Fig. 3

Hypothetical model of TREM2-dependent signaling in cells with and without functional γ-secretase. Degradation of TREM2 CTFs by γ-secretase allows an efficient association of full-length TREM2 with its co-receptor DAP12. Upon ligand binding to TREM2, DAP12 undergoes phosphorylation within its intracellular ITAM domain, resulting in the recruitment of the spleen tyrosine kinase (Syk) and activation of phospholipase C (PLC). PLC-mediated cleavage of phosphatidylinositol-4,5-bisphosphate in cellular membranes leads to generation of inositol-1,4,5-trisphosphate (IP₃) and mobilization in Ca²⁺ from the endoplasmic reticulum, thereby regulating phagocytosis and dynamics of the cytoskeleton. Upon inhibition of γ-secretase, DAP12 might predominantly associate with accumulated TREM2 CTFs, thereby decreasing the availability to bind to full-length TREM2, which would result in impaired signal transduction