Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.
Department of Proteomics and Biological Resources, Genentech Inc., South San Francisco, CA 94080, USA.
Neuron. 2016 Jul 20;91(2):328-40. doi: 10.1016/j.neuron.2016.06.015.
Genetic variants of TREM2, a protein expressed selectively by microglia in the brain, are associated with Alzheimer's disease (AD). Starting from an unbiased protein microarray screen, we identified a set of lipoprotein particles (including LDL) and apolipoproteins (including CLU/APOJ and APOE) as ligands of TREM2. Binding of these ligands by TREM2 was abolished or reduced by disease-associated mutations. Overexpression of wild-type TREM2 was sufficient to enhance uptake of LDL, CLU, and APOE in heterologous cells, whereas TREM2 disease variants were impaired in this activity. Trem2 knockout microglia showed reduced internalization of LDL and CLU. β-amyloid (Aβ) binds to lipoproteins and this complex is efficiently taken up by microglia in a TREM2-dependent fashion. Uptake of Aβ-lipoprotein complexes was reduced in macrophages from human subjects carrying a TREM2 AD variant. These data link three genetic risk factors for AD and reveal a possible mechanism by which mutant TREM2 increases risk of AD. VIDEO ABSTRACT.
TREM2 是一种在大脑中的小胶质细胞中特异性表达的蛋白，其遗传变异与阿尔茨海默病（AD）有关。从一个无偏见的蛋白质微阵列筛选开始，我们确定了一组脂蛋白颗粒（包括 LDL）和载脂蛋白（包括 CLU/APOJ 和 APOE）是 TREM2 的配体。这些配体与 TREM2 的结合被与疾病相关的突变所破坏或减少。野生型 TREM2 的过表达足以增强异源细胞中 LDL、CLU 和 APOE 的摄取，而 TREM2 疾病变体在这种活性中受损。Trem2 敲除小胶质细胞显示 LDL 和 CLU 的内化减少。β-淀粉样蛋白（Aβ）与脂蛋白结合，这种复合物通过 TREM2 依赖的方式被小胶质细胞有效摄取。携带 TREM2 AD 变体的人类受试者的巨噬细胞中 Aβ-脂蛋白复合物的摄取减少。这些数据将 AD 的三个遗传风险因素联系起来，并揭示了突变 TREM2 如何增加 AD 风险的可能机制。视频摘要。
