Wednesday, October 30, 2019 at 12:00pm to 1:00pm
Zilkha Neurogenetic Institute (ZNI), 112
1501 San Pablo, Los Angeles, CA 90033
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. Using human induced pluripotent stem cells (hiPSCs), I have developed 2D brain cell types, 3D organoids and utilized iPSC/mouse chimeric model to investigate the effects of APOE ε4 on several brain cell types. My recent study applied global transcriptomic profiling on brain cell types derived from hiPSCs, human APOE targeted replacement mice and cell type deconvolution of AD post-mortem brain transcriptomes to identify deficits induced by APOE ε4. Gene set enrichment and pathway analyses of transcriptome profiles showed that APOE ε4 is associated with dysregulation of cholesterol homeostasis in human but not mouse astrocytes and microglia.
Elevated matrisome signaling associated with chemotaxis, glial activation and lipid biosynthesis in APOE ε4 mixed neuron/astrocyte cultures parallels altered pathways uncovered in cell-type deconvoluted transcriptomic data from APOE ε4 glia and AD post-mortem brains. Experimental validation of the transcriptomic findings showed that isogenic APOE ε4 is associated with increased lysosomal cholesterol levels and decreased cholesterol efflux, demonstrating decoupled lipid metabolism. APOE ε4 glia also secretes higher levels of proinflammatory chemokines, cytokines and growth factors, indicative of glial activation. Thus, APOE ε4 induces human glia-specific dysregulation that may initiate AD risk.