Epigenomic analysis of neural circuits in Alzheimer's disease mouse models

项目摘要/摘要 阿尔茨海默病(AD)是导致进行性痴呆(记忆和认知)的最常见原因 在老年人中)。目前，超过550万美国人可能患有AD引起的痴呆症。的确有 这种令人衰弱的疾病无法治愈。我们开发更好的早期诊断工具和 这种神经退行性疾病的新治疗策略。先前利用大脑进行的基因表达研究 组织和横断面设计确定其表达与AD进展相关的基因。基因 表达受细胞表观基因组的调控，包括DNA甲基化、组蛋白修饰和非 编码RNA。我们建议刻画负责神经回路的关键细胞类型的表观基因组 学习和记忆。我们的目标是确定表观基因组如何塑造海马区的电路活动和 使用最新的单细胞基因组技术结合功能电路，研究AD进展过程中的行为 测绘和行为分析。我们将使用两个AD小鼠模型来概括神经病理学 在人类阿尔茨海默病中观察到的特征和功能缺陷。我们的指导性假设是AD 神经退行性变导致细胞表观基因组的显著变化，包括 可访问的染色质景观和疾病相关细胞类型的基因表达程序。这又反过来 导致阿尔茨海默病发病过程中特定神经回路功能的缺陷。在目标1中，我们将生成一个 全面的基于表观基因组和转录的海马CA1区和下丘脑的细胞图谱，并鉴定 AD模型小鼠和年龄匹配小鼠每种细胞类型中伴随AD进展的表观基因组学变化 控制小鼠。单核ATAC-SEQ(SnATAC-SEQ)、单核RNA-SEQ(SnRNA-SEQ)和新的 在单细胞中开发用于DNA甲基化和染色质接触联合定位的甲基-HI将是关键 接近了。拟议的工作将允许创建第一个单细胞多组学图谱的海马区 电路，并将使我们能够跟踪多个特定细胞群体在 不同的AD样神经退行性变阶段。在目标2和目标3中，我们将研究特定的细胞亚型 阿尔茨海默病模型神经回路活动及相关记忆行为的表观基因组和基因表达基础 中年老鼠。我们将测量表观基因组和行为变化，以响应基因靶向 个体发育海马区环路操作与组蛋白脱乙酰酶抑制。此外，我们将确定 通过体育锻炼进行简单行为干预对AD相关表观基因组特征的有益影响 目标3.我们提议的研究将为研究分子基础提供一个新的框架 阿尔茨海默病发病过程中神经回路活动的影响。它还将导致识别 新的治疗靶点和分子生物标记物，用于AD的早期发现和更好的治疗。

Project Summary / Abstract Alzheimer’s disease (AD) is the most common cause of progressive dementia (memory and cognitive loss) in older adults. Presently, more than 5.5 million Americans may have dementia caused by AD. There is no cure for this debilitating condition. It is increasingly critical that we develop better early diagnostic tools and new treatment strategies for this neurodegenerative disease. Previous gene expression studies using brain tissue and cross-sectional design identify genes whose expression correlates with AD progression. Gene expression is regulated by the cell’s epigenome comprising of DNA methylation, histone modification and non- coding RNAs. We propose to characterize the epigenome of key cell types in neural circuits responsible for learning and memory. Our goal is to determine how the epigenome shapes hippocampal circuit activity and behaviors during AD progression, using the latest single cell genomic technologies coupled with functional circuit mapping and behavioral analysis. We will use two AD mouse models that recapitulate neuropathological features and functional defects observed in human Alzheimer’s. Our guiding hypothesis is that AD neurodegeneration causes significant alterations in the epigenome of cells, including maladaptive changes in accessible chromatin landscape and gene expression programs in disease relevant cell types. This in turn causes defects in specific neural circuit functionality during AD pathogenesis. In Aim 1, we will generate a comprehensive epigenome- and transcription-based cell atlas for hippocampal CA1 and subiculum, and identify epigenomic changes that accompany AD progression in each cell type in AD model mice and age-matched control mice. Single nucleus ATAC-seq (snATAC-seq), single nucleus RNA-seq (snRNA-seq) and the newly developed Methyl-HI in single cells for joint mapping of DNA methylation and chromatin contacts will be key approaches. The proposed work will allow for creation of the first single cell multi-omics atlas of the hippocampal circuits, and will allow us to track the epigenomic changes exhibited by multiple specific cell populations at different AD-like neurodegeneration stages. In Aims 2 and 3, we will investigate the cell subtype specific epigenomic and gene expression basis of neural circuit activities and related memory behaviors in AD model mice of middle age. We will measure epigenomic and behavioral changes in response to genetically targeted ontogenetic hippocampal circuit manipulation and histone deacetylase inhibition. Further, we will determine the beneficial effects of simple behavioral interventions via physical exercise on AD-related epigenomic signatures in Aim 3. Together, our proposed research will provide a new framework to study the molecular underpinnings of neural circuit activities affected during the course of AD pathogenesis. It will also lead to the identification of new therapeutic targets and molecular biomarkers for early detection and better treatment of AD.