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 项目概要 阿尔茨海默病 (AD) 是全世界最常见的痴呆症，三分之二的患者是女性。 这种较高患病率的一个核心解释被认为是女性体内性激素的波动。 在绝经后雌激素和黄体酮耗尽之前穿越更年期。 据报道，它会引起表观遗传修饰的变化，包括我们和 其他研究表明，对于预防 AD 模型中的记忆衰退很重要，我们还观察到了性别特异性。 令人惊讶的是，人们对老年 3xTg-AD 小鼠大脑中 AD 相关基因的差异知​​之甚少。 更年期过渡对大脑表观遗传机制的影响 重要的是，衰老与衰老密切相关。 DNA 损伤修复失调，这一过程也与更年期有关。 对约 300 个人类大脑的分析表明 DNA 单链断裂 (SSB) 修复酶失调 除了对女性生殖阶段的影响之外，我们还研究了更年期过渡的影响。 调节 DNA 损伤反应 (DDR) 和表观遗传机制，这导致了生物学差异。 研究更年期使用情况的现有 AD 模型在女性和男性 AD 患者之间进行观察。 卵巢切除的小鼠，导致循环雌激素突然终止，我们认为这不是。 代表女性更年期过渡，其中围绝经期荷尔蒙波动可持续 多年来，我们已经成功地在小鼠身上实施了加速卵巢衰竭（AOF）来模仿人类。 在这里，我们将使用 AOF 下的 3xTg-AD 和 5xFAD 小鼠来评估围绝经期和绝经期的影响。 DNA SSB 的绝经后样阶段、表观遗传景观以及随后对 我们开发了一种方法来研究 AD 背景下大脑和血液中的转录组和代谢稳态。 以核苷酸基因组水平分辨率 (SSiNGLe) 绘制单链 DNA 断裂图，可实现高分辨率 分析 DNA SSB 以确定个体的“断裂年龄”，这是一种潜在的新型衰老生物标志物。 将构建网络模型（将 SSB 与转录组改变相关联）以更好地了解如何 更年期驱动的 DNA 修复缺陷对已知的 AD 和衰老途径有影响。 使用我们的人脑和 AD 病例对照血液转录组数据（和公共领域数据）进行的观察 并确定哪些重要网络与药物特征和/或任何可成药的目标相匹配。 所提出的工作将增强我们对更年期引起的 DNA 损伤在 具体来说，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的甲基化和神经营养基因转录，（2）定义 记忆缺陷出现的绝经后阶段之前关键窗口治疗窗口的时间表 观察到，并且（3）发现大脑和外周中与更年期相关的 DNA SSB 之间的联系 淋巴细胞可在未来的衰老和 AD 研究临床研究中用作生物标志物。