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 在不同的细胞类型中被破坏并导致疾病。遗传研究结果表明，淀粉样β蛋白清除 而降解途径、胆固醇代谢和免疫系统与AD的病因有关。 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(snrna-seq)数据为研究提供了详细的分子图谱。 阿尔茨海默病的信号转导通路异常。我们建议加深对基因、网络和 通过对大量神经元和神经胶质细胞进行测序(约为 330万个细胞)来自关键基因突变和高风险变异的人脑携带者，非携带者零星 AD病例和无神经路径对照。我们将利用来自多米尼利的独特的人体组织收集 遗传性阿尔茨海默病网络和骑士-ADRC脑库，并选择220个大脑进行系统细胞- 特定类型转录本分析。这是一项独特而创新的研究，旨在分析特定细胞 高效风险变异体(TREM2和APOE)携带者和完全穿透性变异体携带者的转录转录失调 APP/PSEN1/PSEN2致病基因突变及其与散发性AD和非神经路AD的比较 控制。这是一种解决疾病异质性的有效方法，并将提供非常丰富的信息 对神经退行性变的生物学和病理学的见解。重复这些调查结果将在#年进行 来自诱导多能干细胞来源的神经元、星形胶质细胞和小胶质细胞的SnRNA-seq数据将 对基因组进行编辑，以添加/删除遗传变异，以及正在公开发布的数据集。最后， 我们将创建一个知识门户，在其中统一我们研究中所有经过处理的SnRNA-seq数据 与其他研究小组一起提供了一份全面的分子图谱，这将提供更多的见解 为整个研究界研究阿尔茨海默病的生物学和病理学。

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.