APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer ’s disease

AbstractBeta-amyloid deposition is a defining feature of Alzheimer ’s disease (AD). How genetic risk factors, likeAPOE andTREM2, intersect with cellular responses to beta-amyloid in human tissues is not fully understood. Using single-nucleus RNA sequencing of postmortem human brain with variedAPOE andTREM2 genotypes and neuropathology, we identified distinct microglia subpopulations, including a subpopulation of CD163-positive amyloid-responsive microglia (ARM) that are depleted in cases withAPOE andTREM2 risk variants. We validated our single-nucleus RNA sequencing findings in an expanded cohort of AD cases, demonstrating thatAPOE andTREM2 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.
Source: Acta Neuropathologica - Category: Neurology Source Type: research