Abstract
Beta-amyloid deposition is a defining feature of Alzheimer’s disease (AD). How genetic risk factors, like APOE and TREM2, intersect with cellular responses to beta-amyloid in human tissues is not fully understood. Using single-nucleus RNA sequencing of postmortem human brain with varied APOE and TREM2 genotypes and neuropathology, we identified distinct microglia subpopulations, including a subpopulation of CD163-positive amyloid-responsive microglia (ARM) that are depleted in cases with APOE and TREM2 risk variants. We validated our single-nucleus RNA sequencing findings in an expanded cohort of AD cases, demonstrating that APOE and TREM2 risk variants are associated with a significant reduction in CD163-positive amyloid-responsive microglia. Our results showcase the diverse microglial response in AD and underscore how genetic risk factors influence cellular responses to underlying pathologies.
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17 August 2023
A Correction to this paper has been published: https://doi.org/10.1007/s00401-023-02620-x
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Funding
National Institutes of Health Grants R01NS095793 (EBL), R56AG063344 (EBL), P30AG010124 (EBL), T32AG000255 (ATN), R01GM108600 (ML), R01GM125301 (ML), R37MH057881 (KR), University of Pennsylvania Institute on Aging Pilot Grant (ML).
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EBL, ATN, and ML designed and conceived of the experiments. ATN and JA performed the experiments. KW, GH, ZM, XW, DC, KR, and ML performed bioinformatics analysis. ES and VMV performed genotype analysis. ATN and EBL wrote the manuscript and all authors edited and approved of the final manuscript.
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Nguyen, A.T., Wang, K., Hu, G. et al. APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer’s disease. Acta Neuropathol 140, 477–493 (2020). https://doi.org/10.1007/s00401-020-02200-3
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DOI: https://doi.org/10.1007/s00401-020-02200-3