Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
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DOI：
10.1038/s41593-018-0296-9
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发表时间：
2019-02-01
影响因子：
25
通讯作者：
Haass, Christian
中科院分区：
文献类型：
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作者：
Parhizkar, Samira;Arzberger, Thomas;Haass, Christian
髓样细胞上表达的触发受体2（TREM2）中的编码变体与迟发性阿尔茨海默病（AD）相关。我们证明，淀粉样蛋白斑块播种增加的功能性Trem2的情况下。增加的接种伴随着减少的小胶质细胞聚集在新接种的斑块周围和减少的斑块相关载脂蛋白E（ApoE）。在携带TREM2编码变体的AD患者的脑中也观察到斑块中ApoE沉积减少。蛋白质组学分析和小胶质细胞耗竭实验显示小胶质细胞是斑块相关ApoE的来源之一。纵向淀粉样蛋白小动物正电子发射断层扫描显示加速淀粉样蛋白在Trem2功能丧失突变体的早期阶段，这在一个较低的速度与老化进展。这些发现表明，在缺乏功能性Trem2的情况下，尽管斑块相关ApoE减少，但由于淀粉样蛋白种子的吞噬清除减少，早期淀粉样蛋白生成加速。
Coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late-onset Alzheimer's disease (AD). We demonstrate that amyloid plaque seeding is increased in the absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque-associated apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic analyses and microglia depletion experiments revealed microglia as one origin of plaque-associated ApoE. Longitudinal amyloid small animal positron emission tomography demonstrates accelerated amyloidogenesis in Trem2 loss-of-function mutants at early stages, which progressed at a lower rate with aging. These findings suggest that in the absence of functional Trem2, early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloid seeds despite reduced plaque-associated ApoE.