TRANSCRIPTOMIC PROFILING OF MICROGLIA FROM AN ALZHEIMER'S DISEASE MOUSE MODEL AND FROM HUMAN INDUCED PLURIPOTENT STEM CELLS REVEALS EFFECTS OF THE APOE4 GENOTYPE

Abstract

A number of risk factors for sporadic Alzheimer's disease (AD) have been identified, with the strongest genetic factor being the E4 allele of apolipoprotein E (APOE4). There are a several pathways through which APOE4 can act to increase AD risk, including via its actions on neuroinflammation and glial function. Microglia, one of the major immune cell types of the brain, are known to have a role in AD pathology and have previously been shown to have altered phenotypes in the context of APOE4. Several recent reports have demonstrated that microglia display unique transcriptional profiles in the context of AD and other neurodegenerative conditions. However, whether and how APOE4 may alter microglial transcriptomic signatures has thus far not been examined. We assessed the effects of APOE4 on microglial transcription profiles using both mouse models of AD and human induced pluripotent stem cells (iPSCs). CD11b+ microglia were isolated from EFAD mice, which carry either human APOE3 or APOE4 and the 5xFAD transgenes, and were analyzed by RNAseq. Additionally, iPSCs from APOE3 and APOE4 carriers were differentiated into microglia and their transcriptional profiles were assessed by RNAseq, both at baseline and after inflammatory insults. APOE4 is associated with transcriptional changes in a number of microglial genes, including an up-regulation of a number of inflammatory pathways and altered macrophage-associated networks. Determining how APOE4 affects microglial transcription will be critical in understanding how this AD risk factor alters the function of microglia and contributes to disease. We have identified microglial networks that are altered in the context of APOE4, enabling us to examine how these pathways may be impacting AD risk and progression.