Epigenetic Regulation in Aging and Alzheimer's Disease

衰老和阿尔茨海默病的表观遗传调控

• 批准号: 10564831
• 负责人: Hongxin Dong
• 金额: $ 64.01万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564831
• 关键词: APP-PS1; Acceleration; Adult; Affect; Age; Age Months; Age Years; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s neuropathogenesis; Amyloid; Animal Model; Autopsy; Behavior; Biological Assay; Biological Markers; Brain; CRISPR/Cas technology; DNA Methylation; Development; Diagnosis; Disease; Dose; Elderly; Elements; Environment; Epigenetic Process; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Modified; Genes; Genetic; Genetic Transcription; Glutamate Receptor; Hippocampus; Histone Acetylation; Histones; Human; Individual; Life; Link; MS-275; Maps; Mediating; Memory; Memory Loss; Memory impairment; Molecular; Molecular Target; Mus; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Pathogenesis; Pathway Analysis; Pharmacological Treatment; Play; Prefrontal Cortex; Prevention; Prevention strategy; Promoter Regions; Research; Risk; Risk Factors; Role; Stimulus; Synaptic plasticity; Testing; Therapeutic; Tissues; Twin Studies; Wild Type Mouse; Work; aged; brain tissue; chromatin immunoprecipitation; drug action; epigenetic regulation; epigenome; genetic approach; genome-wide; histone deacetylase 2; histone methylation; histone modification; improved; inhibitor; knock-down; mouse model; neuropathology; new therapeutic target; normal aging; novel; novel therapeutic intervention; overexpression; prevent; promoter; protein expression; response; synaptic function; tool; transcriptome sequencing; treatment strategy; APP-PS1; Acceleration; Adult; Affect; Age; Age Months; Age Years; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s neuropathogenesis; Amyloid; Animal Model; Autopsy; Behavior; Biological Assay; Biological Markers; Brain; CRISPR/Cas technology; DNA Methylation; Development; Diagnosis; Disease; Dose; Elderly; Elements; Environment; Epigenetic Process; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Modified; Genes; Genetic; Genetic Transcription; Glutamate Receptor; Hippocampus; Histone Acetylation; Histones; Human; Individual; Life; Link; MS-275; Maps; Mediating; Memory; Memory Loss; Memory impairment; Molecular; Molecular Target; Mus; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Pathogenesis; Pathway Analysis; Pharmacological Treatment; Play; Prefrontal Cortex; Prevention; Prevention strategy; Promoter Regions; Research; Risk; Risk Factors; Role; Stimulus; Synaptic plasticity; Testing; Therapeutic; Tissues; Twin Studies; Wild Type Mouse; Work; aged; brain tissue; chromatin immunoprecipitation; drug action; epigenetic regulation; epigenome; genetic approach; genome-wide; histone deacetylase 2; histone methylation; histone modification; improved; inhibitor; knock-down; mouse model; neuropathology; new therapeutic target; normal aging; novel; novel therapeutic intervention; overexpression; prevent; promoter; protein expression; response; synaptic function; tool; transcriptome sequencing; treatment strategy

ABSTRACT Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and neuropathological changes in the brain. Aging remains the single largest risk factor for sporadic AD, but the mechanisms underlying this risk are not well understood. Epigenetics has been implicated in both aging and the pathogenesis of AD. Promising results from our group and others have showed that epigenetic alterations occur during aging and thereby affect neuronal function, as well as contributing to memory deficits and the pathogenesis of AD. In the proposed project, we will use mouse models of both aging and AD, as well as human postmortem tissues, to determine the histone modifications in the epigenome that occur during aging. We will also determine whether these changes promote the development of neuropathological changes that are associated with AD. Our hypothesis is that dysregulations of histone modification during aging promote AD by initiating the development of AD-related changes in neuronal networks at the molecular level. In turn, we also hypothesize that histonedeacetylase (HDAC) inhibitorscan mitigate or even prevent the neuropathogenesis of AD. To test our hypotheses, we will first map histone modifications that occur at three critical life stages (3, 12 and 18 months of age) in both wild-type (WT) and APP/PS1 mice, as well as human postmortem tissues (AD patients, young, aged healthy controls), to determine whether differential histone acetylation and methylation contribute to memory deficits and neuropathological changes associated with AD. This will be achieved through CUT&RUN seq and RNA seq combined with pathway analysis to determine the functional consequence of significant genes that are regulated by epigenetics. We will also profile histone modifications at specific gene promoter regions that are related to memory, synaptic plasticity, and the typical elements of AD neuropathology. Second, given that HDACs are key factors in histone modification and in the regulation of gene transcription, we will determine whether dysfunction of any specific HDACs causes memory deficits in AD mouse models. For this purpose, we will utilize genetic editing tools including CRISPR/Cas9-mediated knock-down and AAV9-eGFP- mediated over-expression to identify critical HDACs (eg. HDAC2 and 3) that modulate histone acetylation and methylation marks at gene promoters specifically linked to memory and neuronal plasticity. Finally, we will determine whether HDAC inhibitors have beneficial effects on memory-like behaviors and AD-like neuropathological changes in APP/PS1 mice (3, 12 and 18 months of age) as well as in age-matched WT mice. More specifically, we will investigate whether non-selective (i.e., VPA) or selective HDAC inhibitors (i.e., MS-275 and CI-994) are effective in preventing and/or rescuing memory function and neuronal changes in aging and AD mouse models. Overall, this project will significantly improve our understanding of the epigenetic mechanisms that link aging with the neuropathogenesis of AD. Identification of these mechanisms will lay the basis for developing novel therapeutic strategies for the prevention and treatment of AD.

抽象的 阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，其特征是记忆丧失和 大脑的神经病理学变化。衰老仍然是零星广告的最大风险因素，但 这种风险背后的机制尚不清楚。表观遗传学与衰老和 AD发病机理。我们小组和其他人的有希望的结果表明，表观遗传改变发生了 在衰老期间，从而影响神经元功能，并有助于记忆缺陷和 AD发病机理。在拟议的项目中，我们将使用衰老和AD的鼠标模型以及人类 验尸组织，以确定衰老过程中表观基因组中的组蛋白修饰。我们将 还确定这些变化是否促进了神经病理学变化的发展 与AD相关。我们的假设是，在衰老期间，组蛋白修饰的失调通过 启动分子水平神经元网络中与广告相关的变化的发展。反过来，我们也 假设病变核酸酶（HDAC）抑制剂减轻甚至防止神经病发生 广告。为了检验我们的假设，我们将首先绘制在三个关键寿命阶段发生的组蛋白修饰（3，12 野生型（WT）和APP/PS1小鼠以及人类验尸组织（AD） 患者，年轻的健康对照），以确定差异组蛋白乙酰化和甲基化是否存在 有助于与AD相关的记忆缺陷和神经病理学变化。这将通过 切割和运行SEQ和RNA SEQ与途径分析相结合，以确定功能后果 由表观遗传学调节的重要基因。我们还将在特定基因上介绍组蛋白修饰 与记忆，突触可塑性和AD神经病理学的典型元素有关的启动子区域。 其次，鉴于HDAC是组蛋白修饰和基因转录调节的关键因素，我们 将确定任何特定HDAC的功能障碍是否会导致AD鼠标模型中的存储缺陷。为了这 目的，我们将利用遗传编辑工具，包括CRIS/CAS9介导的敲除和AAV9-EGFP- 中介 过表达 确定调节组蛋白乙酰化和的关键HDAC（例如HDAC2和3） 与记忆和神经元可塑性特别相关的基因启动子的甲基化标记。最后，我们会的 确定HDAC抑制剂是否对内存样行为和类似AD的行为有益影响 APP/PS1小鼠（3、12和18个月大）以及年龄匹配的WT小鼠的神经病理学变化。 更具体地说，我们将研究非选择性（即VPA）或选择性HDAC抑制剂（即MS-275）是 和CI-994）有效预防和/或营救记忆功能以及衰老和AD的神经元变化 鼠标模型。总体而言，该项目将大大提高我们对表观遗传机制的理解 将衰老与AD的神经病发生联系。这些机制的识别将为 开发用于预防和治疗AD的新型治疗策略。