APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer's disease.
Aivi T NguyenKui WangGang HuXuran WangZhen MiaoJoshua A AzevedoEunRan SuhVivianna M Van DeerlinDavid ChoiKathryn RoederMingyao LiEdward B LeePublished in: Acta neuropathologica (2020)
Beta-amyloid deposition is a defining feature of Alzheimer's disease (AD). How genetic risk factors, like APOE and TREM2, intersect with cellular responses to beta-amyloid in human tissues is not fully understood. Using single-nucleus RNA sequencing of postmortem human brain with varied APOE and TREM2 genotypes and neuropathology, we identified distinct microglia subpopulations, including a subpopulation of CD163-positive amyloid-responsive microglia (ARM) that are depleted in cases with APOE and TREM2 risk variants. We validated our single-nucleus RNA sequencing findings in an expanded cohort of AD cases, demonstrating that APOE and TREM2 risk 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.
Keyphrases
- cognitive decline
- risk factors
- inflammatory response
- high fat diet
- neuropathic pain
- copy number
- mild cognitive impairment
- cancer therapy
- single cell
- endothelial cells
- genome wide
- gene expression
- machine learning
- insulin resistance
- lipopolysaccharide induced
- adipose tissue
- induced pluripotent stem cells
- pluripotent stem cells