Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer's disease.
Alberto Serrano-PozoZhaozhi LiAyush NooriHuong N NguyenAziz MezliniLiang LiEloise HudryRosemary J JacksonBradley T HymanSudeshna DasPublished in: Nature aging (2021)
The roles of APOE ε4 and APOE ε2-the strongest genetic risk and protective factors for Alzheimer's disease-in glial responses remain elusive. We tested the hypothesis that APOE 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 APOE ε4 and downregulated in APOE ε2 carriers relative to APOE ε3 homozygotes. This microglia- APOE cluster is enriched in phagocytosis-including TREM2 and TYROBP -and proinflammatory genes, and is also detectable in brains with frequent neuritic plaques. Next, we tested these findings in APOE knock-in mice exposed to acute (lipopolysaccharide challenge) and chronic (cerebral β-amyloidosis) insults and found that these mice partially recapitulate human APOE -linked expression patterns. Thus, the APOE ε4 allele might prime microglia towards a phagocytic and proinflammatory state through an APOE-TREM2-TYROBP axis in normal aging as well as in Alzheimer's disease.
Keyphrases
- cognitive decline
- high fat diet
- mild cognitive impairment
- neuropathic pain
- genome wide
- inflammatory response
- gene expression
- adipose tissue
- poor prognosis
- endothelial cells
- immune response
- intensive care unit
- lipopolysaccharide induced
- blood brain barrier
- hepatitis b virus
- dna methylation
- liver failure
- respiratory failure
- subarachnoid hemorrhage
- multiple myeloma
- cerebral blood flow