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Cell. 2015 Mar 12;160(6):1061-71. doi: 10.1016/j.cell.2015.01.049. Epub 2015 Feb 26.

TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
2
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
4
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: mcolonna@pathology.wustl.edu.

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation. Recent genome-wide association studies have shown that a rare R47H mutation of TREM2 correlates with a substantial increase in the risk of developing Alzheimer's disease (AD). To address the basis for this genetic association, we studied TREM2 deficiency in the 5XFAD mouse model of AD. We found that TREM2 deficiency and haploinsufficiency augment β-amyloid (Aβ) accumulation due to a dysfunctional response of microglia, which fail to cluster around Aβ plaques and become apoptotic. We further demonstrate that TREM2 senses a broad array of anionic and zwitterionic lipids known to associate with fibrillar Aβ in lipid membranes and to be exposed on the surface of damaged neurons. Remarkably, the R47H mutation impairs TREM2 detection of lipid ligands. Thus, TREM2 detects damage-associated lipid patterns associated with neurodegeneration, sustaining the microglial response to Aβ accumulation.

PMID:
25728668
PMCID:
PMC4477963
DOI:
10.1016/j.cell.2015.01.049
[Indexed for MEDLINE]
Free PMC Article

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