title: Functional involvement of γ-secretase in signaling of the triggering receptor expressed on myeloid cells-2 (TREM2).
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.
  
  
  RESULTS
  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.
authors.affiliation: Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. constantine.glebov@ukb.uni-bonn.de.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Glebov
authors.affiliation: Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. Patrick.Wunderlich@gmx.de.
authors.forename: Patrick
authors.initials: P
authors.lastname: Wunderlich
authors.affiliation: Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. Ilker.Karaca@ukb.uni-bonn.de.|Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany. Ilker.Karaca@ukb.uni-bonn.de.
authors.forename: Ilker
authors.initials: I
authors.lastname: Karaca
authors.affiliation: Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. jochen.walter@ukb.uni-bonn.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D020013:Calcium Signaling / Q000502:physiology; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000378:metabolism; D008954:Models, Biological; D022423:Myeloid Cells / Q000378:metabolism*; D010587:Phagocytosis / Q000502:physiology; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D014162:Transfection
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse; D049452:Green Fluorescent Proteins; D053829:Amyloid Precursor Protein Secretases