Functional involvement of γ-secretase in signaling of the triggering receptor expressed on myeloid cells-2 (TREM2)

J Neuroinflammation. 2016 Jan 20;13:17. doi: 10.1186/s12974-016-0479-9.

Abstract

Background: Triggering receptor expressed on myeloid cells-2 (TREM2) exerts important functions in the regulation of monocytes, like dendritic cells, osteoclasts, tissue macrophages, and microglia. Mutations in TREM2 are associated with several diseases, including Nasu-Hakola disease, frontotemporal dementia, and Alzheimer's disease (AD). TREM2 undergoes sequential proteolytic processing by ectodomain shedding and intramembrane proteolysis.

Findings: We show that inhibition of γ-secretase-dependent cleavage of the TREM2 C-terminal fragment in cellular membranes interferes with TREM2-dependent signaling and cellular function. Inhibition of γ-secretase decreases membrane-proximal signaling and intracellular Ca(2+) response. Decreased signaling alters morphological changes and phagocytic activity of cells upon selective stimulation of TREM2.

Conclusions: The data demonstrate the importance of γ-secretase-dependent intramembrane processing in TREM2-mediated signaling and, thus, a functional relation of two AD-associated proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • COS Cells
  • Calcium Signaling / physiology
  • Cell Line, Transformed
  • Chlorocebus aethiops
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Microglia / metabolism
  • Models, Biological
  • Myeloid Cells / metabolism*
  • Phagocytosis / physiology
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Signal Transduction / physiology*
  • Time Factors
  • Transfection

Substances

  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Trem2 protein, mouse
  • Green Fluorescent Proteins
  • Amyloid Precursor Protein Secretases