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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.
Mutations in TREM2 alter risk for Alzheimer’s disease, though the mechanisms underlying risk in human cells are unclear. Here, the authors use iPS-microglia and chimeric mice to highlight altered survival, phagocytosis, migration, and transcriptional programs in microglia lacking TREM2.
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1 University of California Irvine, Department of Neurobiology & Behavior, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); University of California Irvine, Sue and Bill Gross Stem Cell Research Center, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); University of California Irvine, Institute for Memory Impairments and Neurological Disorders, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243)
2 University of North Carolina Charlotte, Department of Mechanical Engineering and Engineering Science, Charlotte, USA (GRID:grid.266859.6) (ISNI:0000 0000 8598 2218); University of North Carolina Charlotte, Department of Biological Sciences, Charlotte, USA (GRID:grid.266859.6) (ISNI:0000 0000 8598 2218); University of North Carolina Charlotte, Nanoscale Science Program, Charlotte, USA (GRID:grid.266859.6) (ISNI:0000 0000 8598 2218); University of North Carolina Charlotte, Center for Biomedical Engineering and Science, Charlotte, USA (GRID:grid.266859.6) (ISNI:0000 0000 8598 2218)
3 University of California Irvine, Department of Physiology and Biophysics, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243)
4 University of California Irvine, Sue and Bill Gross Stem Cell Research Center, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243)
5 University of California Irvine, Department of Neurobiology & Behavior, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); University of California Irvine, Sue and Bill Gross Stem Cell Research Center, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243)
6 University of California Irvine, Sue and Bill Gross Stem Cell Research Center, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); University of California Irvine, Institute for Memory Impairments and Neurological Disorders, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243)
7 University of California Irvine, Institute for Memory Impairments and Neurological Disorders, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243)
8 University of California Irvine, Institute for Memory Impairments and Neurological Disorders, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); National Autonomous University of Mexico, Institute of Neurobiology, Queretaro, Mexico (GRID:grid.9486.3) (ISNI:0000 0001 2159 0001)
9 University of California Irvine, Department of Neurobiology & Behavior, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); University of California Irvine, Sue and Bill Gross Stem Cell Research Center, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); University of California Irvine, Institute for Memory Impairments and Neurological Disorders, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); University of North Carolina Charlotte, Department of Biological Sciences, Charlotte, USA (GRID:grid.266859.6) (ISNI:0000 0000 8598 2218)
10 University of California Irvine, Sue and Bill Gross Stem Cell Research Center, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); University of California Irvine, Institute for Memory Impairments and Neurological Disorders, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); University of California Irvine, Department of Psychology and Human Behavior, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243)
11 University of California Irvine, Department of Neurobiology & Behavior, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243)
12 University of North Carolina Charlotte, Department of Mechanical Engineering and Engineering Science, Charlotte, USA (GRID:grid.266859.6) (ISNI:0000 0000 8598 2218); University of North Carolina Charlotte, Department of Biological Sciences, Charlotte, USA (GRID:grid.266859.6) (ISNI:0000 0000 8598 2218); University of North Carolina Charlotte, Nanoscale Science Program, Charlotte, USA (GRID:grid.266859.6) (ISNI:0000 0000 8598 2218); University of North Carolina Charlotte, Center for Biomedical Engineering and Science, Charlotte, USA (GRID:grid.266859.6) (ISNI:0000 0000 8598 2218); Sungkyunkwan University, Department of Biophysics, Suwon, Korea (GRID:grid.264381.a) (ISNI:0000 0001 2181 989X)