Microglial transcription profiles in mouse and human are driven by APOE4 and sex


Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). APOE4 is known to affect the function of microglia, but to what extent this gene drives microglial gene expression has thus far not been examined. Using a transgenic mouse model of AD that expresses human APOE, we identify a unique transcriptional profile associated with APOE4 expression. We also show a sex and APOE interaction, such that both female sex and APOE4 drive expression of this gene profile. We confirm these findings in human cells, using microglia derived from induced pluripotent stem cells (iMGL). Moreover, we find that these interactions are driven in part by genes related to metal processing, and we show that zinc treatment has APOE genotype-dependent effects on iMGL. These data identify a sex- and APOE4-associated microglial transcription profile and highlight the importance of considering interactive risk factors such as sex and environmental exposures. © 2021 The Authors.

Authors Moser VA, Workman MJ, Hurwitz SJ, Lipman RM, Pike CJ, Svendsen CN
Journal iScience
Publication Date 2021 Nov 19;24(11):103238
PubMed 34746703
PubMed Central PMC8551075
DOI 10.1016/j.isci.2021.103238

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