Intracellular trafficking of TREM2 is regulated by presenilin 1

Yingjun Zhao, Xiaoguang Li, Timothy Huang, Lu Lin Jiang, Zhenqiu Tan, Muxian Zhang, Irene Han Juo Cheng, Xin Wang, Guojun D Bu, Yun Wu Zhang, Qi Wang, Huaxi Xu

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Genetic mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to a variety of neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Parkinson's disease. In the brain, TREM2 is highly expressed on the cell surface of microglia, where it can transduce signals to regulate microglial functions such as phagocytosis. To date, mechanisms underlying intracellular trafficking of TREM2 remain elusive. Mutations in the presenilin 1 (PS1) catalytic subunit of the γ-secretase complex have been associated with increased generation of the amyloidogenic Aβ (amyloid-β) 42 peptide through cleavage of the Aβ precursor amyloid precursor protein. Here we found that TREM2 interacts with PS1 in a manner independent of γ-secretase activity. Mutations in TREM2 alter its subcellular localization and affects its interaction with PS1. Upregulation of PS1 reduces, whereas downregulation of PS1 increases, steady-state levels of cell surface TREM2. Furthermore, PS1 overexpression results in attenuated phagocytic uptake of Aβ by microglia, which is reversed by TREM2 overexpression. Our data indicate a novel role for PS1 in regulating TREM2 intracellular trafficking and pathophysiological function.

Original languageEnglish (US)
Article numbere405
JournalExperimental and Molecular Medicine
Volume49
Issue number12
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

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  • Cite this

    Zhao, Y., Li, X., Huang, T., Jiang, L. L., Tan, Z., Zhang, M., Cheng, I. H. J., Wang, X., Bu, G. D., Zhang, Y. W., Wang, Q., & Xu, H. (2017). Intracellular trafficking of TREM2 is regulated by presenilin 1. Experimental and Molecular Medicine, 49(12), [e405]. https://doi.org/10.1038/emm.2017.200