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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.    Electronic supplementary material  The online version of this article (doi:10.1186/s12974-016-0479-9) contains supplementary material, which is available to authorized users.

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