Cholesterol and Matrisome Pathways Dysregulated in Human APOE ∊4 Glia

Apolipoprotein E (APOE) e4 is the strongest genetic risk factor for Alzheimer's disease (AD). Although its association with AD is well-established, the impact of APOE e4 on human brain cell function remains unclear. Here we investigated the effects of APOE e4 on brain cell types derived from human induced pluripotent stem cells and human APOE targeted replacement mice. Global transcriptomic profiles showed that APOE e4 is associated with dysregulation of cholesterol homeostasis in human but not mouse glia. Elevated matrisome signaling in APOE e4 mixed neuron/astrocyte cultures parallels altered pathways uncovered in cell-type deconvoluted APOE e4 glia and AD post-mortem brains. In vitro study showed that isogenic APOE e4 is associated with increased lysosomal cholesterol levels and decreased cholesterol efflux, demonstrating decoupled lipid metabolism. APOE e4 glia also secrete higher levels of proinflammatory chemokines/cytokines, indicative of glial activation. Thus, APOE e4 induces human glia-specific dysregulation that may initiate AD risk.