2. Academic Validation
  3. TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function

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

  • Neuron. 2018 Mar 7;97(5):1023-1031.e7. 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 8
Affiliations

Affiliations

  • 1 Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 2 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.
  • 3 Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  • 4 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.
  • 5 Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
  • 6 Department of Neurology, Union Hospital, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian 350001, China.
  • 7 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.
  • 8 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. Electronic address: xuh@sbpdiscovery.org.
PMID: 29518356 DOI: 10.1016/j.neuron.2018.01.031
Abstract

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.

Keywords

Alzheimer’s disease; Aβ; R47H; TREM2; microglia; neuroinflammation.

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