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Cited by 361Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammasome and immune disorders

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

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McQuade, Amanda, Kang, You Jung, Hasselmann, Jonathan, Jairaman, Amit, Sotelo, Alexandra, Coburn, Morgan, Shabestari, Sepideh Kiani, Chadarevian, Jean Paul +14 more·2020·Nature Communications
DOI 10.1038/s41467-020-19227-5PMC PMC7584603
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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.

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  • TREM2 is required for the conversion of microglia from a homeostatic to a disease activated state.

    “TREM2 is required for the conversion of microglia from a homeostatic to a disease activated state [14, 15]”

    From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [15]

    The Discussion says TREM2 is “partially required” for transition from homeostatic microglia into disease-associated clusters. The Results also report that TREM2-knockout human microglia fail to activate normally around amyloid plaques. The claim captures TREM2’s role but overstates the paper’s qualified finding as an absolute requirement. (LLM, conf=0.86)

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Research works printed but not linked: 48

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Authors
McQuade, A., Kang, Y. J., Hasselmann, J., Jairaman, A., Sotelo, A., Coburn, M., Shabestari, S. K., Chadarevian, J. P., Fote, G., Tu, C. H., Danhash, E., Silva, J., Martinez, E., Cotman, C., Prieto, G. A., Thompson, L. M., Steffan, J. S., Smith, I., Davtyan, H., Cahalan, M., Cho, H., & Blurton-Jones, M.
Affiliations
  • University of California, Irvine (US)
  • University of North Carolina at Charlotte (US)
Corresponding author
Blurton-Jones, Mathew
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-10-23
Volume
11
Issue
1
Pages
5370-5370
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-19227-5
PMC
PMC7584603
OpenAlex
W3094535741
Cited by
361
References
27
Citations by year
2026: 55 · 2025: 69 · 2024: 77 · 2023: 62 · 2022: 56 · 2021: 41 · 2020: 1
FWCI
15.49
Type
journal article
Language
en
Update notices
correction (2023-03-02)
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NS082174)
  • Foundation for the National Institutes of Health (AG00096, AG000096)
  • HD Care
  • Cure Alzheimer’s Fund
  • California Institute for Regenerative Medicine (RT3-07893)
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (AG016573)
  • Susan Scott Foundation
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
TREM2, Alzheimer's disease, microglia, disease-associated microglia, microglial survival, phagocytosis, apolipoprotein E, amyloid plaques, iPSC-derived microglia, chimeric mouse model, xenotransplantation, single-cell transcriptomics, gene expression
MeSH terms
Alzheimer Disease, Animals, Brain, Cell Line, Chemotaxis, Disease Models, Animal, Female, Gene Expression Regulation, Male, Membrane Glycoproteins, Mice, Inbred BALB C, Mice, Transgenic, Phagocytosis, Receptors, Immunologic, Amyloid beta-Peptides, Cell Death, Microglia, Mice, Knockout, Receptors, CXCR4, Genetic Predisposition to Disease, Mice, Chemokine CXCL12, Gene Knockout Techniques, Plaque, Amyloid, Transcriptome

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