Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2)

Yuka Atagi, Chia Chen Liu, Meghan M. Painter, Xiao Fen Chen, Christophe Verbeeck, Honghua Zheng, Xia Li, Rosa Rademakers, Silvia S. Kang, Huaxi Xu, Steven Younkin, Pritam Das, John D. Fryer, Guojun Bu

Research output: Contribution to journalArticle

173 Scopus citations

Abstract

Several heterozygous missense mutations in the triggering receptor expressed on myeloid cells 2 (TREM2) have recently been linked to risk for a number of neurological disorders including Alzheimer disease (AD), Parkinson disease, and frontotemporal dementia. These discoveries have re-ignited interest in the role of neuroinflammation in the pathogenesis of neurodegenerative diseases. TREM2 is highly expressed in microglia, the resident immune cells of the central nervous system. Along with its adaptor protein, DAP12, TREM2 regulates inflammatory cytokine release and phagocytosis of apoptotic neurons. Here, we report apolipoprotein E (apoE) as a novel ligand for TREM2. Using a biochemical assay, we demonstrated high-affinity binding of apoE to human TREM2. The functional significance of this binding was highlighted by increased phagocytosis of apoE-bound apoptotic N2a cells by primary microglia in a manner that depends on TREM2 expression. Moreover, when the AD-associated TREM2-R47H mutant was used in biochemical assays, apoE binding was vastly reduced. Our data demonstrate that apoE-TREM2 interaction in microglia plays critical roles in modulating phagocytosis of apoE-bound apoptotic neurons and establish a critical link between two proteins whose genes are strongly linked to the risk for AD.

Original languageEnglish (US)
Pages (from-to)26043-26050
Number of pages8
JournalJournal of Biological Chemistry
Volume290
Issue number43
DOIs
StatePublished - Oct 23 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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