Epigenetic changes in synaptic and inflammatory genes involved in the age-dependent development of Alzheimer's disease pathologies andcognitive decline

摘要 年龄是阿尔茨海默病（AD）发展的最大风险因素。因此，了解基因 以及AD神经病理学改变年龄依赖性发展的病理机制 对我们监控和定位这些通路至关重要。组蛋白修饰和DNA甲基化 被认为是介导环境因素对AD相关基因影响的表观遗传因素 表情三甲基化组蛋白H3 K9（H3 K9 me 3）是与细胞凋亡相关的关键组蛋白修饰之一。 降低转录活性和异染色质凝聚。我们发现H3 K9 Me 3水平是 在神经退行性疾病中有显著改变。在这里，我们提出了H3 K9 me 3的综合分析- 染色质免疫沉淀（ChIP）测序（ChIP-seq）、DNA甲基化和mRNA定量， 脑组织，以确定H3 K9 me 3和DNA甲基化驱动的异染色质重塑如何改变 在衰老和AD中的作用，并确定与AD发病机制相关的表观基因组谱。我们的初步数据显示 在AD中，两个主要的通路在遗传上是沉默的，包括突触功能中的一个（例如，脑源性的 神经营养因子（BDNF）和突触结合蛋白XII（SYT 12））和参与神经炎症的一种（例如， 白细胞介素1（IL 1）、磷脂酶A2受体1（PLA 2 R1）和乳胶蛋白（LXN））。我们提出了一个翻译 在最具特征的尸检队列中系统地解决AD神经变性的方法 衰老的DNA，RNA和蛋白质水平，以确定新的表观遗传风险因素的目标， 生物标志物以及可用于药物发现的机制。心脏研究（FHS） 收集了大量的临床和神经心理学数据，在整个过程中跟踪了一个以社区为基础的人群， 一生，并收集大脑死亡。神经病理学上，受试者的范围从认知正常到 AD患者的神经病理改变从病理正常到低AD再到高AD。小说， 数字化的神经心理学测试可以最早检测到认知能力下降。我们的长期目标是 揭示AD和健康老龄化发展的表观遗传和分子机制。 这项研究项目的直接目标是发现突触后神经元的表观遗传沉默的差异， 和神经炎性基因，预测AD病理和认知障碍， 生物标志物和治疗靶点。这项研究对于理解表观遗传变化是如何发生的至关重要。 与衰老和AD的发展相关，为合理的药物设计提供信息，并开发方法， 评估老年人的风险。我们的目标是将表观遗传和蛋白质变异与tau和Aβ的病理学联系起来 在具有明确病理诊断的人类受试者中以及在生命期间的神经心理学轨迹。 在这里，我们提出了一个跨学科的方法，结合专业知识和新技术的表观遗传学， 神经病理学和认知测试，以发现生物标志物开发的新致病途径， 治疗学

ABSTRACT Age is the greatest risk factor for the development of Alzheimer disease (AD). Thus, understanding the genetic and pathological mechanisms that underlie the age-dependent development of AD neuropathological change is critical to our ability to monitor and target these pathways. Histone modifications and DNA methylation have been suggested as epigenetic factors mediating the influence of environmental factors on AD-related gene expression. Trimethylated histone H3K9 (H3K9me3) is one of the key histone modifications associated with decreased transcriptional activity and heterochromatin condensation. We have found that H3K9me3 levels are significantly altered in neurodegenerative disease. Here, we propose an integrated analysis of H3K9me3- chromatin immunoprecipitation (ChIP)-sequencing (ChIP-seq), DNA methylation, and mRNA quantification on brain tissue to determine how heterochromatin remodeling driven by H3K9me3 and DNA methylation is altered in aging and AD and to define the epigenome profiles linked to AD pathogenesis. Our preliminary data shows that two major pathways are genetically silenced in AD, including one in synaptic function (e.g. brain derived neurotrophic factor (BDNF) and synaptotagmin XII (SYT12)) and one involved in neuroinflammation (e.g. interleukin 1 (IL1), phospholipase A2 receptor 1 (PLA2R1), and latexin (LXN)). We propose a translational approach to systematically address AD neurodegeneration in one of the best characterized autopsy cohorts of aging on the DNA, RNA, and protein levels, with the goal of identifying novel epigenetic risk factors, biomarkers, and mechanisms that can be targeted for drug discovery. The Framingham Heart Study (FHS) collects extensive clinical and neuropsychological data, follows a community-based population throughout their lifetime, and collects the brain at death. Neuropathologically, subjects range from cognitively normal to demented and from pathologically normal to low AD neuropathological change to high AD change. Novel, digitized neuropsychological tests allow for the earliest detection of cognitive decline. Our long-term goal is to uncover the epigenetic and molecular mechanisms underlying the development of AD and of healthy aging. The immediate goal of this research project is to discover differences in the epigenetic silencing of synaptic and neuroinflammatory genes that predict AD pathology and cognitive impairment and that may serve as biomarkers and targets for therapy. This research will be critical for understanding how epigenetic changes are associated with aging and the development of AD, informing rational drug design, and for developing ways to assess risk in aging individuals. We aim to link epigenetic and protein variation to the pathology of tau and Aβ in human subjects with a definitive pathological diagnosis and to the neuropsychological trajectory during life. Here we propose a cross-disciplinary approach that combines expertise and novel techniques in epigenetics, neuropathology, and cognitive testing to discover new pathogenic pathways for biomarker development and therapeutics.