A personalized metabolic modelling approach through integrated analysis of RNA-Seq-based genomic variants and gene expression levels in Alzheimer’s disease

Communications Biology, Год журнала: 2025, Номер 8(1)

Опубликована: Март 27, 2025

Generating condition-specific metabolic models by mapping gene expression data to genome-scale (GEMs) is a routine approach elucidate disease mechanisms from perspective. On the other hand, integrating variants that perturb enzyme functionality same RNA-seq may enhance GEM accuracy, offering insights into genome-wide pathology. Our study pioneers extraction of both transcriptomic and genomic reconstruct personalized models. We map genes with significantly higher load pathogenic in Alzheimer's (AD) onto human together data. Comparative analysis resulting patient control shows enhanced accuracy detecting AD-associated pathways compared case where only mapped on GEM. Besides, several otherwise would-be missed are annotated AD considering effect variants. The authors used iMAT algorithm associated Disease (GEMs).

Язык: Английский

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Mechanisms of glutamate metabolic function and dysfunction in vascular dementia

Neuroprotection/Neuroprotection (Chichester, England. Print), Год журнала: 2024, Номер 2(1), С. 33 - 48

Опубликована: Фев. 27, 2024

Abstract As the global population ages, research on pathogenesis and treatment options for older patients with dementia has become increasingly important. Vascular (VaD), second most frequent type of dementia, is characterized by vascular impairment caused inadequate blood supply to brain. VaD a complex neurological disorder involving multiple cells signaling pathways, its prevention pose clinical challenges significant behavioral implications. Glutamate, abundant amino acid in brain, plays critical role as an excitatory neurotransmitter, impacting cognitive function, learning, memory. Abnormal glutamate metabolism been closely linked reduced flow brain can lead excessive accumulation, resulting neuronal death. This article highlights connection between metabolism, aiming identify better methods preventing treating via regulating metabolism.

Язык: Английский

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Cholesterol Accumulation Promotes Photoreceptor Senescence and Retinal Degeneration

Investigative Ophthalmology & Visual Science, Год журнала: 2024, Номер 65(10), С. 29 - 29

Опубликована: Авг. 21, 2024

Purpose: Dysregulated cholesterol metabolism is critical in the pathogenesis of AMD. Cellular senescence contributes to development numerous age-associated diseases. In this study, we investigated link between burden and cellular photoreceptors. Methods: Retinas from rod-specific ATP binding cassette subfamily A member 1 (Abca1) G (Abcg1) (Abca1/g1-rod/-rod) knockout mice fed with a high-fat diet were analyzed for signs senescence. Real-time quantitative PCR immunofluorescence used characterize profile retina cholesterol-treated photoreceptor cell line (661W). Inducible elimination p16(Ink4a)-positive senescent cells (INK-ATTAC) or administration senolytic drugs (dasatinib quercetin: D&Q) examine impact senolytics on AMD-like phenotypes Abca1/g1-rod/-rod retina. Results: Increased accumulation as measured by markers was found Exogenous also induced 661W cells. Selective Abca1/g1-rod/-rod;INK-ATTAC D&Q improved visual function, lipid retinal pigment epithelium, Bruch's membrane thickening. Conclusions: Cholesterol promotes Eliminating photoreceptors improves function model neurodegeneration, senotherapy offers novel therapeutic avenue further investigation.

Язык: Английский

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Causal Relationship Between Basal Metabolic Rate and Alzheimer’s Disease: A Bidirectional Two-sample Mendelian Randomization Study

Neurology and Therapy, Год журнала: 2023, Номер 12(3), С. 763 - 776

Опубликована: Март 10, 2023

Objective observational studies have shown that basal metabolic rate (BMR) decreases in patients with Alzheimer's disease (AD), but the causal relationship between BMR and AD has not been established. We determined by two-way Mendelian randomization (MR) investigated impact of factors associated on AD.We obtained (n = 454,874) from a large genome-wide association study (GWAS) database (21,982 AD, 41,944 controls). The was using MR. Additionally, we identified related BMR, hyperthyroidism (hy/thy) type 2 diabetes (T2D), height weight.BMR had [451 single nucleotide polymorphisms (SNPs), odds ratio (OR) 0.749, 95% confidence intervals (CIs) 0.663-0.858, P 2.40E-03]. There no hy/thy or T2D (P > 0.05). bidirectional MR showed there also (OR 0.992, Cls 0.987-0.997, NSNPs18, 1.50E-03). weight protective effect AD. Based MVMR analysis, found genetically may be adjusted to themselves.Our higher reduced risk lower BMR. Because positive correlation two metabolism-related diseases, T2D,

Язык: Английский

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27-Hydroxycholesterol impairs learning and memory ability via decreasing brain glucose uptake mediated by the gut microbiota

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 168, С. 115649 - 115649

Опубликована: Окт. 6, 2023

Brain glucose hypometabolism is a significant manifestation of Alzheimer's disease (AD). 27-hydroxycholesterol (27-OHC) and the gut microbiota have been recognized as factors possibly influencing pathogenesis AD. This study aimed to investigate link between 27-OHC, microbiota, brain uptake in Here, 6-month-old male C57BL/6 J mice were treated with sterile water or antibiotic cocktails, without 27-OHC and/or synthetic enzyme CYP27A1 inhibitor anastrozole (ANS). The levels, memory ability measured. We observed that altered composition, damaged tissue structures, decreased 2-deoxy-2-[18 F] fluorodeoxyglucose (18F-FDG) value, downregulated gene expression transporter type 4 (GLUT4), reduced colocalization GLUT1/glial fibrillary acidic protein (GFAP) hippocampus, impaired spatial memory. ANS reversed effects 27-OHC. antibiotic-treated did not exhibit similar results after treatment. reveals potential molecular mechanism wherein 27-OHC-induced impairment might be linked uptake, mediated by microbiota.

Язык: Английский

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