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病中的作用 项目摘要 阿尔茨海默病（AD）是世界范围内最常见的痴呆形式，并且三分之二的患者是女性。 这种高患病率的一个核心解释被认为是女性性激素的波动 在绝经后期雌激素和孕激素耗尽之前，经历绝经期。更年期 据报道，引起表观遗传修饰的变化，包括组蛋白乙酰化，我们和 其他的已经显示出对于防止AD模型中的记忆衰退是重要的。我们还观察到性别特异性 老年3xTg-AD小鼠脑中AD相关基因的差异。令人惊讶的是， 更年期对大脑表观遗传机制的影响。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 对大约300个人脑的分析表明，DNA单链断裂（SSB）修复酶失调， 随年龄我们假设，除了对女性生殖阶段的影响外， 调节DNA损伤反应（DDR）和表观遗传机制。这导致了生物学上的差异 观察男女性AD患者的身心状况。研究更年期使用的现有AD模型 卵巢切除小鼠，导致循环雌激素的突然终止。我们认为这不是 代表妇女的更年期过渡，其中围绝经期激素波动可以持续 年我们已经成功地在小鼠中实施了加速卵巢衰竭（AOF），以模拟人类 绝经在这里，使用AOF下的3xTg-AD和5xFAD小鼠，我们将评估抗AD和抗FAD的作用。 绝经后阶段的DNA SSB，表观遗传景观和随后的影响， AD背景下大脑和血液中的转录组和代谢稳态。我们发明了一种方法 以核苷酸基因组水平分辨率（SSiNGLe）绘制单链DNA断裂图谱， 分析DNA SSB以确定个体的“断裂年龄”，这是一种潜在的衰老新生物标志物。我们 将建立网络模型（将SSB与转录组改变相关联），以更好地了解 更年期驱动的DNA修复缺陷影响已知的AD和衰老途径。我们将验证路径 使用我们的人脑和AD病例对照血液转录组学数据（和公共领域数据）进行观察 并识别哪些重要网络与药物特征和/或任何可药物化的目标相匹配。完成 这项工作将增强我们对更年期诱导的DNA损伤在以下方面所起作用的理解： 老化和AD。具体而言，我们将：（1）阐明DNA SSB，DNA 甲基化，和神经营养基因转录在大脑中的更年期过渡，（2）定义一个 绝经后阶段之前的关键治疗窗口的时间轴，在绝经后阶段，记忆缺陷是 观察，（3）发现绝经相关的DNA SSB之间的联系，在大脑和外周血中， 淋巴细胞，可作为生物标志物在未来的临床研究衰老和AD的研究。