Cholesterol and Matrisome Pathways Dysregulated in Human APOE ∊4 Glia

Abstract

Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). Although its association with AD is well-established, the impact of APOE ε4 on human brain cell function remains unclear. Here we investigated the effects of APOE ε4 on brain cell types derived from human induced pluripotent stem cells and human APOE targeted replacement mice. Global transcriptomic profiles showed that APOE ε4 is associated with dysregulation of cholesterol homeostasis in human but not mouse glia. Elevated matrisome signaling in APOE ε4 mixed neuron/astrocyte cultures parallels altered pathways uncovered in cell-type deconvoluted APOE ε4 glia and AD post-mortem brains. In vitro study showed that isogenic APOE ε4 is associated with increased lysosomal cholesterol levels and decreased cholesterol efflux, demonstrating decoupled lipid metabolism. APOE ε4 glia also secrete higher levels of proinflammatory chemokines/cytokines, indicative of glial activation. Thus, APOE ε4 induces human glia-specific dysregulation that may initiate AD risk.

Keywords: APOE, Alzheimer's disease, astrocytes, microglia, cholesterol, matrisome, iPSC, inflammation