期刊
CELL
卷 160, 期 6, 页码 1061-1071出版社
CELL PRESS
DOI: 10.1016/j.cell.2015.01.049
关键词
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资金
- Lilly Innovation Fellowship
- DDRCC [P30 DK52574]
- National Multiple Sclerosis Society [RG4687A1/1]
- Knight Alzheimer's Disease Research Center pilot grant [P50 AG005681-30]
- Cure Alzheimer's Fund
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 beta-amyloid (A beta) accumulation due to a dysfunctional response of microglia, which fail to cluster around Ab plaques and become apoptotic. We further demonstrate that TREM2 senses a broad array of anionic and zwitterionic lipids known to associate with fibrillar Ab 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 Ab accumulation.
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