Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation

Wilbur Song, Basavaraj Hooli, Kristina Mullin, Sheng Chih Jin, Marina Cella, Tyler K. Ulland, Yaming Wang, Rudolph E. Tanzi, Marco Colonna

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Introduction TREM2 is a lipid-sensing activating receptor on microglia known to be important for Alzheimer's disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial. Methods We analyzed AD risk of TREM2 variants in the NIMH AD Genetics Initiative Study and AD Sequencing Project. We compared each variant's risk and functional impact by a reporter assay. Finally, we analyzed expression of TREM2 on human monocytes. Results We provide more evidence for increased AD risk associated with several TREM2 variants, and show that these variants decreased or markedly increased binding to TREM2 ligands. We identify HDL and LDL as novel TREM2 ligands. We also show that TREM2 expression in human monocytes is minimal compared to monocyte-derived dendritic cells. Discussion Our results suggest that TREM2 signaling helps protect against AD but can cause harm in excess, supporting the idea that proper TREM2 function is important to counteract disease progression.

Original languageEnglish
Pages (from-to)381-387
Number of pages7
JournalAlzheimer's and Dementia
Volume13
Issue number4
DOIs
StatePublished - Apr 1 2017

Keywords

  • Alzheimer's disease
  • HDL
  • LDL
  • Lipoprotein
  • Microglia
  • Monocyte
  • TREM2

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