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Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer's
Amanda McQuade1,2,3, You Jung Kang4,5,6,7, Jonathan Hasselmann1,2,3
1Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.
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.
Insights
Triggering receptor expressed on myeloid cells 2 (TREM2) is crucial for microglial function in Alzheimer's disease (AD). TREM2 deficiency impairs microglial survival, phagocytosis, and chemotaxis, hindering the brain's response to amyloid plaques.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- TREM2 is a key risk gene for Alzheimer's disease (AD), highlighting the importance of microglia in AD pathogenesis.
- Understanding TREM2's function in human microglia is critical, as mouse models may not fully recapitulate human biology.
Purpose of the Study:
- To investigate the specific functions of TREM2 in human microglia.
- To elucidate the role of TREM2 in microglial responses relevant to Alzheimer's disease.
Main Methods:
- Generated isogenic, CRISPR-modified TREM2-knockout induced pluripotent stem cell (iPSC)-derived microglia.
- Performed transcriptomic and functional analyses, including phagocytosis and chemotaxis assays.
- Utilized a chimeric AD mouse model and xenotransplantation of human microglia for in vivo validation.
Main Results:
- TREM2 knockout microglia exhibited reduced survival and impaired phagocytosis of substrates like APOE.
- Chemotaxis mediated by SDF-1α/CXCR4 was inhibited in TREM2-deficient microglia.
- Human TREM2 knockout microglia showed a diminished disease-associated microglial (DAM) response, impacting beta-amyloid plaque clearance in vivo.
Conclusions:
- TREM2 plays a critical role in human microglial survival, phagocytic capacity, and migration.
- Loss of TREM2 function impairs the microglial response to AD pathology, including beta-amyloid plaques.
- These findings reveal conserved and novel aspects of human TREM2 biology relevant to AD development and progression.
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