特雷姆2
小胶质细胞
生物
神经退行性变
细胞生物学
突变
受体
淀粉样蛋白(真菌学)
磷酸化
神经科学
疾病
免疫学
炎症
生物化学
基因
内科学
医学
植物
作者
Yaming Wang,Marina Cella,Kaitlin Mallinson,Jason D. Ulrich,Katherine L. Young,Michelle L. Robinette,Susan Gilfillan,Gokul M. Krishnan,Shwetha Sudhakar,Bernd H. Zinselmeyer,David M. Holtzman,John R. Cirrito,Marco Colonna
出处
期刊:Cell
[Elsevier]
日期:2015-02-26
卷期号:160 (6): 1061-1071
被引量:1366
标识
DOI:10.1016/j.cell.2015.01.049
摘要
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.
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