Cell autonomous effects of APOE ε4/ε4 on human iPSC-derived astrocytes and microglia
Julia TCW1*, Sarah E. Bertelsen1, Lu Qian1, Shuang A. Liang2, Cristhian Fimbres2, Raja Jain2, Elizabeth J. Sikora1, Wayne W. Poon2, Alison M. Goate1* 1Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA *Corresponding Author Apolipoprotein E (APOE) is the most significant risk gene for late-onset Alzheimer's disease (AD). APOE ɛ4/ɛ4 homozygosity increases AD risk by >14-fold. Although an association between the APOE ε4 allele and increased AD risk is well-established, the mechanisms underlying this genetic risk on particular brain cell types is elusive. We hypothesized that the APOE ε4/ε4 genotype contributes to disease risk through cell autonomous mechanisms. We differentiated astrocytes, microglia, cortical neurons and brain microvascular endothelial cells from human induced pluripotent stem cells (iPSC) derived from non-isogenic and isogenic of cells selected based on APOE genotype and performed RNAseq. When APOE ε4/ε4 transcriptomes were compared with ε3/ε3 by Gene Set Enrichment Analysis (GSEA) the most significantly enriched pathway is cholesterol biosynthesis (positive enrichment) in astrocytes and lysosome pathway (negative enrichment) in microglia. Overlapping pathway analysis (FDR<0.05) of both cell types showed the same positive enrichment of cholesterol biosynthesis. Functional network analysis by Ingenuity Pathway Analysis (IPA) incorporated with GSEA also showed that APOE ε4/ε4 glia significantly upregulates cholesterol biosynthesis. The lysosome pathway of microglia is associated with phagosome maturation and autophagic function, defects of which lead to increased lipid accumulation and decreased lipid catabolism. Our data suggest a decoupling of cholesterol synthesis and degradation in APOE ε4/ε4 compared to ε3/ε3 glia. Together, human CNS cell type based iPSC models allowed us to elucidate APOE ε4/ε4 cell autonomous effects. Specifically in APOE ε4/ε4 compared to ε3/ε3 astrocytes and microglia we observed deficits in lipid metabolism, leading to increased cholesterol biosynthesis, even in the face of decreased cholesterol efflux.
Funding New York Stem Cell Foundation, The JPB Foundation
Credits: None available.
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