Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer’s disease

Alberto Serrano-Pozo, Zhaozhi Li, Ayush Noori, Huong N. Nguyen, Aziz Mezlini, Liang Li, Eloise Hudry, Rosemary J. Jackson, Bradley T. Hyman, Sudeshna Das (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)919-931
Number of pages13
JournalNature Aging
Volume1
Issue number10
DOIs
Publication statusPublished - 11 Oct 2021

Keywords

  • Ageing
  • Computational biology and bioinformatics
  • Glial biology

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Ageing
  • Geriatrics and Gerontology

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