Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 87, P. 101918 - 101918
Published: March 24, 2023
Language: Английский
Neuron, Journal Year: 2024, Volume and Issue: 112(8), P. 1208 - 1221
Published: Feb. 22, 2024
Alzheimer's disease (AD) and the mechanisms underlying its etiology progression are complex multifactorial. The higher AD risk in women may serve as a clue to better understand these complicated processes. In this review, we examine aspects of that demonstrate sex-dependent effects delve into potential biological responsible, compiling findings from advanced technologies such single-cell RNA sequencing, metabolomics, multi-omics analyses. We review evidence sex hormones chromosomes interact with various during aging, encompassing inflammation, metabolism, autophagy, leading unique characteristics between men women.
Language: Английский
Citations
103
Cell, Journal Year: 2023, Volume and Issue: 186(22), P. 4757 - 4772
Published: Oct. 1, 2023
Alzheimer's disease (AD) research has entered a new era with the recent positive phase 3 clinical trials of anti-Aβ antibodies lecanemab and donanemab. Why did it take 30 years to achieve these successes? Developing potent therapies for reducing fibrillar amyloid was key, as selection patients at relatively early stages disease. Biomarkers target pathologies, including tau PET, insights from past were also critical successes. Moving forward, challenge will be develop more efficacious greater efficiency. Novel trial designs, combination umbrella basket protocols, accelerate development. Better diversity inclusivity participants are needed, blood-based biomarkers may help improve access medically underserved groups. Incentivizing innovation in both academia industry through public-private partnerships, collaborative mechanisms, creation career paths build momentum exciting times.
Language: Английский
Citations
89
Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)
Published: June 22, 2023
Tau protein aggregates in several neurodegenerative disorders, referred to as tauopathies. The tau isoforms observed post mortem human brain is used classify However, distinguishing tauopathies ante remains challenging, potentially due differences between insoluble and soluble body fluids. Here, we demonstrated that differ aggregates, but not extracts. We therefore characterized post-translational modifications of both the aggregated obtained from tissue patients with Alzheimer's disease, cortico-basal degeneration, Pick's frontotemporal lobe degeneration. found specific signatures for each tauopathy its isoforms: including ubiquitination on Lysine 369 degeneration acetylation 311 disease. These findings provide potential targets future development fluid-based biomarker assays able distinguish vivo.
Language: Английский
Citations
46
Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(11), P. 845 - 864
Published: July 16, 2024
Language: Английский
Citations
46
Protein & Cell, Journal Year: 2024, Volume and Issue: unknown
Published: May 11, 2024
Abstract Alzheimer’s disease (AD), the leading cause of dementia, is characterized by accumulation amyloid plaques and neurofibrillary tangles in brain. This condition casts a significant shadow on global health due to its complex multifactorial nature. In addition genetic predispositions, development AD influenced myriad risk factors, including aging, systemic inflammation, chronic conditions, lifestyle, environmental exposures. Recent advancements understanding pathophysiology are paving way for enhanced diagnostic techniques, improved assessment, potentially effective prevention strategies. These discoveries crucial quest unravel complexities AD, offering beacon hope management treatment options millions affected this debilitating disease.
Language: Английский
Citations
35
Nature, Journal Year: 2024, Volume and Issue: 628(8008), P. 648 - 656
Published: March 27, 2024
Abstract Dynamically organized chromatin complexes often involve multiplex interactions and sometimes chromatin-associated RNA 1–3 . Chromatin complex compositions change during cellular differentiation ageing, are expected to be highly heterogeneous among terminally differentiated single cells 4–7 Here we introduce the multinucleic acid interaction mapping in (MUSIC) technique for concurrent profiling of interactions, gene expression RNA–chromatin associations within individual nuclei. When applied 14 human frontal cortex samples from older donors, MUSIC delineated diverse cortical cell types states. We observed that nuclei exhibiting fewer short-range were correlated with both an ‘older’ transcriptomic signature Alzheimer’s disease pathology. Furthermore, type contacts between cis quantitative trait loci a promoter tends which these specifically affect their target gene. In addition, female exhibit XIST non-coding chromosome X, along spatial organizations X chromosomes. presents potent tool exploration architecture transcription at resolution tissues.
Language: Английский
Citations
26
Molecules, Journal Year: 2024, Volume and Issue: 29(12), P. 2812 - 2812
Published: June 13, 2024
Tau protein is a microtubule-associated that widely distributed in the central nervous system and maintains regulates neuronal morphology function. aggregates abnormally forms neurofibrillary tangles neurodegenerative diseases, disrupting structure function of neurons leading to death, which triggers initiation progression neurological disorders. The aggregation tau diseases associated with post-translational modifications, may affect hydrophilicity, spatial conformation, stability protein, promoting formation tangles. Therefore, studying role mechanism aberrant important for understanding finding therapeutic approaches. This review describes possible mechanisms by promotes modifications influencing factors, current status drug discovery development related contribute new approaches alleviate or treat diseases.
Language: Английский
Citations
19
Science Advances, Journal Year: 2025, Volume and Issue: 11(10)
Published: March 5, 2025
Women live longer than men and exhibit less cognitive aging. The X chromosome contributes to sex differences, as females harbor an inactive (Xi) active (Xa), in contrast males with only Xa. Thus, reactivation of silent Xi genes may contribute differences. We use allele-specific, single-nucleus RNA sequencing show that aging remodels transcription the Xa across hippocampal cell types. Aging preferentially changed gene expression on X's relative autosomes. Select underwent activation, new escape cells including dentate gyrus, critical learning memory. Expression escapee Plp1, a myelin component, was increased hippocampus female mice parahippocampus women. AAV-mediated Plp1 elevation gyrus male improved cognition. Understanding how confer advantage could lead novel targets counter brain disease both sexes.
Language: Английский
Citations
8
Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)
Published: Jan. 13, 2025
Astrocytes, the most abundant glial cell type in brain, will convert into reactive state response to proteotoxic stress such as tau accumulation, a characteristic feature of Alzheimer's disease (AD) and other tauopathies. The formation astrocytes is partially attributed disruption autophagy lysosomal signaling, inhibiting some histone deacetylases (HDACs) has been demonstrated reduce molecular functional characteristics astrocytes. However, precise role signaling that regulates pathology remains unclear. We investigated expression class IIa HDAC7 from AD patients PS19 mice. mice were treated with AAVs expressing shRNA for astrocyte-specific promoter selective HDAC inhibitor, TMP195, effects on pathology, gliosis, synaptic plasticity cognition-related behavioral performance measured. Tau uptake degradation assays cultured utilized investigate astrocyte-mediated clearance. Immunoprecipitation, immunofluorescence, western blotting, RT-qPCR, mass spectrometric, luciferase reporter assay used identify substrates, modification site related pathways astrocyte-tau generated new antibody clarify HDAC7-mediated Here, we found level deacetylase 7 (HDAC7) was remarkably increased P301S transgenic (PS19) Genetic or pharmacological inhibition effectively enhanced astrocytic clearance improved cognitive functions could modulate proteins through transcriptional factor EB (TFEB) acetylation-dependent manner. Specifically, deacetylation TFEB at K310 by prevented nuclear translocation reduced biogenesis astrocytes, whereas restored acetylation Our findings suggest upregulation induces AD-like pathologies via deacetylating downregulating HDAC7-TFEB promising arresting
Language: Английский
Citations
3
JAMA Neurology, Journal Year: 2025, Volume and Issue: unknown
Published: March 3, 2025
Importance Alzheimer disease (AD) predominates in females at almost twice the rate relative to males. Mounting evidence adults without AD indicates that exhibit higher tau deposition than age-matched males, particularly setting of elevated β-amyloid (Aβ), but for sex differences accumulation rates is inconclusive. Objective To examine whether female associated with faster high Aβ (as measured positron emission tomography [PET]) and moderating influence on association between APOE ε4 carrier status accumulation. Data Sources This meta-analysis used data from 6 longitudinal aging studies, including Alzheimer’s Disease Neuroimaging Initiative, Berkeley Aging Cohort Study, BioFINDER 1, Harvard Brain Mayo Clinic Study Aging, Wisconsin Registry Prevention. Longitudinal were collected November 2004 May 2022. Selection Included studies required available [ 18 F]flortaucipir or F]-MK-6240 tau-PET scans, as well baseline 11 C] Pittsburgh Compound B, F]flutemetamol F]florbetapir Aβ-PET scans. Recruitment criteria varied across studies. Analyses began August 7, 2023, completed February 5, 2024. Extraction Synthesis In each study, primary analyses extracted estimates (female male) by (high low) using a series mixed-effects models. Secondary models interaction estimate tau-PET. Study-specific model then pooled meta-analysis, global fixed effect (β) total heterogeneity ( I 2 ) estimated. study reported following Preferred Reporting Items Systematic Reviews Meta-analyses (PRISMA) reporting guideline. Main Outcomes Measures Seven outcomes showed cross-sectional examined temporal, parietal, occipital lobes. Results Among assessed, there 1376 participants (761 [55%] female; mean [range] age first scan, 71.9 [46-93] years; 401 [29%] Aβ; 412 carriers [30%]). individuals Aβ, was localized inferior temporal (β = −0.14; 95% CI, −0.22 −0.06; P .009) fusiform −0.13; −0.23 −0.04; .02), lateral regions −0.15; −0.24 compared male sex. carriers, inferior-temporal −0.10; −0.16 −0.03; .01). Conclusions Relevance These findings suggest pathological progression call sex-specific timing considerations when administrating anti-Aβ anti-tau treatments.
Language: Английский
Citations
3