Brain Single-nuclei and iPS-derived cells transcriptomic analysis to define the contribution of neuronal and glial pathw

摘要 阿尔茨海默病（AD）是一种复杂的异质性疾病，其中多个分子通路被阻断。 在不同的细胞类型中被破坏并导致疾病。遗传学发现表明淀粉样β蛋白清除 降解途径、胆固醇代谢和免疫系统与AD病因学有关。 然而，其具体机制、基因和分子网络尚未完全确定。 来自人脑的单核转录组学（snRNA-seq）数据提供了一个详细的分子图谱供研究 在AD中失调的通路。我们建议加深我们对基因、网络和 通过对大量的神经元和神经胶质细胞（大约 3.3关键基因突变和高风险变异的人脑携带者，非携带者散发性 AD病例和无神经病变对照。我们将利用一个独特的人体组织集合， 继承阿尔茨海默网络和Knight-ADRC脑库，并选择+220个大脑进行系统的细胞- 类型特异性转录组学分析。这是一项独特而创新的研究，旨在分析细胞特异性 高效应风险变异体（TREM 2和APOE）和完全外显 APP/PSEN 1/PSEN 2中的致病性突变，并将其与散发性AD病例和无神经病变的AD病例进行比较， 对照这是一种解决疾病异质性的强有力方法， 深入了解神经退行性变的生物学和病理学。这些结果的复制将在 来自诱导多能干细胞衍生的神经元、星形胶质细胞和小胶质细胞样细胞的snRNA-seq数据， 基因组编辑以添加/删除遗传变异，以及公开发布的数据集。最后， 我们将创建一个知识门户网站，在其中协调我们研究中所有经过处理的snRNA-seq数据 与其他研究小组合作，提供一个全面的分子图谱， AD的生物学和病理学研究。

Abstract Alzheimer’s disease (AD) is a complex and heterogenous condition in which multiple molecular pathways are disrupted in different cell-types and lead to disease. Genetic findings indicate that amyloid-beta protein clearance and degradation pathways, cholesterol metabolism and the immune system are associated with AD etiology. However, the specific mechanism, genes and molecular networks have not yet been completely identified. Single-nuclei transcriptomic (snRNA-seq) data from human brains provides a detailed molecular atlas to study the pathways dysregulated in AD. We propose to deepen our understanding of the genes, network and molecular pathways associated with AD by sequencing a high-number of neuronal and glial cells (approximately 3.3 million cells) from human brain carriers of key genetic mutations and high risk variants, non-carrier sporadic AD cases and neuropath-free controls. We will leverage a unique collection of human tissue from the Dominantly Inherited Alzheimer Network and Knight-ADRC brain banks, and select +220 brains to perform systematic cell- type specific transcriptomic analyses. This is a unique and innovative study designed to analyze cell-specific transcriptomic dysregulation in carriers of high effect risk variants (TREM2 and APOE) and fully penetrant pathogenic mutations in APP/PSEN1/PSEN2 and by comparing them to sporadic AD cases and neuropath-free controls. This is a powerful approach to address disease heterogeneity, and will provide highly informative insights into the biology and pathology of neurodegeneration. Replication of these findings will be performed in snRNA-seq data from induced pluripotent stem cell derived neurons, astrocytes, and microglia-like cells that will be genome edited to add/remove genetic variants, as well as datasets that are being publicly released. Finally, we will create a knowledge portal in which all of the processed snRNA-seq data from our study will be harmonized with that of other research groups to provide a comprehensive molecular atlas that will provide additional insights into the biology and pathology of AD for the entire research community.