Effect of <i>APOE</i> alleles on the glial transcriptome in normal aging and Alzheimer's disease.

Abstract

The roles of <i>APOE</i>ε4 and <i>APOE</i>ε2-the strongest genetic risk and protective factors for Alzheimer's disease-in glial responses remain elusive. We tested the hypothesis that <i>APOE</i> alleles differentially impact glial responses by investigating their effects on the glial transcriptome from elderly control brains with no neuritic amyloid plaques. We identified a cluster of microglial genes that are upregulated in <i>APOE</i>ε4 and downregulated in <i>APOE</i>ε2 carriers relative to <i>APOE</i>ε3 homozygotes. This microglia-<i>APOE</i> cluster is enriched in phagocytosis-including <i>TREM2</i> and <i>TYROBP</i>-and proinflammatory genes, and is also detectable in brains with frequent neuritic plaques. Next, we tested these findings in <i>APOE</i> knock-in mice exposed to acute (lipopolysaccharide challenge) and chronic (cerebral β-amyloidosis) insults and found that these mice partially recapitulate human <i>APOE</i>-linked expression patterns. Thus, the <i>APOE</i>ε4 allele might prime microglia towards a phagocytic and proinflammatory state through an <i>APOE-TREM2-TYROBP</i> axis in normal aging as well as in Alzheimer's disease.