Association between calculated remnant cholesterol levels and incident risks of Alzheimer’s disease among elderly patients with type 2 diabetes: a real-world study DOI Creative Commons

Hong Jia,

Liuyu Zhang,

Huijuan Liao

et al.

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 29, 2024

Alzheimer's disease (AD) is a leading cause of dementia, with rising global burden. Remnant cholesterol (RC), component triglyceride-rich lipoproteins, has been implicated in cardiovascular diseases and metabolic disorders, but its role AD remains unclear. This study investigated the association between RC levels risk among elderly patients type 2 diabetes (T2D) real-world clinical setting. We conducted retrospective cohort using electronic medical records from Gongli Hospital Shanghai Pudong New Area, covering period 2013 to 2023. The included 15,364 aged 65-80 years T2D. were calculated equation. primary outcome was diagnosis AD, validated by neurologists ICD-10-CM code G30. Cox proportional hazards models employed estimate hazard ratios (HRs) for across quartiles levels, adjusting potential confounders. Over mean follow-up 3.69 ± 1.33 years, 312 new cases identified. A U-shaped relationship observed risk, lowest associated 0.58-0.64 mmol/L. Both lower (<0.52 mmol/L) higher (≥0.77 linked increased risk. Compared reference group (Q2: 0.52-0.64 mmol/L), adjusted HRs (95% CI) highest 1.891 (1.368-2.613) (1.363-2.622), respectively. Each 1 mmol/L increase 3.47-fold (HR=4.474, 95% CI 2.330-8.592). may serve as predictive biomarker both extremes posing Future studies should explore mechanistic pathways interventions targeting prevent high-risk populations.

Language: Английский

Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies DOI Creative Commons
Jifa Zhang, Yinglu Zhang, Jiaxing Wang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

Citations

129
Lipidome disruption in Alzheimer’s disease brain: detection, pathological mechanisms, and therapeutic implications DOI Creative Commons
Sijia He, Ziying Xu, Xianlin Han

et al.

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 27, 2025

Alzheimer's disease (AD) is among the most devastating neurodegenerative disorders with limited treatment options. Emerging evidence points to involvement of lipid dysregulation in development AD. Nevertheless, precise lipidomic landscape and mechanistic roles lipids pathology remain poorly understood. This review aims highlight significance lipidomics lipid-targeting approaches diagnosis We summarized connection between human brain AD at both genetic species levels. briefly introduced technologies discussed potential challenges areas future advancements field for research. To elucidate central role converging multiple pathological aspects AD, we reviewed current knowledge on interplay major features, including amyloid beta, tau, neuroinflammation. Finally, assessed progresses obstacles lipid-based therapeutics proposed strategies leveraging

Language: Английский

Citations

2
Exosomes in Regulating miRNAs for Biomarkers of Neurodegenerative Disorders DOI
Azhagu Madhavan Sivalingam,

Darshitha D Sureshkumar

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Language: Английский

Citations

1
Navigating the metabolic maze: anomalies in fatty acid and cholesterol processes in Alzheimer’s astrocytes DOI Creative Commons
Xiaoyu Zhang, Chuanying Chen, Yi Liu

et al.

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: March 23, 2024

Abstract Alzheimer’s disease (AD) is the most common cause of dementia, and its underlying mechanisms have been a subject great interest. The mainstream theory AD pathology suggests that primarily associated with tau protein amyloid-beta (Aβ). However, an increasing body research has revealed abnormalities in lipid metabolism may be important event throughout pathophysiology AD. Astrocytes, as members network brain, play significant role this event. study abnormal astrocytes provides new perspective for understanding pathogenesis This review focuses on fatty acids (FAs) cholesterol AD, discusses it from three perspectives: uptake, intracellular breakdown or synthesis metabolism, efflux transport. We found that, despite accumulation their own acids, cannot efficiently uptake neurons, leading to acid within neurons resulting lipotoxicity. In terms exhibit decrease endogenous due exogenous cholesterol. Through thorough investigation these metabolic abnormalities, we can provide insights future therapeutic strategies by literature navigate complex maze bring hope patients disease.

Language: Английский

Citations

6
Brain Cytochrome P450: Navigating Neurological Health and Metabolic Regulation DOI Creative Commons
Pradeepraj Durairaj, Zixiang Liu

Journal of Xenobiotics, Journal Year: 2025, Volume and Issue: 15(2), P. 44 - 44

Published: March 14, 2025

Human cytochrome P450 (CYP) enzymes in the brain represent a crucial frontier neuroscience, with far-reaching implications for drug detoxification, cellular metabolism, and progression of neurodegenerative diseases. The brain’s complex architecture, composed interconnected cell types receptors, drives unique neuronal signaling pathways, modulates enzyme functions, leads to distinct CYP gene expression regulation patterns compared liver. Despite their relatively low levels expression, CYPs exert significant influence on responses, neurotoxin susceptibility, behavior, neurological disease risk. These are essential maintaining homeostasis, mediating cholesterol turnover, synthesizing metabolizing neurochemicals, neurosteroids, neurotransmitters. Moreover, they key participants oxidative stress neuroprotection, inflammation. In addition roles psychotropic drugs, substances abuse, endogenous compounds, impact efficacy, safety, resistance, underscoring importance beyond traditional metabolism. Their involvement critical physiological processes also links them onset Understanding cerebral is vital advancing neuroprotective strategies, personalizing treatments disorders, developing CNS-targeting therapeutics. This review explores emerging enzymes, particularly those within CYP1–3 CYP46 families, highlighting functional diversity pathological consequences dysregulation health. It examines potential CYP-based biomarkers improve diagnosis treatment offering new avenues therapeutic innovation.

Language: Английский

Citations

0
MicroRNA signature of lymphoblasts from amyotrophic lateral sclerosis patients as potential clinical biomarkers DOI Creative Commons
Eva P. Cuevas, Enrique López Madruga,

Ignacio Valenzuela Martínez

et al.

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 106871 - 106871

Published: March 1, 2025

MicroRNAs (miRNAs) are a class of small, non-coding RNAs involved in different cellular functions that have emerged as key regulators neurodegenerative diseases such amyotrophic lateral sclerosis (ALS). ALS is fatal disease lacks not only effective treatments, but also presents delays its diagnosis, since reliable clinical biomarkers unavailable. In recent years, advancements high-throughput sequencing strategies led to the identification novel biomarkers, facilitating earlier diagnosis and assessment treatment efficacy. Since immortalized lymphocytes obtained from peripheral blood suitable model study pathological features ALS, we employed these samples with aim characterize dysregulated miRNAs patients. Next-generation (NGS) was utilized order analyze expression profiles healthy controls, sporadic (sALS), familial mutations superoxide dismutase 1 (SOD1-ALS). The screening analysis NGS data identified set miRNAs, which nine candidates were selected for qRT-PCR validation, identifying first time possible importance hsa-miR-6821-5p potential biomarker. Furthermore, up-regulated predicted direct or indirect interactions genes closely related SIGMAR1, HNRNPA1 TARDBP. Additionally, by Metascape enrichment analysis, found VEGFA/VEGFR2 signaling pathway, previously implicated neuroprotective effects candidate pathway further analyses.

Language: Английский

Citations

0
A cholesterol-coupled N-acetyl-aspartyl-glutamate metabolic network facilitates the neuroprotective impact of estradiol in neurons DOI Creative Commons
Hei‐Man Chow, Jacquelyne Ka‐Li Sun, Deng Wu

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: June 10, 2024

Abstract Sex differences have been demonstrated in Alzheimer's disease (AD), yet the intrinsic cellular changes underlying enhanced vulnerability observed postmenopausal women remain elusive. We demonstrate that sustained loss of peripheral estradiol is correlated with accelerated cognitive and memory decline. The resulting brain transcriptomic metabolomic suggest impairment ERRα. Estradiol supports ERRα activity via its actions on neuronal cholesterol homeostasis. Consequently, this prevents truncation TCA cycle at succinate dehydrogenase, which would otherwise cause a net catabolic shift N-acetyl-aspartyl-glutamate (NAAG), driven by an adaptive aspartate-dependent response attempts to reconstruct “mini-cycle”. free glutamate released alongside catabolism NAAG stochastically presynaptically, thereby increasing spontaneous activities. Coupled bioenergetic incompetency occurs during estradiol-loss, slowly depletes ATP increases susceptibility energy crises triggered additional excitatory insults, ultimately contributing female-biased AD.

Language: Английский

Citations

0
Exposure to lipid mixture induces intracellular lipid droplet formation and impairs mitochondrial functions in astrocytes DOI
Yi‐Chen Li,

Jing‐Ting Fu,

Shun‐Fen Tzeng

et al.

Neurochemistry International, Journal Year: 2024, Volume and Issue: 178, P. 105792 - 105792

Published: June 14, 2024

Language: Английский

Citations

0
Investigating cocaine- and abstinence-induced effects on astrocyte gene expression in the nucleus accumbens DOI Creative Commons
Janay P. Franklin, Anze Testen, Piotr A. Mieczkowski

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 5, 2024

ABSTRACT In recent years, astrocytes have been increasingly implicated in cellular mechanisms of substance use disorders (SUD). Astrocytes are structurally altered following exposure to drugs abuse; specifically, within the nucleus accumbens (NAc) exhibit significantly decreased surface area, volume, and synaptic colocalization after operant self-administration cocaine extinction or protracted abstinence (45 days). However, that elicit these morphological modifications unknown. The current study aims elucidate molecular lead observed astrocyte structural changes rats across using astrocyte-specific RiboTag RNA-seq, as an unbiased, comprehensive approach identify genes whose transcription translation change NAc self- administration extended abstinence. Using this method, our data reveal processes including cholesterol biosynthesis specifically by abstinence, suggesting involvement is changed cocaine-abstinent rats. Overall, results provide insight into functional adaptations occur due during withdrawal, which may pinpoint further contribute cocaine-seeking behavior.

Language: Английский

Citations

0
Lipids and α-Synuclein: adding further variables to the equation DOI Creative Commons
Jana Schepers, Timo Löser, Christian Behl

et al.

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 11

Published: Aug. 12, 2024

Graphical Abstract The graphical abstract summarises factors that might lead to lipid changes and possible influences of on synucleinopathies.

Language: Английский

Citations

0