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了解很粗略，主要集中在特征上 少数病理性蛋白沉积。在大脑倡议的催化下，新一代分子工具 为了描述复杂脑组织中单个细胞的转录组、表观基因组和空间组织 使我们对细胞类型的多样性及其选择性遗传图谱的理解迅速发生革命性变化。这些 工具适用于死后的人脑组织，并有望扩大我们对核心的理解 阿尔茨海默病的细胞和分子相关因素和机制。建议的目标是 该中心将阿尔茨海默病研究专家和大规模分子/解剖学大脑聚集在一起 绘制阿尔茨海默病组织库方法现代化图，并将传统和定量相结合 神经病理学与新出现的单核转录组、单核表观基因组学和空间 转录组技术。应用于不同严重程度的临床典型阿尔茨海默氏症病例 适应性设计，这些技术有望识别相关的日益精细的分子通路 具有特定的神经元和非神经元细胞类型，并对细胞类型选择性易损性提供有价值的见解 或对病理学的抵抗。这提高了AD病理在细胞类型和分子方面的分辨率 途径应该提供关于疾病发生和发展的机械性见解和假说，我们 旨在通过创建一个开放获取的数据资源链接来催化AD研究社区 与其他大规模的脑成像工作一起进行。此中心框架设计为可扩展到其他 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.