Immune cells: Mediators in the metabolites and Alzheimer’s disease

Journal of Alzheimer s Disease, Год журнала: 2025, Номер unknown

Опубликована: Янв. 29, 2025

Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that predominantly affects elderly individuals across the globe. While genetic, environmental, and lifestyle factors are known to influence onset of AD, underlying mechanisms remain unclear. Objective To elucidate intricate interplay between metabolites immune cell activation in ethology determine their collective impact on AD risk. Methods We conducted comprehensive analysis genome-wide association studies data examine relationships metabolites, phenotypes, risk AD. Our study encompassed examination involving 731 distinct types, 1400 large cohort comprising10,520 cases with 401,661 controls. employed univariate Mendelian randomization assess bidirectional cells, as well cells Subsequently, multivariate was then applied evaluate potential mediating role relationship Results Specific histidine/pyruvate ratio homoarginine, were positively associated mediated by cells. Conversely, 4-hydroxycoumarin glycolithocholate sulfate showed protective associations against Immune markers, CD64 monocytes HLA DR CD14 + CD16 − linked higher risk, while CD33 dim CD11b myeloid CD8 T protective. Conclusions This highlights critical pathogenesis demonstrating how interaction specific influences

Язык: Английский

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Longitudinal and concurrent C-reactive protein and diet associations with cognitive function in the population-based Tromsø study

Journal of Alzheimer s Disease, Год журнала: 2025, Номер unknown

Опубликована: Фев. 2, 2025

Background Immune dysregulation has been implicated in Alzheimer's disease; however, precise mechanisms and timing have not established. Objective To investigate the concurrent longitudinal associations of serum C-reactive protein (CRP) dietary inflammatory index (DII) with cognitive decline as observed disease. Methods The study was based on 7613 individuals who participated Tromsø6 (2007–2008) Tromsø7 (2015–2016). We analyzed relationship between CRP levels, DII, function cross-sectionally using linear regression. used mediation analysis to examine if mediates effects DII function. Further, we related baseline change after 7 years follow up. mixed models relate changes levels measured at two time points apart. Results Both level were inversely associated (psychomotor speed, executive function). There no prospective Increase decrease function, verbal memory) measurements model did show convincing evidence a mediating effect association diet Conclusions After comprehensive CRP, conclude that is likely reflect environment occurring parallel decline.

Язык: Английский

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dyphAI dynamic pharmacophore modeling with AI: a tool for efficient screening of new acetylcholinesterase inhibitors

Frontiers in Chemistry, Год журнала: 2025, Номер 13

Опубликована: Фев. 4, 2025

Therapeutic strategies for Alzheimer’s disease (AD) often involve inhibiting acetylcholinesterase (AChE), underscoring the need novel inhibitors with high selectivity and minimal side effects. A detailed analysis of protein-ligand pharmacophore dynamics can facilitate this. In this study, we developed employed dyphAI , an innovative approach integrating machine learning models, ligand-based complex-based models into a model ensemble. This ensemble captures key interactions, including π-cation interactions Trp-86 several π-π residues Tyr-341, Tyr-337, Tyr-124, Tyr-72. The protocol identified 18 molecules from ZINC database binding energy values ranging −62 to −115 kJ/mol, suggesting their strong potential as AChE inhibitors. To further validate predictions, nine were acquired tested inhibitory activity against human AChE. Experimental results revealed that molecules, 4 (P-1894047), its complex multi-ring structure numerous hydrogen bond acceptors, 7 (P-2652815), characterized by flexible, polar framework ten donors exhibited IC₅₀ lower than or equal control (galantamine), indicating potent activity. Similarly, 5 (P-1205609), 6 (P-1206762), 8 (P-2026435), 9 (P-533735) also demonstrated inhibition. contrast, molecule 3 (P-617769798) showed higher IC 50 value, 1 (P-14421887) 2 (P-25746649) yielded inconsistent results, likely due solubility issues in experimental setup. These findings underscore value computational predictions validation, enhancing reliability virtual screening discovery enzyme

Язык: Английский

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In silico study of selected alkaloids as dual inhibitors of β- and γ-secretases for Alzheimer's disease

Journal of Alzheimer s Disease, Год журнала: 2025, Номер unknown

Опубликована: Фев. 16, 2025

Background Alzheimer's disease (AD) has become common as the number of aged people increases making it a socioeconomic problem lately. To date, no success is recorded for disease-modifying therapies AD but only drugs symptomatic relief exist. Research been centered on role amyloid-β pathogenesis AD, which led to development that target Aβ (β- and γ-secretase inhibitors) reduce amount formed. However, existing β inhibitors were associated with harmful side effects, low efficacy, inability cross blood-brain barrier. Objective This study therefore used in silico approach predict inhibitory properties alkaloids potential drug targets against AD. Methods Thus, this current study, 54 from PhytoHub server (phytohub.eu), two approved docked β-secretases. Additionally, galantamine 5 utmost binding β-secretase subjected pharmacokinetics evaluation γ-secretase. Results From result, compounds displayed both docking periods, demissidine, solasodine, tomatidine, solanidine having better BE than control drugs. Based evaluation, 4 possessed good pharmacokinetic biological activities galantamine. Conclusions suggests are promising dual β- proteins silico. there an urgent need carry out vitro vivo experiments these new leads validate findings study.

Язык: Английский

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Drug repurposing for Alzheimer’s disease and other neurodegenerative disorders

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 19, 2025

Repurposed drugs provide a rich source of potential therapies for Alzheimer's disease (AD) and other neurodegenerative disorders (NDD). have information from non-clinical studies, phase 1 dosing, safety tolerability data collected with the original indication. Computational approaches, "omic" drug databases, electronic medical records help identify candidate therapies. Generic repurposed agents lack intellectual property protection are rarely advanced to late-stage trials AD/NDD. In this review we define repurposing, describe advantages challenges offer strategies overcoming obstacles, key contributions repurposing development ecosystem. review, authors discuss obstacles development.

Язык: Английский

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