(W1127) Deciphering cellular metabolisms of glia in APOE4 carriers of Alzheimer's disease brain using hiPSCs to identify small molecule targets for therapeutics
Assistant Professor/Director Boston University Chobanian and Avedisian school of medicine Boston, Massachusetts, United States
Abstract: The ɛ4 allele of the APOE gene (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). We previously investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice (TCW et al. Cell, 2022). Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. Thus, we further focused on investigating the downstream mechanisms by which APOE4 leads to dysfunction in human astrocytes to identify druggable targets. We found downregulation of lysosomal gene expression as a major transcriptomic deficit of APOE4 astrocytes derived from AD patient tissue and isogenic human iPSCs. This transcriptomic profile is associated with major shifts in the synthesis and catabolism of lipids and proteins in astrocytes. Homozygous APOE4 (APOE 44) astrocytes display reduced lysosomal proteolysis, lipid catabolism, macroautophagy, and endosomal microautophagy. We demonstrated that APOE 44 astrocytes exhibit mTORC1 dysfunctions that lead to increase of lipid synthesis via enhancing SREBP2 signaling. Finally, mTORC1 inhibition rescued lysosome, lipid, and inflammatory phenotypes in APOE 44 astrocytes, suggesting mTORC1 signaling and autophagy-lysosome pathways may be promising therapeutic targets for APOE4 carriers.
