TREM2 in CNS homeostasis and neurodegenerative disease

Mol Neurodegener. 2015 Sep 4:10:43. doi: 10.1186/s13024-015-0040-9.

Abstract

Myeloid-lineage cells accomplish a myriad of homeostatic tasks including the recognition of pathogens, regulation of the inflammatory milieu, and mediation of tissue repair and regeneration. The innate immune receptor and its adaptor protein—triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12)—possess the ability to modulate critical cellular functions via crosstalk with diverse signaling pathways. As such, mutations in TREM2 and DAP12 have been found to be associated with a range of disease phenotypes. In particular, mutations in TREM2 increase the risk for Alzheimer's disease and other neurodegenerative disorders. The leading hypothesis is that microglia, the resident immune cells of the central nervous system, are the major myeloid cells affected by dysregulated TREM2-DAP12 function. Here, we review how impaired signaling by the TREM2-DAP12 pathway leads to altered immune responses in phagocytosis, cytokine production, and microglial proliferation and survival, thus contributing to disease pathogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Central Nervous System / pathology
  • Central Nervous System / physiology*
  • Cytokines / physiology
  • Homeostasis*
  • Humans
  • Immunity, Innate
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology*
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Mice
  • Microglia / pathology
  • Microglia / physiology*
  • Models, Biological
  • Mutation
  • Myeloid Cells / pathology
  • Myeloid Cells / physiology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Neurodegenerative Diseases / immunology
  • Neurodegenerative Diseases / physiopathology*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / physiology*
  • Regeneration
  • Toll-Like Receptors / physiology
  • Wound Healing

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • Membrane Glycoproteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Receptors, Immunologic
  • TREM2 protein, human
  • TYROBP protein, human
  • Toll-Like Receptors