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

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TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function.
Neuron ( IF 14.7 ) Pub Date : 2018-Mar-07 , DOI: 10.1016/j.neuron.2018.01.031
Yingjun Zhao ₁ , Xilin Wu ₂ , Xiaoguang Li ₁ , Lu-Lin Jiang ₁ , Xun Gui ₃ , Yan Liu ₄ , Yu Sun ₁ , Bing Zhu ₁ , Juan C Piña-Crespo ₁ , Muxian Zhang ₅ , Ningyan Zhang ₃ , Xiaochun Chen ₆ , Guojun Bu ₇ , Zhiqiang An ₃ , Timothy Y Huang ₁ , Huaxi Xu ₄

Affiliation

Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Department of Neurology, Union Hospital, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian 350001, China.
Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
Department of Neurology, Union Hospital, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian 350001, China.
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, China; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

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 β-amyloid (Aβ) oligomers with nanomolar affinity, whereas AD-associated TREM2 mutations reduce Aβ binding. TREM2 deficiency impairs Aβ degradation in primary microglial culture and mouse brain. Aβ-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 Aβ, regulating downstream phosphorylation of SYK and GSK3β. Our data demonstrate TREM2 as a microglial Aβ receptor transducing physiological and AD-related pathological effects associated with Aβ.

中文翻译：

TREM2是介导小胶质细胞功能的β-淀粉样蛋白的受体。

髓样细胞2（TREM2）上表达的触发受体突变与阿尔茨海默氏病（AD）风险增加有关。TREM2及其病理生理配体的神经生物学功能仍然难以捉摸。在这里，我们发现TREM2以纳摩尔亲和力直接结合至β-淀粉样蛋白（Aβ）寡聚物，而与AD相关的TREM2突变降低了Aβ结合。TREM2缺乏会损害原代小胶质细胞培养物和小鼠大脑中的Aβ降解。Aβ诱导的小胶质细胞去极化，K ⁺内向电流的诱导，细胞因子的表达和分泌，迁移，增殖，凋亡和形态变化均取决于TREM2。另外，通过Aβ增强了TREM2与其信号转导接头DAP12的相互作用，从而调节了SYK和GSK3β的下游磷酸化。我们的数据表明，TREM2是一种小胶质Aβ受体，可转导与Aβ相关的生理和AD相关病理效应。

更新日期：2018-03-08

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