A platform for cell type-level transcriptomic, epigenomic and spatial interrogation of Alzheimer's disease

摘要（总体） 我们对阿尔茨海默病的神经病理学的理解是粗糙的，主要集中在特征性的 一些病理性蛋白质的沉积。在新一代分子工具BRAIN Initiative的催化下， 为了表征复杂脑组织中单个细胞的转录组、表观基因组和空间组织， 迅速地改变了我们对细胞类型多样性及其选择性遗传特征的理解。这些 这些工具适用于死后的人脑组织，并有望扩大我们对大脑核心的理解。 细胞和分子相关性和阿尔茨海默病的潜在机制。建议的目标 该中心是汇集阿尔茨海默病研究和大规模分子/解剖大脑的专家 使阿尔茨海默病组织库方法现代化，并将联合收割机传统和定量 神经病理学与新兴的单核转录组学、单核表观基因组学和空间 转录组学技术。应用于不同严重程度的临床典型阿尔茨海默氏症病例， 自适应设计，这些技术预计将确定日益完善的分子途径相关的 与特定的神经元和非神经元细胞类型，并产生有价值的见解细胞类型的选择性脆弱性 或对病理学的抵抗。这增加了AD病理学在细胞类型和分子水平方面的分辨率。 通路应该提供关于疾病发生和进展的机制性见解和假设， 旨在通过创建一个开放获取的数据资源， 与其他大规模的大脑绘图工作。此中心框架旨在可扩展到其他 数据模式和技术进步以及代表阿尔茨海默病的更广泛的队列 亚型和阿尔茨海默病相关疾病的未来。

ABSTRACT (OVERALL) Our understanding of the neuropathology in Alzheimer’s disease is crude and largely centered on characteristic deposition of a few pathological proteins. Catalyzed by the BRAIN Initiative, a new generation of molecular tools to characterize the transcriptome, epigenome and spatial organization of single cells in complex brain tissues is rapidly revolutionizing our understanding of the diversity of cell types and their selective genetic profiles. These tools are applicable to postmortem human brain tissues and promise to expand our understanding of the core cellular and molecular correlates and mechanisms underlying Alzheimer’s disease. The goal of the proposed Center is to bring together experts in Alzheimer’s disease research and large-scale molecular/anatomical brain mapping to modernize Alzheimer’s disease tissue banking methods, and to combine traditional and quantitative neuropathology with emerging single nucleus transcriptomics, single nucleus epigenomics and spatial transcriptomics technologies. Applied to clinically typical Alzheimer’s cases of varying severity in an iterative and adaptive design, these techniques are expected to identify increasingly refined molecular pathways associated with specific neuronal and non-neuronal cell types and yield valuable insights into cell-type selective vulnerability or resistance to pathology. This increased resolution of AD pathology in terms of cell types and molecular pathways should provide mechanistic insights and hypotheses on disease initiation and progression, which we aim to use to catalyze the AD research community through the creation of an open access data resource linked with other large-scale brain mapping efforts. This Center framework is designed to be extensible to additional data modalities and technological advances as well as broader cohorts representing Alzheimer’s disease subtypes and Alzheimer’s disease related disorders in the future.