Fig. 1

Schematic illustration of TREM2 signaling. The membrane-bound TREM2 receptor interacts with various ligands, including lipids, lipoproteins, apolipoproteins and amyloid-β. Ligand binding to TREM2 triggers the phosphorylation of tyrosine residues within the ITAM motif of the DAP12 cytoplasmic domain by SRC family kinases. The phosphorylated ITAM recruit the protein tyrosine kinase SYK to activate downstream signaling pathways. Additionally, TREM2 can associate with DAP10 homodimer, which contains YXNM motifs. These motifs directly recruit PI3K, activating further signaling pathways. SYK activation drives key pathways, including PLCγ2, Rac1/Cdc42, ERK, and PI3K. PLCγ2 activation is critical for microglial phagocytosis and lipid metabolism. Meanwhile, Rac1/Cdc42-GTPase signaling plays a key role in cytoskeletal remodeling and cell migration. Additionally, the ERK pathway is essential for microglial survival, proliferation, and inflammatory responses. In parallel, the PI3K/Akt pathway, activated by both DAP10 and SYK, governs essential cellular processes such as survival, proliferation, and glucose metabolism. PIP3, phosphatidylinositol 3,4,5-trisphosphate; PIP2, phosphatidylinositol (4,5)-bisphosphate; PLCγ2, phospholipase Cγ2; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; PKC, protein kinase C; PI3K, phosphatidylinositol 3-kinase; ERK, extracellular signal-regulated kinase; GSK3β, glycogen synthase kinase 3β; mTOR, mechanistic target of rapamycin