Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics

Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

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Senescent brain cell types in Alzheimer's disease: Pathological mechanisms and therapeutic opportunities

Neurotherapeutics, Journal Year: 2025, Volume and Issue: 22(3), P. e00519 - e00519

Published: Jan. 6, 2025

Cellular senescence is a cell state triggered by programmed physiological processes or cellular stress responses. Stress-induced senescent cells often acquire pathogenic traits, including toxic secretome and resistance to apoptosis. When form faster than they are cleared the immune system, accumulate in tissues throughout body contribute age-related diseases, neurodegeneration. This review highlights evidence of brain their role Alzheimer's disease (AD), leading cause dementia older adults. We also discuss progress challenges senotherapies, pharmacological strategies clear mitigate effects, which hold promise as interventions for AD related dementias (ADRD).

Language: Английский

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Epigenetics in Neurodegenerative Diseases

Sub-cellular biochemistry/Subcellular biochemistry, Journal Year: 2025, Volume and Issue: unknown, P. 73 - 109

Published: Jan. 1, 2025

Language: Английский

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The impact of genetic variability on Alzheimer’s therapies: obstacles for pharmacogenetic progress

Expert Opinion on Drug Metabolism & Toxicology, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 28

Published: Jan. 21, 2025

Genetic load influences the therapeutic response to conventional drugs in Alzheimer's disease (AD). Pharmacogenetics (PGx) is best option reduce drug-drug interactions and adverse drug reactions patients undergoing polypharmacy regimens. However, there are important limitations that make it difficult incorporate pharmacogenetics into routine clinical practice. This article analyzes pharmacogenetic apparatus made up of pathogenic, mechanistic, metabolic, transporter, pleiotropic genes responsible for efficacy safety pharmacological treatment, impact genetic on outcome multifactorial treatments, practical aspects effective use PGx. Over 120 closely associated with AD. There an accumulation cerebrovascular (CVn) neurodegenerative (ADn) APOE-4 carriers accumulate more deleterious related other CVn ADn genes, develop earlier, at a biological disadvantage compared non-carriers. CYP2D6-PMs worst responders anti-dementia drugs. Some hinder implementation PGx practice, including lack information many drugs, low number screening protocols, educational deficiencies medical community regarding genomic medicine.

Language: Английский

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Accelerated epigenetic aging in Huntington’s disease involves polycomb repressive complex 1

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 11, 2025

Abstract Loss of epigenetic information during physiological aging compromises cellular identity, leading to de-repression developmental genes. Here, we assessed the epigenomic landscape vulnerable neurons in two reference mouse models Huntington neurodegenerative disease (HD), using cell-type-specific multi-omics, including temporal analysis at three stages via FANS-CUT&Tag. We show accelerated genes HD striatal neurons, involving histone re-acetylation and depletion H2AK119 ubiquitination H3K27 trimethylation marks, which are catalyzed by polycomb repressive complexes 1 2 (PRC1 PRC2), respectively. further identify a PRC1-dependent subcluster bivalent transcription factors that is re-activated neurons. This mechanism likely involves progressive paralog switching between PRC1-CBX genes, promotes upregulation normally low-expressed PRC1-CBX2/4/8 isoforms alongside down-regulation predominant these cells (e.g., CBX6/7). Collectively, our data provide evidence for

Language: Английский

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Functional insight into East Asian–specific genetic risk loci for Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(2)

Published: Feb. 1, 2025

Abstract INTRODUCTION The functional study of genetic risk factors for Alzheimer's disease (AD) provides insights into the underlying mechanisms and identification potential therapeutic targets. Investigating AD‐associated loci identified in East Asian populations using single‐nucleus RNA‐sequencing data may identify novel contributors. METHODS Cell type–specific expression quantitative trait (eQTL) peak‐to‐gene links were used to genes associated with 26 from seven genome‐wide association studies (GWAS) AD Asians. RESULTS KCNJ6 MAPK1IP1L as significant eQTLs loci. peaks related four genes, CLIC4 being connected across different cell types. Genes European GWAS interacted within networks enriched pathology pathways astrocytes. DISCUSSION Our findings suggest providing insight architecture Highlights Integrated analysis was performed. (eQTLs) assay transposase‐accessible chromatin genes. An variant linked through an oligodendrocyte progenitor cell–specific eQTL. maps open chromatin, six Astrocyte differentially expressed by are

Language: Английский

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Integrating amyloid and tau imaging with proteomics and genomics in Alzheimer’s disease

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(9), P. 101735 - 101735

Published: Sept. 1, 2024

Language: Английский

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Single‐Cell Patch‐Clamp/Proteomics of Human Alzheimer's Disease iPSC‐Derived Excitatory Neurons Versus Isogenic Wild‐Type Controls Suggests Novel Causation and Therapeutic Targets

Advanced Science, Journal Year: 2024, Volume and Issue: 11(29)

Published: May 21, 2024

Abstract Standard single‐cell (sc) proteomics of disease states inferred from multicellular organs or organoids cannot currently be related to physiology. Here, a scPatch‐Clamp/Proteomics platform is developed on single neurons generated hiPSCs bearing an Alzheimer's (AD) genetic mutation and compares them isogenic wild‐type controls. This approach provides both current voltage electrophysiological data plus detailed information single‐cells. With this new method, the authors are able observe hyperelectrical activity in AD hiPSC‐neurons, similar that observed human brain, correlate it ≈1400 proteins detected at neuron level. Using linear regression mediation analyses explore relationship between abundance individual neuron's mutational status, yields therapeutic targets excitatory not attainable by traditional methods. combined patch‐proteomics technique creates proteogenetic‐therapeutic strategy genotypic alterations physiology with protein expression

Language: Английский

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The broken Alzheimer’s disease genome

Cell Genomics, Journal Year: 2024, Volume and Issue: 4(5), P. 100555 - 100555

Published: May 1, 2024

The complex pathobiology of late-onset Alzheimer's disease (AD) poses significant challenges to therapeutic and preventative interventions. Despite these difficulties, genomics related disciplines are allowing fundamental mechanistic insights emerge with clarity, particularly the introduction high-resolution sequencing technologies. After all, disrupted processes at interface between DNA gene expression, which we call broken AD genome, offer detailed quantitative evidence unrestrained by preconceived notions about disease. In addition highlighting biological pathways beyond classical pathology hallmarks, advances have revitalized drug discovery efforts driving improvements in clinical tools. We review genetic, epigenomic, expression findings pathogenesis explore how their integration enables a better understanding multicellular imbalances contributing this heterogeneous condition. frontiers opening on back research milestones promise future care that is both more personalized predictive.

Language: Английский

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A bibliometric and visual analysis of epigenetic research publications for Alzheimer’s disease (2013–2023)

Frontiers in Aging Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: Jan. 16, 2024

Background Currently, the prevalence of Alzheimer’s disease (AD) is progressively rising, particularly in developed nations. There an escalating focus on onset and progression AD. A mounting body research indicates that epigenetics significantly contributes to AD holds substantial promise as a novel therapeutic target for its treatment. Objective The objective this article present areas interest, comprehend contextual framework subject research, investigate prospective direction future development. Methods ln Web Science Core Collection (WOSCC), we searched documents by specific terms their corresponding free words. VOSviewer, CiteSpace Scimago Graphica were used perform statistical analysis measurement metrics such number published papers, national cooperative networks, publishing countries, institutions, authors, co-cited journals, keywords, visualize networks related content elements. Results We selected 1,530 articles from WOSCC January 2013 June 2023 about Based visual analysis, could get China United States countries with most field. Bennett DA was contributed prestigious scientist. top 3 cited journals Journal Disease, Neurobiology Aging Molecular Neurobiology. According keywords frequency citations, ncRNAs, transcription factor, genome, histone modification, blood DNA methylation, acetylation, biomarkers hot directions today. Conclusion bibliometric epigenetic promising direction, had potential be targets.

Language: Английский

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