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APOE4 genotype confers transcriptomic and functional alterations to primary mouse microglia

ABSTRACT: Relative to E3 microglia, E4 microglia exhibit altered morphology, increased numbers of endosomes and lysosomes, increased cytokine/chemokine production, and increased lipid accumulation at baseline. These changes were accompanied by increased activation of kinases that mediate global repression of translation. In a subsequent phagocytosis assay, E4 microglia exhibited increased accumulation of a variety of substrates when compared to E3 microglia. While transcriptomic profiling of myelin-challenged microglia revealed a largely overlapping response profile across genotypes, differential regulation of several pathways including interferon-related signaling, translation-related processes was identified in E4 versus E3 microglia both at baseline and following myelin challenge. Here we identify and describe several important functional alterations in E4 relative to E3 microglia. Together, our results suggest E4 genotype confers elevated levels of baseline stress to microglia relative to E3 genotype, even prior to treatment with exogenous stimuli. This work provides insight into the molecular mechanisms by which E4 genotype may increase risk for AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE171280 | GEO | 2022/03/17

REPOSITORIES: GEO

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Project description:Cerebrovascular dysfunction is a hallmark feature of Alzheimer's disease (AD). One of the greatest risk factor for AD is the apolipoprotein E4 (E4) allele. APOE4 genotype has been shown to negatively impact on perivascular amyloid clearance, however, its direct influence along with the other APOE variants (APOE2 and APOE3) on the molecular integrity of the cerebrovasculature has not been largely explored. To address this, we employed a 10-plex tandem isobaric mass tag approach in combination with an ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method, to interrogate unbiased proteomic changes in cerebrovessels from AD and healthy control brains on different APOE genotype backgrounds. We first interrogated changes between healthy control homozygote E2/E2, E3/E3 and E4/E4 cases to identify underlying genotype specific effects on cerebrovessels. EIF2 signaling, regulation of eIF4 and 70S6K signaling and mTOR signaling were the top significantly altered pathways in E4/E4 compared to E3/E3 cases. EIF2, nitric oxide and sirtuin signaling pathways were the top significantly altered pathways in E4/E4 compared to E2/E2 cases. We used a Two-way ANOVA analysis to identify AD-dependent changes and their interactions with APOE genotype. The highest number of significantly regulated proteins from this interaction was observed in E3/E4 (192) and E4/E4 (189) cases. As above, EIF2, mTOR signaling and eIF4 and 70S6K signaling were the top three significantly altered pathways in E4 allele carriers (i.e. E3/E4 and E4/E4 genotypes). Of all the cerebrovascular cell specific markers identified in our proteomic analyses, endothelial cell, astrocyte, and smooth muscle cell specific protein markers were significantly altered in E4/E4 cases, while endothelial cells and astrocyte specific protein markers were altered in E3/E4 cases. These proteomic changes provide novel insights to explain the longstanding link between APOE4 and cerebrovascular dysfunction. The early and converging APOE4 dependent changes we identified could provide novel targets in the cerebrovasculature for developing disease modifying strategies to mitigate the effects of APOE4 genotype on increasing the risk for, and the path towards AD pathogenesis.

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APOE4 genotype confers transcriptomic and functional alterations to primary mouse microglia

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