Cholesterol and matrisome pathways dysregulated in APOE ε4 human microglia and astrocytes [populationAPOE]

The impact of Apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cell models, post-mortem brain and APOE targeted replacement mice. Population and isogenic models uncover that APOE4 local haplotype rather than a single risk allele alone contributes to the risk. Global transcriptomic analyses reveal human specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 leads to elevated de novo cholesterol synthesis despite the intracellular cholesterol accumulation due to lysosomal sequestration of cholesterol in astrocytes. Transcriptome analyses uncovered Matrisome dysregulation associated with upregulated chemotaxis, glial activation and lipid biosynthesis in astrocytes, co-cultured with neurons that recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk. We performed bulk RNA-sequencing on population iPSC-derived, CRISPR-edited isogenic iPSC-derived astrocytes, microglia, mixed cortical cultures, BMECs from APOE 33 vs APOE 44 and mouse astrocytes and microglia from APOE 33, APOE 44, Apoe WT and Apoe KO. This particular dataset is population APOE 33 and APOE 44 cell types.