Ageing Research Reviews, Год журнала: 2023, Номер 87, С. 101918 - 101918
Опубликована: Март 24, 2023
Язык: Английский
Neuron, Год журнала: 2024, Номер 112(8), С. 1208 - 1221
Опубликована: Фев. 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.
Язык: Английский
Процитировано
101
Cell, Год журнала: 2023, Номер 186(22), С. 4757 - 4772
Опубликована: Окт. 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.
Язык: Английский
Процитировано
87
Nature Communications, Год журнала: 2023, Номер 14(1)
Опубликована: Июнь 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.
Язык: Английский
Процитировано
46
Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 25(11), С. 845 - 864
Опубликована: Июль 16, 2024
Язык: Английский
Процитировано
43
Protein & Cell, Год журнала: 2024, Номер unknown
Опубликована: Май 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.
Язык: Английский
Процитировано
32
Nature, Год журнала: 2024, Номер 628(8008), С. 648 - 656
Опубликована: Март 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.
Язык: Английский
Процитировано
26
Science Advances, Год журнала: 2025, Номер 11(10)
Опубликована: Март 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.
Язык: Английский
Процитировано
8
Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)
Опубликована: Янв. 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
Язык: Английский
Процитировано
3
International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(7), С. 6354 - 6354
Опубликована: Март 28, 2023
The term "neurodegenerative diseases" (NDs) identifies a group of heterogeneous diseases characterized by progressive loss selectively vulnerable populations neurons, which progressively deteriorates over time, leading to neuronal dysfunction. Protein aggregation and have been considered the most characteristic hallmarks NDs, but growing evidence confirms that significant dysregulation innate immune pathways plays crucial role as well. NDs vary from multiple sclerosis, in autoimmune inflammatory component is predominant, more "classical" such Parkinson's disease, Alzheimer's amyotrophic lateral spinal muscular atrophy. Of interest, many clinical differences reported seem be closely linked sex, may justified changes mechanisms between affected females males. In this review, we examined some studied looking at their pathogenic phenotypical features highlight sex-related discrepancies, if any, with particular interest individuals' responses treatment. We believe pointing out these practice help achieve successful precision personalized care.
Язык: Английский
Процитировано
40
Biomedicines, Год журнала: 2023, Номер 11(4), С. 1154 - 1154
Опубликована: Апрель 11, 2023
Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number TBI survivors, impact and awareness this problem are growing. The mechanisms by which increases disease, however, not completely understood. a result, there no protective treatments for patients. Here, we review current literature surrounding epidemiology potential mechanistic relationships between In addition to increasing all forms dementia, most prominent conditions that accelerated amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease (PD), Alzheimer's (AD), with ALS FTD being least well-established. Mechanistic links reviewed include oxidative stress, dysregulated proteostasis, neuroinflammation. Disease-specific TAR DNA binding protein 43 motor cortex lesions FTD; alpha-synuclein, dopaminergic cell death, synergistic toxin exposure PD; insulin resistance, amyloid beta pathology, tau pathology AD. While compelling have been identified, expanded investigation field is needed develop therapies protect
Язык: Английский
Процитировано
30