Alzheimer’s disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-β plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown. We generated transgenic mice expressing human CV or R47H TREM2 and lacking endogenous TREM2 in the 5XFAD AD model. Only the CV transgene restored amyloid-β–induced microgliosis and microglial activation, indicating that R47H impairs TREM2 function in vivo. Remarkably, soluble TREM2 was found on neurons and plaques in CV- but not R47H-expressing 5XFAD brains, although in vitro CV and R47H were shed similarly via Adam17 proteolytic activity. These results demonstrate that TREM2 interacts with neurons and plaques duing amyloid-β accumulation and R47H impairs this interaction.

阿尔茨海默氏病（AD）是一种神经退行性疾病，可导致迟发性痴呆。在全基因组关联研究中，小胶质细胞受体TREM2的R47H变异使AD风险增加了三倍。在小鼠AD模型中，缺乏TREM2的小胶质细胞无法增殖并聚集在AD的淀粉样β斑块周围。在体外，TREM2的常见变异体（CV）与阴离子脂质结合，而R47H突变会削弱结合。然而，在体内，TREM2配体的身份和R47H变体的作用仍然未知。我们生成了在5XFAD AD模型中表达人CV或R47H TREM2且缺乏内源性TREM2的转基因小鼠。只有CV转基因恢复了淀粉样β诱导的小胶质细胞增生和小胶质细胞活化，表明R47H在体内损害TREM2的功能。值得注意的是 尽管在体外CV和R47H通过Adam17蛋白水解活性类似地脱落，但在表达CV的神经元和斑块中发现了可溶性TREM2，而在表达R47H的5XFAD脑中没有。这些结果表明，TREM2在淀粉样蛋白-β积累期间与神经元和斑块相互作用，而R47H削弱了这种相互作用。