The Role of Menopause-Driven DNA Damage and Epigenetic Dysregulation in Alzheimer s Disease

更年期驱动的 DNA 损伤和表观遗传失调在阿尔茨海默病中的作用

• 批准号: 10531959
• 负责人: Claude-Henry Volmar
• 金额: $ 48.69万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10531959
• 关键词: 3xTg-AD mouse; 4-vinylcyclohexene diepoxide; AD transgenic mice; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Astrocytes; Behavioral; Biological; Biological Markers; Blood; Brain; Brain region; Chromatin; Clinical Research; Coupled; DNA Damage; DNA Methylation; DNA Repair; DNA Single Strand Break; DNA analysis; Data; Data Analyses; Defect; Dementia; Detection; Disease; Energy Metabolism; Epigenetic Process; Estrogens; Exhibits; Female; Florida; Functional disorder; Future; Gene Expression; Genes; Genetic Transcription; Genome; Gonadal Steroid Hormones; High Prevalence; Histone Acetylation; Homeostasis; Hormonal; Human; Impaired cognition; Individual; Inflammation; Inflammatory Response; Injections; Insulin Resistance; Lead; Learning; Link; London; Lymphocyte; Maps; Mediating; Memory; Memory Loss; Memory impairment; Menopause; Metabolic; Metabolism; Methods; Microglia; Mind; Modeling; Modification; Molecular; Mus; Mutation; Nerve Degeneration; Neurons; Nucleotides; Pathologic; Pathway Analysis; Pathway interactions; Patients; Perimenopause; Peripheral; Pharmaceutical Preparations; Play; Postmenopause; Process; Progesterone; Proteins; Public Domains; Quantitative Reverse Transcriptase PCR; Reporting; Research; Resolution; Role; Sex Differences; Single Strand Break Repair; Study models; Testing; Therapeutic; TimeLine; Tissues; Wild Type Mouse; Woman; Work; aged; base; behavior test; biobank; brain cell; case control; chromatin remodeling; cognitive control; cohort; design; digital; druggable target; epigenetic drug; glucose metabolism; glucose tolerance; health inequalities; histone modification; insulin tolerance; male; men; mild cognitive impairment; mouse model; nano-string; network models; neuropathology; novel; novel marker; ovarian failure; potential biomarker; presenilin-1; prevent; repair enzyme; reproductive; response; sex; sexual dimorphism; spatiotemporal; transcriptome; transcriptomics

The Role of Menopause-Driven DNA Damage and Epigenetic Dysregulation in Alzheimer's Disease PROJECT SUMMARY Alzheimer's disease (AD) is the most common form of dementia worldwide, and 2 out of 3 patients are women. A central explanation for this higher prevalence is thought to be the fluctuations in sex hormones as women traverse menopause, prior to depletion of estrogen and progesterone in the post-menopause period. Menopause has been reported to cause changes in epigenetic modifications, including histone acetylation which we and others have shown to be important to prevent memory decline in AD models. We have also observed sex-specific differences in AD-related genes in the brain of aged 3xTg-AD mice. Surprisingly little is known about the effects of the menopausal transition on epigenetic mechanisms in the brain. Important, aging is strongly associated with dysregulation of DNA damage repair, a process that has also been linked to menopause. Our preliminary data analyzing some 300 human brains show that DNA Single Strand Break (SSB) repair enzymes are dysregulated with age. We hypothesize that beyond its effects on reproductive stages in females, the menopause transition modulates DNA damage response (DDR) and epigenetic mechanisms. This results in the biological differences observed between female and male AD patients' mind and body. Existing AD models studying menopause use ovariectomized mice, resulting in an abrupt termination of circulating estrogen. We believe this is not representative of the menopause transition in women, in which peri-menopausal hormonal fluctuations can last years. We have successfully implemented accelerated ovarian failure (AOF) in mice to mimic human menopause. Here, using both the 3xTg-AD and 5xFAD mice under AOF, we will assess the effects of peri- and post-menopause-like stages on DNA SSB, the epigenetic landscape and the subsequent impact on the transcriptome and metabolic homeostasis in brain and blood in the context of AD. We developed a method to map Single-Strand DNA breaks at Nucleotide Genome Level resolution (SSiNGLe) that allows high-resolution analysis of DNA SSBs to determine the “Breakome age” of individuals, a potential novel biomarker of aging. We will build network models (associating SSBs with transcriptome alterations) to better understand how menopause-driven defects in DNA repair impact on known AD and Aging pathways. We will verify pathway observations using our human brain and AD case-control blood transcriptomics data (and public domain data) and identify which significant networks match to drug-signatures and/or any druggable targets. Completion of the work proposed will enhance our understanding of the role that menopause-induced DNA damage plays in both aging and AD. Specifically, we will: (1) elucidate the spatiotemporal relationship between DNA SSBs, DNA methylation, and neurotrophic gene transcription in the brain during the menopause transition, (2) define a timeline for the critical therapeutic window prior to the post-menopause stage where memory deficits are observed, and (3) discover connections between menopause-associated DNA SSB in the brain and in peripheral lymphocytes that can be used as biomarkers in future clinical studies for aging and AD research.

更年期驱动的DNA损伤和表观遗传失调在阿尔茨海默氏病中的作用 项目摘要 阿尔茨海默氏病（AD）是全球痴呆症最常见的形式，女性中有2例是女性。 对这种较高流行率的中心解释被认为是性激素的波动 遍历更年期，在雌激素和孕酮耗尽之前。绝经 据报道会导致表观遗传修饰的变化，包括我们和我们和 其他人则证明对于防止AD模型的记忆力下降很重要。我们还观察到了特定的性别 年龄3xTG-AD小鼠大脑中与AD相关基因的差异。令人惊讶的是对效果知之甚少 大脑表观遗传机制的更年期过渡。重要的是，衰老与 DNA损伤修复的失调，这一过程也与更年期有关。我们的初步数据 分析约300个人的大脑表明DNA单链断裂（SSB）修复酶失调 随着年龄的增长。我们假设它超出了其对女性生殖阶段的影响，更年期过渡 调节DNA损伤反应（DDR）和表观遗传机制。这导致生物学差异 在男性和男性广告患者的身心之间观察到。现有研究更年期使用的广告模型 卵巢切除小鼠，导致循环雌激素的突然终止。我们相信这不是 代表女性的更年期过渡，在这种情况下，在这种情况下，在这种情况下可以持续下去 年。我们已经成功实施了小鼠的加速卵巢衰竭（AOF）以模仿人类 绝经。在这里，在AOF下使用3XTG-AD和5XFAD小鼠，我们将评估周期和周期的影响 DNA SSB，表观遗传景观以及随后对的影响的年份后阶段 在AD的背景下，大脑和血液中的转录组和代谢稳态。我们开发了一种方法 MAP单链DNA在核苷酸基因组水平分辨率（SSingle）上断裂，该分辨率允许高分辨率 DNA SSB的分析以确定个体的“突发年龄”，这是一种潜在的新型衰老生物标志物。我们 将构建网络模型（将SSB与转录组更改相关联），以更好地了解 DNA修复对已知的AD和衰老途径的更年期驱动的缺陷。我们将验证途径 使用人类大脑和AD病例对照血液转录组学数据（以及公共领域数据）进行观察 并确定哪些重要网络与药物签名和/或任何可药物靶标相匹配。完成 提出的工作将增强我们对更年期诱导的DNA损伤在中的作用的理解 衰老和广告。具体而言，我们将：（1）阐明DNA SSB，DNA之间的时空关系 更年期过渡期间大脑中甲基化和神经营养基因转录，（2）定义A 在登机后阶段的记忆定义为之前的关键理论窗口的时间表 观察到的，（3）发现大脑中与更年期相关的DNA SSB和外围的连接 在衰老和AD研究的未来临床研究中，可以用作生物标志物的淋巴细胞。