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

绝经后DNA损伤和表观遗传异常在阿尔茨海默病中的作用 项目总结 阿尔茨海默病(AD)是全世界最常见的痴呆症，每3名患者中就有2名是女性。 这种高患病率的一个主要原因被认为是女性性激素的波动。 在绝经后雌激素和黄体酮耗尽之前横穿绝经期。更年期 已被报道引起表观遗传修饰的变化，包括我们和 其他因素对防止AD模型中的记忆力下降也很重要。我们还观察到了特定的性别 老年3xTg-AD小鼠脑内AD相关基因的差异。令人惊讶的是，人们对这种影响知之甚少 更年期转变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)修复酶是失调的 随着年龄的增长。我们假设，除了对女性生殖阶段的影响外，更年期过渡 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AD患者的心身状况。研究更年期使用的现有AD模型 卵巢切除的小鼠，导致循环中的雌激素突然停止。我们认为这不是 妇女绝经过渡的代表，在此期间围绝经期荷尔蒙波动可能持续 好几年了。我们已经成功地在小鼠身上实施了加速性卵巢衰竭(AOF)，以模拟人类 更年期。在这里，我们将使用3xTg-AD和5xFAD小鼠在AOF下，评估周围和 DNA SSB的绝经后阶段、表观遗传格局以及随后对 阿尔茨海默病背景下脑和血液中的转录组和代谢稳态。我们开发了一种方法来 支持高分辨率的核苷酸基因组水平MAP单链DNA断裂(SSiNGLe) 分析DNA SSB以确定个体的“突破年龄”，这是一种潜在的衰老新生物标记物。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 更年期导致的DNA修复缺陷会影响已知的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签名和/或任何可用药目标相匹配。完成 提出的这项工作将加强我们对更年期诱导的DNA损伤在 衰老和阿尔茨海默病。具体地说，我们将：(1)阐明DNA SSB、DNA 更年期期间大脑中的甲基化和神经营养基因转录，(2)定义了 绝经后记忆缺陷的关键治疗窗口的时间表 观察，以及(3)发现更年期相关DNA SSB在大脑和外周之间的联系 淋巴细胞可在未来衰老和AD研究的临床研究中用作生物标志物。

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.