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

Yingjun Zhao, Xilin Wu, Xiaoguang Li, Lu Lin Jiang, Xun Gui, Yan Liu, Yu Sun, Bing Zhu, Juan C. Piña-Crespo, Muxian Zhang, Ningyan Zhang, Xiaochun Chen, Guojun Bu, Zhiqiang An, Timothy Y. Huang, Huaxi Xu

Research output: Contribution to journalArticle

109 Scopus citations

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. Genetic variations in TREM2 confer AD risk, but AD-related ligands for TREM2 are poorly characterized. Zhao et al. demonstrate that TREM2 is a microglial receptor for Aβ and transduces Aβ-induced downstream signaling, providing insight into microglial pathogenicity in AD.

Original languageEnglish (US)
Pages (from-to)1023-1031.e7
JournalNeuron
Volume97
Issue number5
DOIs
StatePublished - Mar 7 2018

Keywords

  • Alzheimer's disease
  • R47H
  • TREM2
  • microglia
  • neuroinflammation

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function'. Together they form a unique fingerprint.

  • Cite this

    Zhao, Y., Wu, X., Li, X., Jiang, L. L., Gui, X., Liu, Y., Sun, Y., Zhu, B., Piña-Crespo, J. C., Zhang, M., Zhang, N., Chen, X., Bu, G., An, Z., Huang, T. Y., & Xu, H. (2018). TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function. Neuron, 97(5), 1023-1031.e7. https://doi.org/10.1016/j.neuron.2018.01.031