| TREM2 (triggering receptor expressed on myeloid cells 2) is a type I transmembrane immunoreceptor of the TREM family that is highly and selectively expressed on microglia in the CNS as well as on peripheral myeloid cells, where it acts as a lipid- and damage-associated pattern recognition receptor that couples extracellular sensing of apolipoproteins, phospholipids, and amyloid species to intracellular DAP12–SYK–PI3K signaling programs controlling microglial survival, metabolism, chemotaxis, and phagocytosis. The receptor comprises an N‑terminal V‑type Ig-like ectodomain that binds ligands including ApoE, ApoJ/CLU, anionic and aminophospholipids, and multiple forms of amyloid‑β, a single-pass transmembrane segment that associates with the ITAM-bearing adaptor DAP12, and a short cytoplasmic tail that relies on DAP12 for signal propagation; ectodomain shedding at the H157/S158 site generates a soluble TREM2 fragment with distinct signaling properties. Ligand engagement stabilizes TREM2–DAP12 complexes and promotes phosphorylation of the DAP12 ITAM, recruitment and activation of SYK, and downstream activation of PI3K–AKT–mTOR, ERK, and PLCγ pathways, which together enhance microglial survival, proliferation, and metabolic reprogramming, drive chemotactic responses toward amyloid deposits or damaged myelin, and induce a transcriptional switch from homeostatic to disease-associated microglia characterized by upregulation of genes involved in phagocytosis, lipid handling, lysosomal function, and complement. TREM2 supports microglial clustering around plaques, compaction of amyloid cores, and efficient phagocytic clearance of Aβ aggregates and dystrophic neurites, whereas TREM2 deficiency or expression of hypomorphic variants reduces microglial proliferation and plaque encasement, leads to more diffuse and neurotoxic plaque morphology, increases neuritic damage, and accelerates both amyloid deposition and tau seeding and spread. Rare missense variants such as R47H and loss-of-function mutations in TREM2 confer substantially increased risk of late‑onset Alzheimer’s disease and cause Nasu–Hakola disease when biallelic, and mechanistic analyses indicate that these variants reduce ligand binding and/or surface expression, blunt DAP12–SYK signaling, and impair acquisition of the disease-associated microglial phenotype required for effective containment of Aβ and tau pathology. |
