The APOE isoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia in a xenotransplantation model of Alzheimer's disease [ATAC-seq]

Microglia play a key role in the response to amyloid beta in Alzheimer's disease (AD). In this context, the major transcriptional response of microglia is the upregulation of APOE, the strongest late-onset AD risk gene. Of its three isoforms, APOE2 is thought to be protective, while APOE4 increases AD risk. We hypothesised that the isoforms functionally alter microglia by shaping their transcriptomic and chromatin landscapes. We used ATAC- 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 on APOE genotype, and are corroborated across the profiling assays. Overall design: To investigate the effects of the human APOE isoforms (APOE2, APOE3, APOE4) and the APOE-KO on the microglial response to amyloid beta pathology, we performed RNA-seq and ATAC-seq to profile the transcriptomic and epigenomic landscapes of human microglia xenotransplanted into the brains of the AppNL-G-F mouse model of Alzheimer's disease.