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

Aivi T Nguyen; Kui Wang; Gang Hu; Xuran Wang; Zhen Miao; Joshua A Azevedo; EunRan Suh; Vivianna M Van Deerlin; David Choi; Kathryn Roeder; Mingyao Li; Edward B Lee

doi:10.1007/s00401-020-02200-3

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

Acta Neuropathol. 2020 Oct;140(4):477-493. doi: 10.1007/s00401-020-02200-3. Epub 2020 Aug 25.

Authors

Aivi T Nguyen^#^{1

2}, Kui Wang^#^{3

4}, Gang Hu^#^{3

5}, Xuran Wang⁶, Zhen Miao⁷, Joshua A Azevedo^{1

2}, EunRan Suh², Vivianna M Van Deerlin², David Choi⁸, Kathryn Roeder^{6

9}, Mingyao Li¹⁰, Edward B Lee^{11

12}

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.
² Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, 213 Blockley Hall, 423 Guardian Drive, Philadelphia, PA, 19104, USA.
⁴ Department of Information Theory and Data Science, School of Mathematical Sciences and LPMC, Nankai University, Tianjin, China.
⁵ School of Statistics and Data Science, Key Laboratory for Medical Data Analysis and Statistical Research of Tianjin, Nankai University, Tianjin, China.
⁶ Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA, USA.
⁷ Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Heinz College of Public Policy and Information Systems, Carnegie Mellon University, Pittsburgh, PA, USA.
⁹ Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA.
¹⁰ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, 213 Blockley Hall, 423 Guardian Drive, Philadelphia, PA, 19104, USA. mingyao@pennmedicine.upenn.edu.
¹¹ 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. edward.lee@pennmedicine.upenn.edu.
¹² Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. edward.lee@pennmedicine.upenn.edu.

^# Contributed equally.

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.

Keywords: APOE; Alzheimer’s disease; Microglia; TREM2; Transcriptomics; snRNA-seq.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / metabolism*
Alzheimer Disease / pathology*
Amyloid beta-Peptides / metabolism
Apolipoproteins E / genetics*
Humans
Membrane Glycoproteins / genetics*
Microglia / pathology*
Receptors, Immunologic / genetics*

Substances

Amyloid beta-Peptides
ApoE protein, human
Apolipoproteins E
Membrane Glycoproteins
Receptors, Immunologic
TREM2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding