TheAPOEisoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia in a xenotransplantation model of Alzheimer’s disease

Abstract

AbstractMicroglia play a key role in the response to amyloid beta in Alzheimer’s disease (AD). In this context, a major transcriptional response of microglia is the upregulation ofAPOE, the strongest late-onset AD risk gene. Of its three isoforms,APOE2is thought to be protective, whileAPOE4increases AD risk. We hypothesised that the isoforms functionally alter microglia by shaping their transcriptomic and chromatin landscapes. We used RNA- and ATAC-sequencing to profile gene expression and chromatin accessibility of human microglia isolated from a xenotransplantation model of AD. We identified widespread transcriptomic and epigenomic differences which are dependent onAPOEgenotype, and are corroborated across the profiling assays. Our results indicate that impaired microglial proliferation, migration and immune responses may contribute to the increased risk for late-onset AD inAPOE4carriers, while increased DNA-binding of the vitamin D receptor inAPOE2microglia may contribute to the isoform’s protective role.