DNA methylation signatures of Alzheimer's disease in aged astrocytes

老年星形胶质细胞中阿尔茨海默病的 DNA 甲基化特征

• 批准号: 10807864
• 负责人: Melanie Carless
• 金额: $ 41.03万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10807864
• 关键词: Aberrant DNA Methylation; Acceleration; Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Area; Astrocytes; Autopsy; Biological Assay; Biological Models; Blood - brain barrier anatomy; Brain; Brain Diseases; Calcium; Calcium Signaling; Cell Aging; Cell Line; Chronic; Clinical Research; Coculture Techniques; DNA Methylation; DNA Repair; DNA methylation profiling; Data; Development; Disease; Disease Progression; Embryo; Endosomes; Epigenetic Process; Etiology; Evaluation; Exhibits; Fibroblasts; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genotype; Glutamates; Goals; Healthcare Systems; Homeostasis; Human; Image; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin; Knowledge; Late Onset Alzheimer Disease; Length; Methods; Mission; Mitochondria; Modeling; Modification; Molecular; Molecular Profiling; Nerve Degeneration; Neuroglia; Neurons; Outcomes Research; Oxidative Stress; Pattern; Persons; Phenotype; Play; Process; Protocols documentation; Public Health; Publishing; Research; Risk Factors; Role; Signal Transduction; Specificity; Standardization; Study models; System; Testing; Therapeutic; Therapeutic Studies; Tissues; Toxic effect; United States National Institutes of Health; Validation; age related; aged; apolipoprotein E-3; apolipoprotein E-4; biological adaptation to stress; brain cell; brain health; cell type; cytokine; disorder risk; fetal; gene network; healthy aging; human model; immunocytochemistry; improved; in vitro Model; induced pluripotent stem cell; insight; lipid metabolism; methylomics; mouse model; nervous system disorder; neuroinflammation; novel; pre-clinical; response; senescence; small molecule inhibitor; stem cell model; synaptic function; telomere; transcriptome sequencing; transcriptomics; uptake

PROJECT SUMMARY Age-related neurological disorders like Alzheimer’s disease (AD) affect millions worldwide and pose a major burden to the healthcare system. While most studies focus on neuronal degeneration in AD, there is substantial evidence that non-neuronal cells, such as astrocytes, play an important role in disease progression. Importantly, a major risk factor for late-onset AD, APOE, is highly expressed in astrocytes and is a major contributor to amyloid-beta-associated cellular toxicity, which in turn, dysregulates astrocytic functionality. While the etiological basis for AD in disease-associated astrocytes is unclear, epigenetic modifications like DNA methylation (DNAm), which are known contributors to both healthy aging and neurodegeneration, are likely to play a role. While induced pluripotent stem cell (iPSC)-derived models of AD provide valuable insight into the molecular basis for the disease, they lack the inherent ability to recapitulate age-associated DNA methylation, transcription, and cellular phenotypes that are highly relevant in such late-stage, age-associated brain disorders. Studies show that direct conversion of fibroblasts to neurons retains such age-associated methylomic and transcriptomic patterns. We therefore developed an efficient direct conversion strategy of adult human fibroblast-derived induced-astrocytes (FDIAs), which we propose to validate as an “age-in-a-dish” model that captures age- associated DNA methylation, gene expression, and cellular phenotypes. Using this model, we also aim to elucidate the association of age- and disease-related changes in DNAm to astrocyte functionality using the following aims: 1) establish age-associated DNAm and transcriptional signatures and cellular phenotypes of FDIAs; and 2) evaluate the relationship between DNAm and astrocytic function and elucidate their contribution to AD risk. Through this research, we expect to efficiently develop an ‘age-in-a-dish’ model of human astrocytes that accurately captures age-associated DNAm and transcriptional signatures, which we will be assessed for their role in neuroinflammatory and neurodegenerative processes in AD. Our study is unique in both the validation of an aged astrocyte model (FDIAs), and in the evaluation of astrocytic DNAm and transcriptional signatures in AD, thus improving our understanding of the molecular etiology of age-related brain disorders, including AD.

项目摘要 阿尔茨海默病（AD）等与神经系统疾病有关的神经系统疾病影响着全球数百万人， 给医疗系统带来负担。虽然大多数研究集中在AD中的神经元变性，但存在大量的 证据表明，非神经元细胞，如星形胶质细胞，在疾病进展中发挥重要作用。重要的是， 晚发性AD的一个主要危险因素APOE在星形胶质细胞中高度表达， 淀粉样蛋白-β-相关的细胞毒性，这反过来又使星形胶质细胞功能失调。虽然病因学 疾病相关星形胶质细胞中AD的基础尚不清楚，表观遗传修饰如DNA甲基化（DNAm）， 这些已知的促进健康老化和神经退化的因素可能发挥作用。 虽然诱导多能干细胞（iPSC）衍生的AD模型提供了对AD分子机制的有价值的见解， 疾病的基础，他们缺乏重演与年龄相关的DNA甲基化，转录， 以及与这种晚期、年龄相关的脑部疾病高度相关的细胞表型。研究表明 成纤维细胞向神经元的直接转化保留了这种与年龄相关的甲基化组和转录组， 模式.因此，我们开发了一种有效的成人成纤维细胞衍生的直接转化策略。 诱导星形胶质细胞（FDIA），我们建议验证作为一个“年龄在一个盘子”模型，捕捉年龄- 相关的DNA甲基化、基因表达和细胞表型。利用这个模型，我们还旨在 阐明年龄和疾病相关的DNA m变化与星形胶质细胞功能的关系， 以下目标：1）建立年龄相关的DNA m和转录特征以及细胞表型， FDIA; 2）评估DNAm和星形胶质细胞功能之间的关系并阐明它们的贡献 AD风险。 通过这项研究，我们希望有效地开发一种人类星形胶质细胞的“培养皿中年龄”模型， 准确地捕捉年龄相关的DNA和转录签名，我们将评估他们的 在AD的神经炎症和神经变性过程中的作用。我们的研究是独一无二的， 老化星形胶质细胞模型（FDIA），以及在AD中星形胶质细胞DNAm和转录特征的评价中， 从而提高我们对包括AD在内的与年龄相关的脑疾病的分子病因学的理解。