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APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer’s disease

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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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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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Author notes

  1. Aivi T. Nguyen, Kui Wang, and Gang Hu have contributed equally to this work.

Authors and Affiliations

  1. Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 613A Stellar Chance Laboratories, 422 Curie Blvd, Philadelphia, PA, 19104, USA

    Aivi T. Nguyen, Joshua A. Azevedo & Edward B. Lee

  2. Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, 213 Blockley Hall, 423 Guardian Drive, Philadelphia, PA, 19104, USA

    Kui Wang, Gang Hu & Mingyao Li

  3. Department of Information Theory and Data Science, School of Mathematical Sciences and LPMC, Nankai University, Tianjin, China

    Kui Wang

  4. School of Statistics and Data Science, Key Laboratory for Medical Data Analysis and Statistical Research of Tianjin, Nankai University, Tianjin, China

    Gang Hu

  5. Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA, USA

    Xuran Wang & Kathryn Roeder

  6. Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Zhen Miao

  7. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Aivi T. Nguyen, Joshua A. Azevedo, EunRan Suh, Vivianna M. Van Deerlin & Edward B. Lee

  8. Heinz College of Public Policy and Information Systems, Carnegie Mellon University, Pittsburgh, PA, USA

    David Choi

  9. Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA

    Kathryn Roeder

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  1. Aivi T. Nguyen
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Contributions

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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Correspondence to Mingyao Li or Edward B. Lee.

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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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