (Basel, Switzerland)},
volume = {10},
number = {1},
pages = {},
doi = {10.3390/geriatrics10010021},
pmid = {39997520},
issn = {2308-3417},
support = {LCM12365//Roche Pharma AG (Germany)/ ; },
abstract = {Objectives: Mild cognitive impairment (MCI) is a heterogeneous clinical syndrome and is important for the diagnosis and management of Alzheimer's disease (AD). With the expansion of biomarker-based diagnostics, the aim of this study is to clarify the current attitudes towards and the use of MCI, and MCI due to AD, in German memory clinics. Methods: An online survey (50 items) was performed in 2022 among specialized clinicians (N = 45) in German memory clinics to assess the use of MCI and biomarkers in current diagnosis and treatment. Attitudinal and frequency items were assessed with a five-point numeric scale (strongly disagree = 1 to completely agree = 5 and never = 1 to always = 5, respectively). Results: All respondents used MCI as a clinical diagnosis. The benefits of diagnosing MCI were labeling deficits as disease symptoms (M = 4.4, SD = 0.7), improving coping with symptoms (M = 4.1, SD = 0.9), and motivating risk reduction activities (M = 4.0, SD = 0.9). Overall, 37 respondents used specialized diagnostic criteria for MCI due to AD, and all had access to biomarker diagnostics. Patients with MCI due to AD received more frequent counseling on memory training (p < 0.001), other non-pharmacological treatments (p < 0.001), and antidementive drug treatment (p < 0.001) than patients with MCI of other etiologies. Acetylcholinesterase inhibitors were prescribed significantly more frequently to patients with MCI due to AD (p < 0.001) compared to other MCI patients. Conclusions: MCI is commonly used as a clinical diagnosis in German memory clinics. AD biomarker assessment is well established and influences patient counseling and treatment recommendations.},
}

@article {pmid39997199,
year = {2025},
author = {Peng, P and Yu, H and Xian, M and Qu, C and Guo, Z and Li, S and Zhu, Z and Xiao, J},
title = {Preparation of Acetylcholinesterase Inhibitory Peptides from Yellowfin Tuna Pancreas Using Moderate Ultrasound-Assisted Enzymatic Hydrolysis.},
journal = {Marine drugs},
volume = {23},
number = {2},
pages = {},
doi = {10.3390/md23020075},
pmid = {39997199},
issn = {1660-3397},
support = {32360578//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Tuna ; *Pancreas/enzymology ; *Cholinesterase Inhibitors/pharmacology/chemistry ; Hydrolysis ; *Molecular Docking Simulation ; *Acetylcholinesterase/metabolism ; *Peptides/pharmacology/chemistry/isolation & purification ; Fish Proteins/pharmacology/chemistry/isolation & purification ; Molecular Dynamics Simulation ; Ultrasonic Waves ; Tandem Mass Spectrometry ; Alzheimer Disease/drug therapy ; },
abstract = {Bioactive peptides represent a promising therapeutic approach for Alzheimer's disease (AD) by maintaining cholinergic system homeostasis through the inhibition of acetylcholinesterase (AChE) activity. This study focused on extracting AChE inhibitory peptides from yellowfin tuna pancreas using moderate ultrasound-assisted enzymatic hydrolysis (MUE). Firstly, papain and MUE stood out from five enzymes and four enzymatic hydrolysis methods, respectively, by comparing the degree of hydrolysis and AChE inhibitory activity of different pancreatic protein hydrolysates. Subsequently, the optimal MUE conditions were obtained by single-factor, Plackett-Burman, and response surface methodologies. The pancreatic protein hydrolysate prepared under optimal MUE conditions was then purified by ultrafiltration followed by RP-HPLC, from which a novel AChE inhibitory peptide (LLDF) was identified by LC-MS/MS and virtual screening. LLDF effectively inhibited AChE activity by a competitive inhibition mechanism, with an IC50 of 18.44 ± 0.24 μM. Molecular docking and molecular dynamic simulation revealed that LLDF bound robustly to the active site of AChE via hydrogen bonds. These findings provided a theoretical basis for the valuable use of yellowfin tuna pancreas and introduced a new viewpoint on the potential therapeutic advantages of AChE inhibitory peptides for future AD treatment.},
}

Animals
*Tuna
*Pancreas/enzymology
*Cholinesterase Inhibitors/pharmacology/chemistry
Hydrolysis
*Molecular Docking Simulation
*Acetylcholinesterase/metabolism
*Peptides/pharmacology/chemistry/isolation & purification
Fish Proteins/pharmacology/chemistry/isolation & purification
Molecular Dynamics Simulation
Ultrasonic Waves
Tandem Mass Spectrometry
Alzheimer Disease/drug therapy

@article {pmid39997198,
year = {2025},
author = {Liu, Y and Xu, X and Wu, X and Yang, G and Luo, J and Liang, X and Chen, J and Li, Y},
title = {TMF Attenuates Cognitive Impairment and Neuroinflammation by Inhibiting the MAPK/NF-κB Pathway in Alzheimer's Disease: A Multi-Omics Analysis.},
journal = {Marine drugs},
volume = {23},
number = {2},
pages = {},
doi = {10.3390/md23020074},
pmid = {39997198},
issn = {1660-3397},
support = {82060697//National Natural Science Foundation of China/ ; 20212BBG71007//the Jiangxi Key Research and Development Program/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Cognitive Dysfunction/drug therapy ; Mice ; *NF-kappa B/metabolism ; *Neuroinflammatory Diseases/drug therapy ; *Disease Models, Animal ; *Neuroprotective Agents/pharmacology/therapeutic use ; Microglia/drug effects/metabolism ; Mice, Transgenic ; Male ; Flavones/pharmacology ; Humans ; Mice, Inbred C57BL ; Signal Transduction/drug effects ; Cell Line ; MAP Kinase Signaling System/drug effects ; Anti-Inflammatory Agents/pharmacology ; Multiomics ; },
abstract = {The rising prevalence of Alzheimer's disease (AD) underscores the urgent need for novel therapeutic agents derived from natural sources. Among flavonoids, 3',4',5,7-tetramethoxyflavone (TMF), a structural analog of luteolin, has gained attention for its favorable pharmacokinetics and potential neuroprotective properties. Despite the significant neuroprotective effects and favorable pharmacokinetics of TMF, its efficacy and mechanism of action in AD remain unclear. This study explored TMF's pharmacological effects in AD models, highlighting its ability to improve memory and cognitive deficits in APP/PS1 mice. TMF reduced Aβ plaques, NFTs formation, and glial activation while suppressing neuroinflammation through the MAPK/NF-κB pathway. Further analysis in LPS-induced BV2 cells revealed TMF's ability to reduce microglial activation. These findings highlight the anti-neuroinflammatory activity of TMF, suggesting its potential as a treatment for AD.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism
*Cognitive Dysfunction/drug therapy
Mice
*NF-kappa B/metabolism
*Neuroinflammatory Diseases/drug therapy
*Disease Models, Animal
*Neuroprotective Agents/pharmacology/therapeutic use
Microglia/drug effects/metabolism
Mice, Transgenic
Male
Flavones/pharmacology
Humans
Mice, Inbred C57BL
Signal Transduction/drug effects
Cell Line
MAP Kinase Signaling System/drug effects
Anti-Inflammatory Agents/pharmacology
Multiomics

@article {pmid39996839,
year = {2025},
author = {Zheng, Y and Gao, X and Tang, J and Gao, L and Cui, X and Liu, K and Zhang, X and Jin, M},
title = {Exploring the Efficacy and Target Genes of Atractylodes Macrocephala Koidz Against Alzheimer's Disease Based on Multi-Omics, Computational Chemistry, and Experimental Verification.},
journal = {Current issues in molecular biology},
volume = {47},
number = {2},
pages = {},
doi = {10.3390/cimb47020118},
pmid = {39996839},
issn = {1467-3045},
support = {2023YFC3505000//National Key Research and Development Program for Young Scientists/ ; tsqn202312233//Taishan Scholars Program for MJ/ ; 202228035//Jinan Talent Project for Universities/ ; WSR2024032//Two Hundred Foreign Experts Program/ ; },
abstract = {OBJECTIVE: To unveil the efficacy and ferroptosis-related mechanisms of Atractylodes Macrocephala Koidz (AMK) against Alzheimer's disease (AD), which is the most widespread neurodegenerative disease.

METHODS: Gene set variation analysis (GSVA) scores were used to investigate the relationship between ferroptosis and AD. Logistic regression with seven feature selections and a deep learning model were utilized to identify potential targets of AMK based on transcriptomic data from multiple tissues. A transcriptome-wide association study (TWAS), summary-data-based mendelian randomization (SMR), and mendelian randomization (MR) were utilized to validate the causal relationship between target genes and AD risk. A single-gene gene set enrichment analysis (GSEA) was employed to investigate the biological pathways associated with the target genes. Three molecular docking strategies and a molecular dynamics simulation were employed to verify the binding domains interacting with AMK. Furthermore, the anti-AD effects of AMK were validated in a zebrafish AD model by testing behavior responses, apoptosis, and the deposition of beta-amyloid (Aβ) in the brain. Ultimately, real-time qPCR was used to verify the ferroptosis-related targets, which was identified via multi-omics.

RESULTS: Ferroptosis is an important pathogenic mechanism of AD, as suggested by the GSVA scores. AMK may exert its anti-AD activity through targets genes identified in the brain (ATP5MC3, GOT1, SAT1, EGFR, and MAPK9) and blood (G6PD, PGD, ALOX5, HMOX1, and ULK1). EGFR and HMOX1 were further confirmed as target genes mediating the anti-AD activity of AMK through TWAS, SMR, and MR analyses. The GSEA results indicated that EGFR may be involved in oxidative phosphorylation-related pathways, while HMOX1 may be associated with lysosome and phagosome pathways. The results of three molecular docking strategies and molecular dynamics simulations implied that the kinase domain of EGFR and the catalytic domain of HMOX1 played pivotal roles in the interaction between AMK and the targets. In a zebrafish model, AD-like symptoms including motor slowness and delayed responses, neuronal apoptosis, and plaque deposition in the brain, were significantly improved after AMK treatment. Accordingly, AMK reversed the abnormal expression of egfra and hmox1a, two core targets genes involved in ferroptosis.

CONCLUSIONS: AMK significantly alleviated AD-like symptoms through the modulation of EGFR and HMOX1, which might reduce lipid peroxidation, thereby suppressing ferroptosis. This study provided evidence supporting the efficacy and therapeutic targets associated with ferroptosis in AMK-treated AD, which aid in the development of therapeutic interventions.},
}

@article {pmid39996836,
year = {2025},
author = {Savulescu-Fiedler, I and Dorobantu-Lungu, LR and Dragosloveanu, S and Benea, SN and Dragosloveanu, CDM and Caruntu, A and Scheau, AE and Caruntu, C and Scheau, C},
title = {The Cross-Talk Between the Peripheral and Brain Cholesterol Metabolisms.},
journal = {Current issues in molecular biology},
volume = {47},
number = {2},
pages = {},
doi = {10.3390/cimb47020115},
pmid = {39996836},
issn = {1467-3045},
abstract = {Cholesterol is an essential element for the development and normal function of the central nervous system. While peripheral cholesterol is influenced by liver metabolism and diet, brain cholesterol metabolism takes place in an isolated system due to the impermeability of the blood-brain barrier (BBB). However, cross-talk occurs between the brain and periphery, specifically through metabolites such as oxysterols that play key roles in regulating cholesterol balance. Several neurodegenerative conditions such as Alzheimer's disease or Parkinson's disease are considered to be affected by the loss of this balance. Also, the treatment of hypercholesterolemia needs to consider these discrete interferences between brain and peripheral cholesterol and the possible implications of each therapeutic approach. This is particularly important because of 27-hydroxycholesterol and 24-hydroxycholesterol, which can cross the BBB and are involved in cholesterol metabolism. This paper examines the metabolic pathways of cholesterol metabolism in the brain and periphery and focuses on the complex cross-talk between these metabolisms. Also, we emphasize the regulatory role of the BBB and the need for an integrated approach to cholesterol management.},
}

@article {pmid39996817,
year = {2025},
author = {Dimitrova, D and Dimitrova, S and Kehayova, G and Dragomanova, S},
title = {Meroterpenoids from Terrestrial and Marine Fungi: Promising Agents for Neurodegenerative Disorders-An Updated Review.},
journal = {Current issues in molecular biology},
volume = {47},
number = {2},
pages = {},
doi = {10.3390/cimb47020096},
pmid = {39996817},
issn = {1467-3045},
abstract = {BACKGROUND: Meroterpenoids represent a remarkably diverse class of natural secondary metabolites, some of which are synthesized via terpenoid biosynthetic pathways. Over the past ten years, these compounds have gained interest because of their wide range of biological activities, such as anti-cholinesterase, COX-2 inhibitory, antibacterial, antiviral, antidiabetic, antioxidant, anti-inflammatory, antineoplastic, and cardioprotective properties. This review aims to consolidate the recognized neuroprotective effects of meroterpenoids from marine and terrestrial fungi.

METHODS: Data compiled from several databases, including PubMed, Science Direct, Scopus, and Google Scholar, include articles published since 2000 using keywords such as "neuroprotective", "fungi", "mushroom", "marine sponge", "neurodegeneration", and "dementia" in connection with "meroterpenoids".

RESULTS: Meroterpenoids modulate different cell signaling pathways and exhibit different and often combined mechanisms of action to ameliorate neuronal damage and dysfunction. Reported activities include anti-cholinesterase, antioxidant, BACE1 inhibition, and anti-inflammatory activities, all of which have potential in the treatment of dementia associated with neurodegenerative diseases such as Alzheimer's and Parkinson's.

CONCLUSIONS: Meroterpenoids have the potential to be developed as effective tools for neuropathological diseases. Ongoing research to elucidate the various neuroprotective pathways remains essential and requires further investigation.},
}

@article {pmid39996737,
year = {2025},
author = {Balkhi, S and Di Spirito, A and Poggi, A and Mortara, L},
title = {Immune Modulation in Alzheimer's Disease: From Pathogenesis to Immunotherapy.},
journal = {Cells},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/cells14040264},
pmid = {39996737},
issn = {2073-4409},
support = {FAR2023//Fondi di Ateneo per la Ricerca, Università dell'Insubria/ ; FAR2024//Fondi di Ateneo per la Ricerca, Università dell'Insubria/ ; },
mesh = {*Alzheimer Disease/immunology/therapy/pathology ; Humans ; *Immunotherapy/methods ; Animals ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Microglia/immunology/pathology/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, affecting a significant proportion of the elderly population. AD is characterized by cognitive decline and functional impairments due to pathological hallmarks like amyloid β-peptide (Aβ) plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Microglial activation, chronic neuroinflammation, and disruptions in neuronal communication further exacerbate the disease. Emerging research suggests that immune modulation could play a key role in AD treatment given the significant involvement of neuroinflammatory processes. This review focuses on recent advancements in immunotherapy strategies aimed at modulating immune responses in AD, with a specific emphasis on microglial behavior, amyloid clearance, and tau pathology. By exploring these immunotherapeutic approaches, we aim to provide insights into their potential to alter disease progression and improve patient outcomes, contributing to the evolving landscape of AD treatment.},
}

*Alzheimer Disease/immunology/therapy/pathology
Humans
*Immunotherapy/methods
Animals
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Microglia/immunology/pathology/metabolism

@article {pmid39996369,
year = {2025},
author = {Wolfe, MS},
title = {Presenilin, γ-Secretase, and the Search for Pathogenic Triggers of Alzheimer's Disease.},
journal = {Biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biochem.4c00830},
pmid = {39996369},
issn = {1520-4995},
abstract = {Cerebral plaques of the amyloid β-peptide (Aβ) are a defining pathology in Alzheimer's disease (AD). The amyloid hypothesis of AD pathogenesis has dominated the field for over 30 years, ostensibly validated by rare AD-causing mutations in the substrate and enzyme that produce Aβ. The γ-secretase complex carries out intramembrane proteolysis of the substrate derived from the amyloid precursor protein (APP). Mutations in APP and presenilin, the catalytic component of γ-secretase, typically increase the ratio of aggregation-prone 42-residue Aβ (Aβ42) over the more soluble 40-residue form (Aβ40). Nevertheless, the inability to clarify how Aβ aggregation leads to neurodegeneration, along with poor progress in developing effective AD therapeutics that target Aβ, raises concern about whether Aβ is the primary disease driver. γ-Secretase carries out processive proteolysis on the APP substrate, producing long Aβ peptides that are generally trimmed in tripeptide intervals to shorter secreted peptides. Recent studies on effects of AD-causing mutations on the complicated proteolytic processing of the APP substrate by γ-secretase has led to the discovery that these mutations reduce─but do not abolish─processive proteolysis. Reduced proteolysis is apparently due to stabilization of enzyme-substrate complexes, and these stalled substrate-bound γ-secretase complexes can trigger synaptic degeneration even in the absence of Aβ production. Thus, the stalled process rather than the proteolytic products may be a principal initiator of AD pathogenesis. This new amyloid-independent hypothesis suggests that pharmacological agents that rescue stalled γ-secretase enzyme-substrate complexes might be effective therapeutics for AD prevention and/or treatment.},
}

@article {pmid39996130,
year = {2025},
author = {Dilliott, AA and Costanzo, MC and Bandres-Ciga, S and Blauwendraat, C and Casey, B and Hoang, Q and Iwaki, H and Jang, D and Kim, JJ and Leonard, HL and Levine, KS and Makarious, M and Nguyen, TT and Rouleau, GA and Singleton, AB and Smadbeck, P and Solle, J and Vitale, D and Nalls, M and Flannick, J and Burtt, NP and Farhan, SMK},
title = {The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.},
journal = {Neurology. Genetics},
volume = {11},
number = {2},
pages = {e200246},
pmid = {39996130},
issn = {2376-7839},
abstract = {Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathologic mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across 10 different phenotypic groups, including neurologic conditions such as Alzheimer disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively use the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for patients with neurodegenerative disease.},
}

@article {pmid39995763,
year = {2025},
author = {Ahmed, RM and Piguet, O and Mummery, CJ and Naismith, SL and Irish, M},
title = {The Holy Grail: highlighting the need for equitable access to dementia treatments and clinical trials.},
journal = {The Lancet regional health. Western Pacific},
volume = {55},
number = {},
pages = {101492},
pmid = {39995763},
issn = {2666-6065},
abstract = {In the last 5 years significant progress has been made in potential dementia treatments, yet many of these treatments come with significant burdens on the healthcare system that may limit access to treatment and care for patients. Often patients in remote and rural regions and those in low income regions are disadvantaged. Many clinical trials for dementia patients are biased to recruiting a homogenous group of patients that does not represent cultural and linguistic diversity, meaning the generalisability of trials is limited. This viewpoint discusses the barriers to access to early treatments and clinical trials for patients with dementia and offers a potential framework to address these including provision of infrastructure, regulatory change and patient education.},
}

@article {pmid39995734,
year = {2025},
author = {Yuan, Z and Qi, N and Zhou, Z and Ding, J and Chen, X and Wu, J and Wang, J and Zhao, J},
title = {Diagnosis of Alzheimer's disease using transfer learning with multi-modal 3D Inception-v4.},
journal = {Quantitative imaging in medicine and surgery},
volume = {15},
number = {2},
pages = {1455-1467},
pmid = {39995734},
issn = {2223-4292},
abstract = {BACKGROUND: Deep learning (DL) technologies are playing increasingly important roles in computer-aided diagnosis in medicine. In this study, we sought to address issues related to the diagnosis of Alzheimer's disease (AD) based on multi-modal features, and introduced a multi-modal three-dimensional Inception-v4 model that employs transfer learning for AD diagnosis based on magnetic resonance imaging (MRI) and clinical score data.

METHODS: The multi-modal three-dimensional (3D) Inception-v4 model was first pre-trained using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Subsequently, independent validation data were used to fine-tune the model with pre-trained weight parameters. The model was quantitatively evaluated using the mean values obtained from five-fold cross-validation. Further, control experiments were conducted to verify the performance of the model patients with AD, and in the study of disease progression.

RESULTS: In the AD diagnosis task, when a single image marker was used, the average accuracy (ACC) and area under the curve (AUC) were 62.21% and 71.87%, respectively. When transfer learning was not employed, the average ACC and AUC were 75.74% and 83.13%, respectively. Conversely, the combined approach proposed in this study achieved an average ACC of 87.84%, and an average AUC of 90.80% [with an average precision (PRE) of 87.21%, an average recall (REC) of 82.52%, and an average F1 of 83.58%].

CONCLUSIONS: In comparison with existing methods, the performance of the proposed method was superior in terms of diagnostic accuracy. Specifically, the method showed an enhanced ability to accurately distinguish among various stages of AD. Our findings show that multi-modal feature fusion and transfer learning can be valuable resources in the treatment of patients with AD, and in the study of disease progression.},
}

@article {pmid39995599,
year = {2025},
author = {Schindler, SE and Musiek, ES and Morris, JC},
title = {Anti-amyloid treatments: Why we think they are worth it.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {1},
pages = {e70055},
pmid = {39995599},
issn = {2352-8737},
abstract = {UNLABELLED: Years of experience watching our patients progressively decline and die from complications of Alzheimer's disease (AD) has strongly motivated us to provide newly approved anti-amyloid treatments to appropriate patients. Following detailed and personalized discussions of the potential risks and benefits of these treatments with patients and their families, almost 300 patients at our clinic have chosen to receive lecanemab infusions. We have found the frequency and severity of complications, including amyloid-related imaging abnormalities (ARIA), to be manageable and as expected based on clinical trials. While the longer-term benefits of these treatments are not yet clear, our patients and their families are accepting of even a modest slowing of disease progression. We have experienced the complexities, burdens, costs, and major logistical challenges associated with the treatment of AD with anti-amyloid treatments. However, we also understand that for some of our current patients with early symptomatic AD, anti-amyloid treatments are their best option for fighting this devastating disease, and we find it worthwhile to provide these treatments to our patients.

HIGHLIGHTS: Many of our former patients have died from complications of AD.Our clinic now has nearly 300 patients receiving anti-amyloid treatments.We have found the complications of anti-amyloid treatments to be manageable.Despite the challenges, we find anti-amyloid treatments worthwhile.},
}

@article {pmid39995567,
year = {2025},
author = {Paul, JK and Malik, A and Azmal, M and Gulzar, T and Afghan, MTR and Talukder, OF and Shahzadi, S and Ghosh, A},
title = {Advancing Alzheimer's Therapy: Computational strategies and treatment innovations.},
journal = {IBRO neuroscience reports},
volume = {18},
number = {},
pages = {270-282},
pmid = {39995567},
issn = {2667-2421},
abstract = {Alzheimer's disease (AD) is a multifaceted neurodegenerative condition distinguished by the occurrence of memory impairment, cognitive deterioration, and neuronal impairment. Despite extensive research efforts, conventional treatment strategies primarily focus on symptom management, highlighting the need for innovative therapeutic approaches. This review explores the challenges of AD treatment and the integration of computational methodologies to advance therapeutic interventions. A comprehensive analysis of recent literature was conducted to elucidate the broad scope of Alzheimer's etiology and the limitations of conventional drug discovery approaches. Our findings underscore the critical role of computational models in elucidating disease mechanisms, identifying therapeutic targets, and expediting drug discovery. Through computational simulations, researchers can predict drug efficacy, optimize lead compounds, and facilitate personalized medicine approaches. Moreover, machine learning algorithms enhance early diagnosis and enable precision medicine strategies by analyzing multi-modal datasets. Case studies highlight the application of computational techniques in AD therapeutics, including the suppression of crucial proteins implicated in disease progression and the repurposing of existing drugs for AD management. Computational models elucidate the interplay between oxidative stress and neurodegeneration, offering insights into potential therapeutic interventions. Collaborative efforts between computational biologists, pharmacologists, and clinicians are essential to translate computational insights into clinically actionable interventions, ultimately improving patient outcomes and addressing the unmet medical needs of individuals affected by AD. Overall, integrating computational methodologies represents a promising paradigm shift in AD therapeutics, offering innovative solutions to overcome existing challenges and transform the landscape of AD treatment.},
}

@article {pmid39995296,
year = {2025},
author = {Wang, C and Zhang, X and Zhuang, Y and Song, X and Sun, S and Chen, Y and Qi, G and Yang, Y and Li, P and Wei, W},
title = {Natural Bioactive Compounds Solanesol and Chlorogenic Acid Assembled Nanomicelles for Alzheimer's Disease Therapy.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.4c22621},
pmid = {39995296},
issn = {1944-8252},
abstract = {Solanesol (Sol) and chlorogenic acid (CHA) are naturally active compounds. Sol exhibits a significant free radical absorption ability and strong antioxidant activity. CHA, a typical phenolic acid, exhibits excellent anticancer, anti-inflammation, and antibacterial properties. Herein, bifunctional nanomicelles (CI@SPK) were skillfully designed to take advantage of the unique properties of Sol and CHA to treat Alzheimer's disease (AD). Hydrophobic Sol was modified with poly(ethylene glycol) to self-assemble into stable nanomicelles (SP). CHA could be encapsulated into the hydrophobic core of these nanomicelles, which increased its bioavailability greatly. Short peptide K (CKLVFFAED) was incorporated (CI@SPK) to facilitate their crossing the blood-brain barrier. Then, CI@SPK targeted the AD lesion area, and CHA was released in greater quantities with the help of IR780 under irradiation with an 808 nm laser, resulting in synergistically scavenging reactive oxygen species (ROS) with Sol. Consequently, the nanomicelles CI@SPK demonstrated capabilities in scavenging ROS, inhibiting β-amyloid (Aβ) aggregation, and eventually modulating microglia phenotype from M1 to M2 to promote Aβ phagocytosis and clearance. In vivo studies indicated that nanomicelles CI@SPK improved the learning and cognitive impairments of APP/PS1 mice by reducing Aβ plaque and inflammation, signifying the potential value of CI@SPK in clinical application for AD treatment.},
}

@article {pmid39995125,
year = {2025},
author = {Kalinin, AP and Zubkova, ES and Menshikov, MY and Parfyonova, YV},
title = {ISR Modulators in Neurological Diseases.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X361653250213114821},
pmid = {39995125},
issn = {1875-6190},
abstract = {The dysfunction of different cells lies in the pathogenesis of neurological diseases and is usually associated with cellular stress. Various stressors trigger the integrated stress response (ISR) signaling, whose highly conserved mechanism is primarily aimed at protecting a stress-exposed cell to cope as safely as possible with such stressful conditions. On the contrary, if a cell is unable to cope with excessive stress, the ISR can induce apoptosis. The ISR mechanism, whose main stage is the inhibition of translation machinery in favor of the synthesis of specific proteins, including the transcription factors ATF3, ATF4, CEBPA, and CEBPB, which function only as dimers and determine the uniqueness of the ISR response in each individual case, thus ensures different outcomes of the ISR. Inhibition of global protein synthesis is achieved through phosphorylation of eIF2α by PERK, HRI, PKR, or GCN2. To date, a number of compounds have been developed that modulate the ISR, including activators and inhibitors of the abovementioned ISR kinases as well as modulators of p-eIF2α dephosphorylation. They target different ISR stages, allowing a broad ISR modulation strategy. At the same time, there are no drugs that are both exceptionally safe and effective for the treatment of several neurological diseases, so there is an urgent need for new approaches to the treatment of these disorders. In this review, we represent ISR signaling as an important participant in the pathogenesis of neurological diseases. We also describe how various ISR modulators may become a part of future therapies for these diseases.},
}

@article {pmid39994624,
year = {2025},
author = {Huang, Y and Zhai, Y and Zhao, D and Wu, M and Shen, Q and Zhao, W and Wang, Q and Yao, L and Li, W},
title = {UHPLC-Q Exactive-Orbitrap-MS and network pharmacology analyses to investigate the mechanism by which Danggui-Shaoyao-San affects 27-OHC-induced cell damage in SH-SY5Y/C6 coculture.},
journal = {BMC complementary medicine and therapies},
volume = {25},
number = {1},
pages = {75},
pmid = {39994624},
issn = {2662-7671},
support = {81973919//National Natural Science Foundation of China/ ; 82274616//National Natural Science Foundation of China/ ; 82074505//National Natural Science Foundation of China/ ; 2022A1515220121//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023A1515011835//Basic and Applied Basic Research Foundation of Guangdong Province/ ; },
mesh = {*Drugs, Chinese Herbal/pharmacology ; Humans ; *Network Pharmacology ; Chromatography, High Pressure Liquid ; *Coculture Techniques ; Alzheimer Disease/drug therapy ; Cell Line, Tumor ; Animals ; Mass Spectrometry ; Rats ; },
abstract = {BACKGROUND: Danggui-Shaoyao-San (DSS) is a classic Chinese medicine formula that has been extensively studied for its efficacy in treating Alzheimer's disease (AD). However, its mechanism of action is still unclear.

METHODS: In this study, UHPLC-Q Exactive-Orbitrap-MS was used to analyze and identify the compounds in DSS. Network pharmacology was used to analyze the common targets of drug-containing serum chemistries and AD, as well as the AD pathways in which drug-containing serum chemistries may be involved. The 27-OHC-induced SH-SY5Y/C6 coculture cell injury model was used to explore the mechanism of action of DSS in the treatment of AD.

RESULTS: UHPLC-Q Exactive-Orbitrap-MS analysis identified 73 chemical constituents in DSS aqueous extract and 39 compounds in drug-containing serum. According to network pharmacology analysis, DSS and AD share 181 common targets, with interleukin-6 (IL-6) and tumor necrosis factor (TNF) being the main effective targets. Furthermore, DSS may treat AD through the modulation of lipid metabolism-related pathways and the interleukin-17 (IL-17) signaling pathway. 27-hydroxycholesterol acid (27-OHC) significantly reduced the viability of SH-SY5Y cells and C6 cells in vitro, while DSS administration upregulated the expression of cytochrome P450 46A1 (CYP46A1) and cytochrome P450 7B1 (CYP7B1) enzymes and reduced cholesterol levels in SH-SY5Y cells. Additionally, DSS decreased reactive oxygen species (ROS) levels and increased glutathione (GSH) levels in coculture systems. DSS downregulated the expression of IL-17 in 27-OHC-injured SH-SY5Y cells and downregulated the expression of TNF-α, IL-6 and transforming growth factor-β1 (TGF-β1) in 27-OHC-injured C6 cells.

CONCLUSION: This study revealed the effective components, targets and mechanisms of DSS in the treatment of AD, highlighting the significant potential of DSS in treating this disease.},
}

*Drugs, Chinese Herbal/pharmacology
Humans
*Network Pharmacology
Chromatography, High Pressure Liquid
*Coculture Techniques
Alzheimer Disease/drug therapy
Cell Line, Tumor
Animals
Mass Spectrometry
Rats

@article {pmid39994231,
year = {2025},
author = {Arnold, M and Buyukozkan, M and Doraiswamy, PM and Nho, K and Wu, T and Gudnason, V and Launer, LJ and Wang-Sattler, R and Adamski, J and , and , and De Jager, PL and Ertekin-Taner, N and Bennett, DA and Saykin, AJ and Peters, A and Suhre, K and Kaddurah-Daouk, R and Kastenmüller, G and Krumsiek, J},
title = {Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {1910},
pmid = {39994231},
issn = {2041-1723},
mesh = {*Alzheimer Disease/metabolism ; Humans ; *Energy Metabolism ; *Carnitine/analogs & derivatives/metabolism/blood ; Male ; Aged ; Female ; *Biomarkers/blood/metabolism ; Aged, 80 and over ; Mitochondria/metabolism ; Brain/metabolism/diagnostic imaging ; Disease Progression ; Middle Aged ; Glucose/metabolism ; },
abstract = {Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer's disease (AD), with symptom-free periods of varying duration that likely reflect individual differences in metabolic resilience. We propose a systemic "bioenergetic capacity", the individual ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from the AD Neuroimaging Initiative as a blood-based readout for this capacity, we identified subgroups with distinct clinical and biomarker presentations of AD. Our data suggests that improving beta-oxidation efficiency can decelerate bioenergetic aging and disease progression. The estimated treatment effects of targeting the bioenergetic capacity were comparable to those of recently approved anti-amyloid therapies, particularly in individuals with specific mitochondrial genotypes linked to succinylcarnitine metabolism. Taken together, our findings provide evidence that therapeutically enhancing bioenergetic health may reduce the risk of symptomatic AD. Furthermore, monitoring the bioenergetic capacity via blood acylcarnitine measurements can be achieved using existing clinical assays.},
}

*Alzheimer Disease/metabolism
Humans
*Energy Metabolism
*Carnitine/analogs & derivatives/metabolism/blood
Male
Aged
Female
*Biomarkers/blood/metabolism
Aged, 80 and over
Mitochondria/metabolism
Brain/metabolism/diagnostic imaging
Disease Progression
Middle Aged
Glucose/metabolism

@article {pmid39993744,
year = {2025},
author = {Tsuru, M and Ito, T and Komai, K and Kunitomo, F and Nakayama, Y and Murakami, T and Ohuchi, K and Shinkai, Y and Kimura, T and Miura, N and Kumagai, Y and Hozumi, I and Inden, M and Kurita, H},
title = {Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor, FG4592, Induces Endogenous Metallothionein3 Expression in Human Neuronal Cell Line, ReNcell CX Cells.},
journal = {Biological & pharmaceutical bulletin},
volume = {48},
number = {2},
pages = {137-143},
doi = {10.1248/bpb.b24-00792},
pmid = {39993744},
issn = {1347-5215},
mesh = {Humans ; *Metallothionein 3 ; *Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/genetics ; *Neurons/metabolism/drug effects ; Cell Line ; Isoquinolines/pharmacology ; Prolyl-Hydroxylase Inhibitors/pharmacology ; Nerve Tissue Proteins/metabolism/genetics ; Phenylurea Compounds/pharmacology ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism/antagonists & inhibitors ; Glycine/analogs & derivatives ; },
abstract = {Metallothionein (MT) is a small-molecule protein that functions in essential trace element homeostasis. Among MT isoforms, MT3 is involved in neuronal activity, and its expression is reported to be decreased in patients with neurodegenerative conditions such as Alzheimer's disease; however, only a few effective drugs have been reported to induce MT3 expression. In this study, we evaluated existing drugs for the induction of MT3 expression in the neuronal cell line of ReNcell CX cells. Using recombinant proteins of MT isoforms with the 3× Flag tag, we performed Western blotting (WB) with the primary antibodies against MT3 or Flag tag, and this method of WB for MT3 was confirmed specifically to detect the MT3 protein. We treated ReNcell CX cells with several HIF-PH inhibitors and evaluated MT3 expression via real-time RT-PCR. We found that FG4592 significantly enhanced MT3 expression at both RNA and protein levels. FG4592 treatment increased the amount of hypoxia-inducible factor 1 alpha (HIF1α) binding to the MT3 promoter. These findings indicate that FG4592 induces MT3 expression via increased HIF1α. In conclusion, we found FG4592 to be an endogenous MT3 inducer in the cells of the nervous system in this study. The findings of this study are expected to lead to the development of new MT3-inducing drugs for neurodegenerative diseases based on FG4592.},
}

Humans
*Metallothionein 3
*Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/genetics
*Neurons/metabolism/drug effects
Cell Line
Isoquinolines/pharmacology
Prolyl-Hydroxylase Inhibitors/pharmacology
Nerve Tissue Proteins/metabolism/genetics
Phenylurea Compounds/pharmacology
Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism/antagonists & inhibitors
Glycine/analogs & derivatives

@article {pmid39993451,
year = {2025},
author = {Pattanaik, S and Ghose, A and Pakeeraiah, K and Paidesetty, SK and Prusty, SK and Sahu, PK},
title = {Repurposing Drugs: A Promising Therapeutic Approach against Alzheimer's Disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102698},
doi = {10.1016/j.arr.2025.102698},
pmid = {39993451},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is an insidious, irreversible, complex neurodegenerative disorder characterized by progressive cognitive decline and memory loss; affecting millions worldwide. Despite decades of research, no effective disease-modifying treatment exists. However, drug repurposing is a progressive step in identifying new therapeutic uses of existing drugs. It has emerged as a promising strategy in the quest to combat AD. Various classes of repurposed drugs, such as antidiabetic, antihypertensive, antimicrobial, and anti-inflammatory, have shown potential neuroprotective effects in preclinical and clinical studies. These drugs act by combating free radicals generation, neuroinflammation, amyloid-beta aggregation, and tau hyper-phosphorylation. Furthermore, repurposing offers several advantages, including reduced time and cost compared to de novo drug development. It holds immense promise as a complementary approach to traditional drug discovery. Future research efforts should focus on elucidating the underlying mechanisms of repurposed drugs in AD, optimizing drug combinations, and conducting large-scale clinical trials to validate their efficacy and safety profiles. This review overviews recent advancements and findings in preclinical and clinical fields of different repurposed drugs for AD treatment.},
}

@article {pmid39992990,
year = {2025},
author = {Liu, J and Chen, L and Zhang, ZL and Wen, W and Zhang, X and Wu, Z and Wang, S},
title = {Nano-Collision Electrochemistry for Real-Time Monitoring of Amyloid-β Oligomerization and Rapid Screening of Degrading Drugs.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.4c04598},
pmid = {39992990},
issn = {1520-6882},
abstract = {Toxic oligomers of amyloid-β (Aβ) are important in the pathology of Alzheimer's disease (AD), and degradation of Aβ oligomers (AβO) in the brain is considered a promising strategy for drug development. However, conventional drug screening techniques face challenges in the rapid and real-time assessment of AβO. Here, we report a simple and reliable nanocollision electrochemical method based on silver nanoparticles (AgNPs) "tagging" that can in situ monitor Aβ oligomerization and screen potential AβO-degrading drugs. The differences in collision signals between AgNPs-Aβ complexes and AgNPs were compared to achieve rapid identification of Aβ complexes with different aggregation degrees. The degradation effect following the addition of AβO-degrading drugs can be quickly evaluated by the recovery of collision frequency (f, number of peaks per unit time), which is effective if f > 0.15. Degradation efficiency was further quantified using current lifetimes (τ, the time required for the current to decay to 1/e of the original), based on the percentage of τ ≤ 10 ms. The practicability of the method was tested using Aβ-degrading protease and several small molecules, confirming the rapid screening of AβO-degrading drugs and offering a novel strategy to accelerate the development of drugs for AD treatment.},
}

@article {pmid39992888,
year = {2025},
author = {Hao, Z and Ji, R and Su, Y and Wang, H and Yang, W and Zhang, S and Liu, Y and Ma, S and Guan, F and Cui, Y},
title = {Indole-3-Propionic Acid Attenuates Neuroinflammation and Cognitive Deficits by Inhibiting the RAGE-JAK2-STAT3 Signaling Pathway.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.4c08548},
pmid = {39992888},
issn = {1520-5118},
abstract = {Cognitive disorders such as Alzheimer's disease (AD) are highly prevalent and place heavy burdens on society. Neuroinflammation is a driver of cognitive impairment, with no effective drugs. Indole 3-propionic acid (IPA) is a tryptophan metabolite mainly produced byClostridium sporogenes, which exhibits multiple functions, including antioxidant, anti-inflammatory, antiaging, and neuroprotective properties. However, the restorative effects and molecular mechanisms of IPA in cognitive impairment remain to be investigated. In this study, we found that IPA reduced LPS-induced apoptosis and oxidative damage in HT22 cells and decreased LPS-induced inflammation in BV2 cells. Besides, IPA promoted neurogenesis, inhibited glial cell activation, maintained the integrity of the BBB and intestinal barrier, and remodeled the gut microbiota, thereby alleviating memory impairment in LPS-induced cognitively impaired mice. At the mechanistic level, IPA inhibited the RAGE-JAK2-STAT3 signaling pathway and thus ameliorated neuroinflammation. Interestingly, Colivelin TFA, an activator of JAK2-STAT3 signaling, partially reversed the neurorestorative effects of IPA. In conclusion, IPA ameliorates neuroinflammation and cognitive deficits via the inhibition of the RAGE-JAK2-STAT3 signaling pathway. Thus, IPA may be a potential drug for the treatment of cognitive disorders.},
}

@article {pmid39992792,
year = {2025},
author = {Liu, M and Zhu, J and Zheng, J and Han, X and Jiang, L and Tong, X and Ke, Y and Guo, Z and Huang, W and Cong, J and Liu, M and Lin, SY and Zhu, S and Mei, L and Zhang, X and Zhang, W and Xin, WJ and Zhang, Z and Guo, Y and Chen, R},
title = {GPNMB and ATP6V1A interact to mediate microglia phagocytosis of multiple types of pathological particles.},
journal = {Cell reports},
volume = {44},
number = {3},
pages = {115343},
doi = {10.1016/j.celrep.2025.115343},
pmid = {39992792},
issn = {2211-1247},
abstract = {Pronounced elevation of glycoprotein non-metastatic melanoma B (GPNMB) is a common phenomenon in a variety of brain diseases, but the expression patterns, functions, and molecular signaling of GPNMB have not been well studied. Here, we showed that pathological factors, including neuronal degeneration caused by seizures, caspase-3-induced neuronal apoptosis, neuronal debris, and β-amyloid, induced "on-demand" GPNMB expression in hippocampal microglia. Genetic ablation of GPNMB did not affect acute seizures but worsened chronic epileptogenesis. We found that GPNMB functioned in phagocytosis, deficiency of which resulted in defects in both phagocytic engulfment and degradation. GPNMB could be internalized into cells, where it wrapped engulfed pathogenic particles and presented them to lysosomes through interaction with lysosomal vacuolar-type proton ATPase catalytic subunit A (ATP6V1A). Activating ATP6V1A was able to rescue GPNMB-deficiency-caused phagocytosis impairment. Thus, microglial GPNMB-ATP6V1A might be a common treatment target of a batch of chronic neurological disorders, and clearing the degenerative neurons might be more valuable than reserving them to protect the brain.},
}

@article {pmid39992588,
year = {2025},
author = {Wang, YH and Wu, HY and Xin, C and Zhang, KX and Zhang, JW and Zhi, HW},
title = {Identification and Validation of Biomarkers for Alzheimer's Disease Based on Akt and Wnt Signaling Pathways in Mouse Models.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {39992588},
issn = {1559-1182},
support = {82205064//Natural Science Foundation of China/ ; ZR2021QH110//Natural Science Foundation of Shandong Province/ ; Z-2022060//Shandong TCM science and technology development plan/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease that remains challenging to treat. Akt and Wnt play a role in complex cellular signaling, which is crucial for examining the onset of AD. In this study, we aimed to identify and analyze Akt pathway-related genes (ARGs) and Wnt pathway-related genes (WRGs) as AD biomarkers, determine the effects of ARGs and WRGs on AD, and verify these effects in AD mouse models. We searched for differentially expressed genes in the Gene Expression Omnibus database, constructed candidate gene protein-protein interaction networks, and used least absolute shrinkage and selection operator regression analysis and the support vector machine-recursive feature elimination algorithm to screen key genes. Correlation and functional similarity analyses of key genes, immune infiltration analysis, competing endogenous RNA network construction, and drug prediction of key genes were performed. Expression of key genes in streptozotocin-treated (STZ)-treated AD mice was validated using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Bioinformatics analysis identified five key genes in AD: PRKACA, CDH3, ATP6V0C, DLL1, and CELSR2. Step-down tests, immunohistochemistry, and silver plate staining confirmed successful treatment of STZ-induced AD in mice. According to RT-qPCR analysis, the relative expression of DLL1 mRNA in AD mice was higher than that in control mice, whereas the relative expression of ATP6V0C and PRKACA mRNA in AD mice was lower than that in control mice; this was consistent with the results of bioinformatics analysis (p < 0.05). This study screened and validated AD biomarkers associated with the Akt and Wnt pathways in mouse models.},
}