TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function

被引：582

作者：

Zhao, Yingjun ^{[1
]}

Wu, Xilin ^{[1
,2
,3
]}

Li, Xiaoguang ^{[1
]}

Jiang, Lu-Lin ^{[1
]}

Gui, Xun ^{[4
]}

Liu, Yan ^{[1
,5
]}

Sun, Yu ^{[1
]}

Zhu, Bing ^{[1
]}

Pina-Crespo, Juan C. ^{[1
]}

Zhang, Muxian ^{[5
]}

Zhang, Ningyan ^{[4
]}

Chen, Xiaochun ^{[2
,3
]}

Bu, Guojun ^{[5
,6
]}

An, Zhiqiang ^{[4
]}

Huang, Timothy Y. ^{[1
]}

Xu, Huaxi ^{[1
,5
]}

机构：

[1] Sanford Burnham Prebys Med Discovery Inst, Neurosci Initiat, La Jolla, CA 92037 USA

[2] Fujian Med Univ, Union Hosp, Dept Neurol, Fuzhou 350001, Fujian, Peoples R China

[3] Fujian Med Univ, Fujian Key Lab Mol Neurol, Fuzhou 350001, Fujian, Peoples R China

[4] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Texas Therapeut Inst, Houston, TX 77030 USA

[5] Xiamen Univ, Coll Med, Inst Neurosci, Fujian Prov Key Lab Neurodegenerat Dis & Aging Re, Xiamen 361102, Fujian, Peoples R China

[6] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

来源：

NEURON | 2018年 / 97卷 / 05期

基金：

中国国家自然科学基金;

关键词：

ALZHEIMERS-DISEASE; VARIANTS; DEFICIENCY; MODEL; PROLIFERATION; CHEMOTAXIS; EXPRESSION; RESPONSES; IMPAIRS; BRAIN;

D O I：

10.1016/j.neuron.2018.01.031

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

Mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to increased Alzheimer's disease (AD) risk. Neurobiological functions of TREM2 and its pathophysiological ligands remain elusive. Here we found that TREM2 directly binds to beta-amyloid (A beta) oligomers with nanomolar affinity, whereas AD-associated TREM2 mutations reduce A beta binding. TREM2 deficiency impairs A beta degradation in primary microglial culture and mouse brain. A beta-induced microglial depolarization, K+ inward current induction, cytokine expression and secretion, migration, proliferation, apoptosis, and morphological changes are dependent on TREM2. In addition, TREM2 interaction with its signaling adaptor DAP12 is enhanced by A beta, regulating downstream phosphorylation of SYK and GSK3 beta. Our data demonstrate TREM2 as a microglial A beta receptor transducing physiological and AD-related pathological effects associated with A beta.

引用

页码：1023 / +

页数：16

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