TY - JOUR
T1 - Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer’s disease
AU - Serrano-Pozo, Alberto
AU - Li, Zhaozhi
AU - Noori, Ayush
AU - Nguyen, Huong N.
AU - Mezlini, Aziz
AU - Li, Liang
AU - Hudry, Eloise
AU - Jackson, Rosemary J.
AU - Hyman, Bradley T.
AU - Das, Sudeshna
N1 - Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/10/11
Y1 - 2021/10/11
N2 - The roles of APOEε4 and APOEε2—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 APOEε4 and downregulated in APOEε2 carriers relative to APOEε3 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 APOEε4 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.
AB - The roles of APOEε4 and APOEε2—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 APOEε4 and downregulated in APOEε2 carriers relative to APOEε3 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 APOEε4 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.
KW - Ageing
KW - Computational biology and bioinformatics
KW - Glial biology
UR - http://www.scopus.com/inward/record.url?scp=85128087438&partnerID=8YFLogxK
U2 - 10.1038/s43587-021-00123-6
DO - 10.1038/s43587-021-00123-6
M3 - Article
AN - SCOPUS:85128087438
VL - 1
SP - 919
EP - 931
JO - Nature Aging
JF - Nature Aging
IS - 10
ER -