Metabolism and metabolomics in senescence, aging, and age-related diseases: a multiscale perspective

Frontiers of Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Language: Английский

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Low-density lipoprotein cholesterol levels and risk of incident dementia: a distributed network analysis using common data models

Journal of Neurology Neurosurgery & Psychiatry, Journal Year: 2025, Volume and Issue: unknown, P. jnnp - 334708

Published: April 1, 2025

Background The link between low-density lipoprotein cholesterol (LDL-C) levels and dementia risk is poorly understood, with conflicting evidence on the role of LDL-C impact statin therapy cognitive outcomes. Thus, we aimed to examine association assess influence therapy. Methods We retrospectively analysed data from 11 university hospitals participating in Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). Participants a prior diagnosis or those <180 days observation before cohort inclusion, included both cohorts were excluded. primary outcome was all-cause dementia, secondary being Alzheimer’s disease-related (ADRD). study utilised 1:1 propensity score matching compare individuals below 70 mg/dL (1.8 mmol/L) against above 130 (3.4 mmol/L), resulting analysis 108 980 matched patients. Secondary analyses further examined thresholds 55 (1.4 use. Results associated 26% reduction 28% ADRD, compared mmol/L). For there an 18% for Among <70 (<1.8 use 13% 12% decrease ADRD non-users. Conclusion Low (<70 mmol/L)) are significantly reduced including providing additional protective effects. These findings support necessity targeted lipid management as preventive strategy indicating importance personalised treatment approaches.

Language: Английский

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Modulation of C5a–C5aR1 signaling alters the dynamics of AD progression

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: July 11, 2022

The complement system is part of the innate immune that clears pathogens and cellular debris. In healthy brain, influences neurodevelopment neurogenesis, synaptic pruning, clearance neuronal blebs, recruitment phagocytes, protects from pathogens. However, excessive downstream activation leads to generation C5a, C5a engagement with its receptor C5aR1, instigates a feed-forward loop inflammation, injury, death, making C5aR1 potential therapeutic target for neuroinflammatory disorders. ablation in Arctic (Arc) model Alzheimer's disease against cognitive decline injury without altering amyloid plaque accumulation.

Language: Английский

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The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis

Acta Neuropathologica Communications, Journal Year: 2022, Volume and Issue: 10(1)

Published: March 16, 2022

Previous studies show that 3β-hydroxysterol-Δ24 reductase (DHCR24) has a remarked decline in the brain of AD patients. In cholesterol synthetic metabolism, DHCR24 is known as heavily key synthetase synthesis. Moreover, mutations gene result inhibition enzymatic activity DHCR24, causing deficiency and desmosterol accumulation. Furthermore, vitro also demonstrated knockdown lead to synthesis, decrease plasma membrane intracellular level. Obviously, could play crucial role maintaining homeostasis via control Over past two decades, accumulating data suggests downregulated by major risk factors for AD, suggesting potential link between downregulation pathogenesis. Thus, loss seems be induced possible causative AD. According previous our study, we further found reduced level compartments obviously was involved β-amyloid generation, tau hyperphosphorylation, apoptosis. Importantly, increasing evidences reveal lipid raft disorganization are linked neuropathological impairments which associated with Therefore, based on research suppose deficiency/loss might pathogenesis

Language: Английский

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CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice

Science Advances, Journal Year: 2024, Volume and Issue: 10(4)

Published: Jan. 24, 2024

The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting into 24 S -hydroxycholesterol (24OH). Dysregulation of brain and reduced levels are observed in Alzheimer’s disease (AD). In this study, we report that overexpression aged female mice leads to enhanced estrogen signaling the hippocampus improved cognitive functions. contrast, age-matched overexpressing males show anxiety-like behavior, worsened memory, elevated 5α-dihydrotestosterone hippocampus. We that, neurons, 24OH contributes these divergent effects activating sex hormone signaling, including receptors. protects from memory impairments induced ovariectomy while having no gonadectomized males. Last, measured cerebrospinal fluid a clinical cohort patients with AD found negatively correlates neurodegeneration markers only women. suggest activation is valuable pharmacological target for enhancing women at risk developing neurodegenerative diseases.

Language: Английский

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Non-linear relationship between serum cholesterol levels and cognitive change among older people in the preclinical and prodromal stages of dementia: a retrospective longitudinal study in Taiwan

BMC Geriatrics, Journal Year: 2024, Volume and Issue: 24(1)

Published: May 30, 2024

Abstract Background Adverse effects of rigorously lowering low-density lipoprotein cholesterol on cognition have been reported; therefore, we aimed to study the contribution serum in cognitive decline older people with or without dementia. Methods Cognitive function was assessed by Abilities Screening Instrument (CASI). We investigated associations between using multiple regressions controlling for demographics, vascular risk factors, and treatments. Results Most CASI scores could be explained non-linear inverted U-shaped relationships ( R 2 = 0.003–0.006, p < 0.016, Šidákcorrection). The were most evident changes at preclinical prodromal stages dementia (R 0.02–0.064, values 0.016). There no differences level individuals 1st decile 10th groups 0.266–0.972). However, triglyceride stable normal functions showed significant improvement compared those t (202) 2.275, 0.05). Conclusion These findings implicate that may not suitable prevention among people, especially

Language: Английский

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Exploring the Dynamic Changes of Brain Lipids, Lipid Rafts, and Lipid Droplets in Aging and Alzheimer’s Disease

Biomolecules, Journal Year: 2024, Volume and Issue: 14(11), P. 1362 - 1362

Published: Oct. 26, 2024

Aging induces complex changes in the lipid profiles across different areas of brain. These can affect function brain cells and may contribute to neurodegenerative diseases such as Alzheimer's disease. Research shows that while overall profile human remains quite steady throughout adulthood, specific occur with age, especially after age 50. include a slow decline total content shifts composition fatty acids, particularly glycerophospholipids cholesterol levels, which vary depending on region. Lipid rafts play crucial role maintaining membrane integrity facilitating cellular signaling. In context disease, have been associated development For example, alterations raft lead increased accumulation amyloid β (Aβ) peptides, contributing neurotoxic effects. droplets store neutral lipids are key for energy metabolism. As organisms dynamics change, evidence suggesting metabolic activity over time. This reduced an imbalance synthesis mobilization, processes. model like Drosophila, studies shown metabolism be influenced by diet insulin signaling pathways, balance. The interplay between metabolism, oxidative stress, inflammation is critical aging peroxidation, consequence formation reactive aldehydes further damage neurons. Inflammatory processes also disrupt pathology AD. Consequently, oxidized integrity, influencing pathways involved neuronal survival function.

Language: Английский

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Synapses, Microglia, and Lipids in Alzheimer’s Disease

Frontiers in Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: Jan. 12, 2022

Alzheimer’s disease (AD) is characterised by synaptic dysfunction accompanied the microscopically visible accumulation of pathological protein deposits and cellular dystrophy involving both neurons glia. Late-stage AD shows pronounced loss synapses across several differentially affected brain regions. Recent studies advanced using post-mortem samples have demonstrated direct involvement microglia in changes. Variants Apolipoprotein E Triggering Receptors Expressed on Myeloid Cells gene represent important determinants microglial activity but also lipid metabolism cells central nervous system. Here we review evidence that may help to explain how abnormal metabolism, activation, pathophysiology are inter-related AD.

Language: Английский

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Alzheimer’s Precision Neurology: Epigenetics of Cytochrome P450 Genes in Circulating Cell-Free DNA for Disease Prediction and Mechanism

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2876 - 2876

Published: Feb. 2, 2023

Precision neurology combines high-throughput technologies and statistical modeling to identify novel disease pathways predictive biomarkers in Alzheimer's (AD). Brain cytochrome P450 (CYP) genes are major regulators of cholesterol, sex hormone, xenobiotic metabolism, they could play important roles neurodegenerative disorders. Increasing evidence suggests that epigenetic factors contribute AD development. We evaluated cytosine ('CpG')-based DNA methylation changes using circulating cell-free (cfDNA), which neuronal cells known contribute. investigated CYP-based mechanisms for pathogenesis detection. performed a case-control study 25 patients with 23 cognitively healthy controls the cfDNA CYP genes. logistic regression analysis MetaboAnalyst software computer program molecular pathway based on epigenetically altered Cytoscape program. identified 130 significantly (false discovery rate correction q-value < 0.05) differentially methylated CpG sites within The top two were CYP51A1 CYP2S1. significant perturbed (i) androgen estrogen biosynthesis (ii) C21 steroid hormone (iii) arachidonic acid metabolism. Existing potential role each these biochemical pathogenesis. Next, we randomly divided group into validation sub-sets, consisting control patients. Regression models prediction markers developed or training tested independent group. achieved high accuracy. After 10-fold cross-validation, combination cg17852385/cg23101118 + cg14355428/cg22536554 an AUC (95% CI) 0.928 (0.787~1.00), 100% sensitivity 92.3% specificity detection performance remained test group, achieving 0.942 (0.905~0.979) 90% specificity. Our findings suggest modification may have accurately non-invasively detect AD.

Language: Английский

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White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: Feb. 10, 2023

We postulate that myelin injury contributes to cholesterol release from and dysmetabolism which Abeta dysmetabolism, combined with genetic AD risk factors, leads increased amyloid plaques. Increased damages form a vicious cycle. Thus, white matter injury, interact produce or worsen neuropathology. The cascade is the leading hypothesis for cause of Alzheimer’s disease (AD). failure clinical trials based on this has raised other possibilities. Even possible new success (Lecanemab), it not clear whether result disease. With discovery in 1993 apolipoprotein E type 4 allele (APOE4) was major factor sporadic, late-onset (LOAD), there been increasing interest since APOE transporter. Recent studies show metabolism intricately involved (Aβ)/amyloid transport metabolism, down-regulating Aβ LRP1 transporter upregulating RAGE receptor, both would increase brain Aβ. Moreover, manipulating rodent models can ameliorate pathology cognitive deficits, them depending upon manipulation. Though (WM) noted initial observations, recent have shown abnormal every brain. age-related WM normal individuals occurs earlier worse APOE4 genotype. precedes formation plaques tangles human Familial (FAD) plaque models. Restoring improves cognition without affecting pathology. we cascade, and/or further primary initiating event could be related any three, age diet genes FAD dysmetabolism.

Language: Английский

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