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

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.

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Fig. 1: Workflow of integrative analyses of APOE associations with microglia and astrocyte transcriptomic phenotypes.
Fig. 2: Identification of a microglial gene signature associated with APOE genotype in normal aging.
Fig. 3: The microglia-APOE signature is independent of known APOE effects on AD neuropathological changes.
Fig. 4: Astrocyte transcriptomic changes associated with APOE genotype in normal aging.
Fig. 5: Cross-validation of microglia-APOE cluster in APOE knock-in mice.

Data availability

ROSMAP and MSBB RNA-seq data are available from the AMP-AD Knowledge Portal (https://doi.org/10.7303/syn3388564 and https://doi.org/10.7303/syn3157743, respectively). Mouse RNA-seq data from Zhao et. al. are available at the AMP-AD Knowledge Portal (https://doi.org/10.7303/syn20808171), and those from Nuriel et al. at Gene Expression Omnibus (no. GSE102334). The data from our APOE knock-in mice are available in Supplementary Table 4.

Code availability

Code for all data analyses is available on GitHub at https://mindds.github.io/apoe-glia.

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Acknowledgements

The results published here are in whole or in part based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.org). ROSMAP data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA. Data collection was supported through funding by NIA grant nos. P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNA-seq), R01AG17917 (MAP), R01AG30146, R01AG36042 (5hC methylation, ATAC–seq), RC2AG036547 (H3K9Ac), R01AG36836 (RNA-seq), R01AG48015 (monocyte RNA-seq), RF1AG57473 (single-nucleus RNA-seq), U01AG32984 (genomic and whole-exome sequencing), U01AG46152 (ROSMAP AMP-AD, targeted proteomics), U01AG46161(TMT proteomics), U01AG61356 (whole-genome sequencing, targeted proteomics, ROSMAP AMP-AD), the Illinois Department of Public Health (ROSMAP) and the Translational Genomics Research Institute (genomic). Additional phenotypic data can be requested at www.radc.rush.edu. MSBB data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by E. Schadt from Mount Sinai School of Medicine. This work was supported by the National Institute on Aging (nos. K08AG064039 to A.S.-P., T32AG000222-27 to R.J.J. and P30AG062421 to S.D. and B.T.H.), the Alzheimer’s Association (nos. AACF-17-524184 and AACF-17-524184-RAPID to A.S.-P.), the JPB Foundation (to B.T.H.) and the Jack Satter Foundation (to A.S.-P. and S.D.).

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A.S.-P. conducted conceptualization, supervision, writing of the original draft, writing, review and editing and funding acquisition. Z.L. was responsible for formal analysis, software, visualization, data curation, writing, review and editing. A.N. undertook formal analysis, software, visualization, data curation, writing, review and editing. H.N.N., A.M. and L.L. conducted investigations. E.H. contributed to conceptualization. R.J.J. undertook formal analysis, supervision, writing, review and editing. B.T.H. contributed to conceptualization, resources, writing, review, editing and funding acquisition. S.D. was involved in conceptualization, methodology, supervision, resources, project administration, writing of the original draft, writing, review, editing and funding acquisition.

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Correspondence to Sudeshna Das.

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Serrano-Pozo, A., Li, Z., Noori, A. et al. Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer’s disease. Nat Aging 1, 919–931 (2021). https://doi.org/10.1038/s43587-021-00123-6

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