期刊
ACTA NEUROPATHOLOGICA
卷 140, 期 4, 页码 477-493出版社
SPRINGER
DOI: 10.1007/s00401-020-02200-3
关键词
APOE; TREM2; Microglia; Alzheimer's disease; Transcriptomics; snRNA-seq
资金
- National Institutes of Health [R01NS095793, R56AG063344, P30AG010124, T32AG000255, R01GM108600, R01GM125301, R37MH057881]
- University of Pennsylvania Institute on Aging Pilot Grant
Beta-amyloid deposition is a defining feature of Alzheimer's disease (AD). How genetic risk factors, likeAPOEandTREM2, intersect with cellular responses to beta-amyloid in human tissues is not fully understood. Using single-nucleus RNA sequencing of postmortem human brain with variedAPOEandTREM2genotypes and neuropathology, we identified distinct microglia subpopulations, including a subpopulation of CD163-positive amyloid-responsive microglia (ARM) that are depleted in cases withAPOEandTREM2risk variants. We validated our single-nucleus RNA sequencing findings in an expanded cohort of AD cases, demonstrating thatAPOEandTREM2risk variants are associated with a significant reduction in CD163-positive amyloid-responsive microglia. Our results showcase the diverse microglial response in AD and underscore how genetic risk factors influence cellular responses to underlying pathologies.
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