Single-cell multiregion dissection of Alzheimer's disease

• 成果类型: Article
• 署名作者: Mathys, Hansruedi; Boix, Carles A.; Akay, Leyla Anne; Xia, Ziting; Davila-Velderrain, Jose; Ng, Ayesha P.; Jiang, Xueqiao; Abdelhady, Ghada; Galani, Kyriaki; Mantero, Julio; Band, Neil; James, Benjamin T.; Babu, Sudhagar; Galiana-Melendez, Fabiola; Louderback, Kate; Prokopenko, Dmitry; Tanzi, Rudolph E.; Bennett, David A.; Tsai, Li-Huei; Kellis, Manolis
• 署名单位: Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Massachusetts Institute of Technology (MIT); Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Harvard University; Human Technopole; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Rush University; Stanford University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4026
• DOI: 10.1038/s41586-024-07606-7
• 发表日期: 2024-08-22
• 页码: 858-+
• 关键词: entorhinal cortex neurons; genome-wide association; nucleus rna-seq; human-brain; cognitive performance; memory; atlas; choline; architecture; individuals

摘要

Alzheimer's disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood(1-3). Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer's disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer's disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer's disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer's disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer's disease pathology.