The roles of ε4 and ε2-the strongest genetic risk and protective factors for Alzheimer's disease-in glial responses remain elusive. We tested the hypothesis that 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 ε4 and downregulated in ε2 carriers relative to ε3 homozygotes. This microglia- cluster is enriched in phagocytosis-including and -and proinflammatory genes, and is also detectable in brains with frequent neuritic plaques. Next, we tested these findings in knock-in mice exposed to acute (lipopolysaccharide challenge) and chronic (cerebral β-amyloidosis) insults and found that these mice partially recapitulate human -linked expression patterns. Thus, the ε4 allele might prime microglia towards a phagocytic and proinflammatory state through an axis in normal aging as well as in Alzheimer's disease.
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| http://dx.doi.org/10.1038/s43587-021-00123-6 | DOI Listing |
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