The impact of Alzheimer's disease susceptibility alleles on microglia transcriptome

项目总结 阿尔茨海默病(AD)是一种以进行性认知为特征的与年龄相关的神经退行性疾病 衰老和痴呆症。尽管阿尔茨海默病的机制在很大程度上仍不清楚，但很明显，衰老 脑部疾病是这种疾病的一个关键风险因素。多条证据表明，小胶质细胞，即髓系细胞 大脑的免疫细胞在中枢神经正常老化的过程中起着至关重要的作用。 系统和AD的发展。最近的遗传学研究已经确定了20多个新的AD风险基因座，以及 网络分析表明，这些基因座的主要部分在髓系免疫系统中发挥作用。在……里面 此外，在老年组、阿尔茨海默病组和阿尔茨海默病组的小胶质细胞中发现了基因表达的变化。 阿尔茨海默病模型小鼠的小胶质细胞。这些小胶质细胞的变化如何导致AD尚不清楚。回答这个问题 这个问题是了解AD相关机制的重要一步。此外，这可能会 导致揭开治疗阿尔茨海默病和相关神经退行性疾病的新靶点。长期的 这个项目的目标是加深我们对小胶质细胞在AD中的作用的了解，并识别与小胶质细胞相关的 治疗与年龄相关的中枢神经系统疾病的目标。迈出重要的第一步 达到这一目标是为了了解在AD中发现的小胶质细胞的变化在以下方面告诉我们 基因和蛋白质表达和功能的变化。因此，这项研究的总体目标是 确定与AD相关的常见遗传变异，这些变异在基线和 对炎性刺激的反应。通过将两个PI在隔离和文化方面的独特专业知识结合起来 人类小胶质细胞，以及人类髓系免疫细胞的高级计算基因组学分析。在……里面 目标1，我们将使用264个现有的小胶质细胞样本，这些样本是我们之前从103个不同区域分离出来的 脑捐赠者生成基因和转录组图谱。通过将这些数据与现有的小胶质细胞相结合 转录数据集，我们将能够生成AD相关遗传基因座如何影响基因的地图 表达(或表达数量性状基因座，eQTL)和剪接(SQTL)。在目标2中，我们将使用干扰素 (干扰素)刺激的小胶质细胞样本，我们以前收集了这些样本来表征AD相关风险 变异体改变干扰素刺激的转录组变化。这些图谱将在新的小胶质细胞中得到验证 来自15名捐赠者的独立队列的转录本，以确定这些样本对 干扰素和Aβ，并对不同吞噬能力的亚群进行分类。转录组配置文件和 将在这两个目标中产生的表达和剪接QTL将公开可用，我们 我将把这些图谱应用于老龄和阿尔茨海默病脑组织和外周的非常大的可用基因数据集 单核细胞研究基因表达变化与小胶质细胞功能变化的关系。在一起，我们 预计这项研究将为AD遗传学与小胶质细胞分子机制之间的联系提供关键信息。 为未来在模型系统中进行力学研究奠定了基础。

PROJECT SUMMARY Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive decline and dementia. Although the mechanisms underlying AD are still largely unknown, it is clear that aging of the brain is a key risk factor for this disease. Several lines of evidence indicate that microglia, the myeloid immune cells of the brain, play a crucial role in the processes involved in normal aging of the central nervous system and development of AD. Recent genetic studies have identified over twenty novel AD risk loci, and network analysis have shown that a major part of these loci play a role in the myeloid immune system. In addition, gene expression changes have been found in microglia of aged individuals, subjects with AD and in microglia in mice models for AD. How these microglia changes contribute to AD is not yet clear. Answering this question is an important step towards understanding the mechanisms involved in AD. In addition, this could lead to unravelling novel targets for treatment of AD and related neurodegenerative disorders. The long-term goal of this project is to deepen our insight into the role of microglia cells in AD and to identify microglia-related targets for treatment of age-related disorders of the central nervous system. An important first step towards reaching this goal is to understand what the changes that have been found microglia in AD tell us in terms of changes in gene and protein expression and functions. The overall objective of this study is therefore to identify the AD-associated common genetic variants that alters microglia gene expression at baseline and in response to inflammatory stimuli. By combining the unique expertise of the two PIs in the isolation and culture of human microglia, as well as advanced computational genomics analysis of human myeloid immune cells. In Aim 1, we will use 264 existing microglia samples that we have previously isolated of different regions of 103 brain donors to generate genotype and transcriptome profiles. By combining these data with existing microglia transcriptomic datasets, we will be able to generate a map of how AD-associated genetic loci influence gene expression (or expression quantitative trait loci, eQTL) and splicing (sQTL). In aim 2, we will use interferon (IFN) stimulated microglial samples that we have previously collected to characterize how AD-associated risk variants alter IFN-stimulated transcriptome changes. These profiles will be validated in new microglia transcriptomes from an independent cohort of 15 donors to determine the response of these samples to interferon and Aβ and sort subsets with different phagocytic capacity. The transcriptome profiles and expression and splicing QTL that will be generated in these two aims will be made publically available and we will apply these profiles to very large available gene datasets on aged and AD brain tissue and peripheral monocytes to investigate how gene expression changes relate to changes in microglia function. Together, we expect that this study will provide key information bridging AD genetics to molecular mechanisms in microglia, setting the stage for future mechanistic studies in model systems.