TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia

被引：728

作者：

Yeh, Felix L. ^{[1
]}

Wang, Yuanyuan ^{[1
]}

Tom, Irene ^{[2
]}

Gonzalez, Lino C. ^{[2
,3
]}

Sheng, Morgan ^{[1
]}

机构：

[1] Genentech Inc, Dept Neurosci, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Prote & Biol Resources, San Francisco, CA 94080 USA

[3] 23andMe Inc, Mountain View, CA 94041 USA

来源：

NEURON | 2016年 / 91卷 / 02期

关键词：

DENSITY-LIPOPROTEIN RECEPTOR; GENOME-WIDE ASSOCIATION; ALZHEIMERS-DISEASE; A-BETA; IDENTIFIES VARIANTS; TYPE-4; ALLELE; MOUSE MODEL; CELLS; CLEARANCE; RISK;

D O I：

10.1016/j.neuron.2016.06.015

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

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. beta-amyloid (A beta) binds to lipoproteins and this complex is efficiently taken up by microglia in a TREM2-dependent fashion. Uptake of A beta-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.

引用

页码：328 / 340

页数：13

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