Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer’s disease

Amanda McQuade, You Jung Kang, Jonathan Hasselmann, Amit Jairaman, Alexandra Sotelo, Morgan Coburn, Sepideh Kiani Shabestari, Jean Paul Chadarevian, Gianna Fote, Christina H. Tu, Emma Danhash, Jorge Silva, Eric Martinez, Carl Cotman, G. Aleph Prieto, Leslie M. Thompson, Joan S. Steffan, Ian Smith, Hayk Davtyan, Michael Cahalan, Hansang Cho and Mathew Blurton-Jones ()
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Amanda McQuade: University of California Irvine
You Jung Kang: University of North Carolina Charlotte
Jonathan Hasselmann: University of California Irvine
Amit Jairaman: University of California Irvine
Alexandra Sotelo: University of California Irvine
Morgan Coburn: University of California Irvine
Sepideh Kiani Shabestari: University of California Irvine
Jean Paul Chadarevian: University of California Irvine
Gianna Fote: University of California Irvine
Christina H. Tu: University of California Irvine
Emma Danhash: University of California Irvine
Jorge Silva: University of California Irvine
Eric Martinez: University of California Irvine
Carl Cotman: University of California Irvine
G. Aleph Prieto: University of California Irvine
Leslie M. Thompson: University of California Irvine
Joan S. Steffan: University of California Irvine
Ian Smith: University of California Irvine
Hayk Davtyan: University of California Irvine
Michael Cahalan: University of California Irvine
Hansang Cho: University of North Carolina Charlotte
Mathew Blurton-Jones: University of California Irvine

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract The discovery of TREM2 as a myeloid-specific Alzheimer’s disease (AD) risk gene has accelerated research into the role of microglia in AD. While TREM2 mouse models have provided critical insight, the normal and disease-associated functions of TREM2 in human microglia remain unclear. To examine this question, we profile microglia differentiated from isogenic, CRISPR-modified TREM2-knockout induced pluripotent stem cell (iPSC) lines. By combining transcriptomic and functional analyses with a chimeric AD mouse model, we find that TREM2 deletion reduces microglial survival, impairs phagocytosis of key substrates including APOE, and inhibits SDF-1α/CXCR4-mediated chemotaxis, culminating in an impaired response to beta-amyloid plaques in vivo. Single-cell sequencing of xenotransplanted human microglia further highlights a loss of disease-associated microglial (DAM) responses in human TREM2 knockout microglia that we validate by flow cytometry and immunohistochemistry. Taken together, these studies reveal both conserved and novel aspects of human TREM2 biology that likely play critical roles in the development and progression of AD.

Date: 2020
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DOI: 10.1038/s41467-020-19227-5

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