TREM-2

TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is an innate immune receptor predominantly expressed by microglia and functions as a critical regulator of microglial activation, phagocytosis, metabolic fitness, and tissue surveillance in the central nervous system^[1][2]. Mechanistically, TREM2 coordinates microglial responses to lipid-associated and neurodegenerative cues and supports the transition of microglia toward disease-associated functional states that maintain tissue homeostasis during stress and injury^[1][3]. The TREM2-APOE pathway has emerged as a key regulatory axis controlling disease-associated microglia, linking lipid metabolism, immune signaling, and neurodegenerative responses^[1][4]. In neurodegenerative disease models, particularly Alzheimer’s disease, TREM2 regulates microglial responses to amyloid pathology, promotes plaque-associated microglial activation, and supports protective barrier formation around amyloid deposits^[5][6]. Genetic studies further demonstrate that loss-of-function variants, including the R47H variant, impair ligand binding, phagocytosis, and downstream transcriptional responses while increasing susceptibility to Alzheimer’s disease^[5]. Compared with other members of the TREM receptor family, TREM2 is distinguished by its central role in microglial biology and neurodegeneration-associated immune adaptation rather than primarily amplifying acute inflammatory responses^[1]. TREM2 also regulates cellular metabolism, including lipid handling and bioenergetic capacity, which are required for sustained microglial function under pathological conditions^[2][7]. For experimental applications, TREM2-targeting agonistic antibodies have been shown to enhance microglial metabolism, proliferation, and protective responses in preclinical neurodegeneration models, supporting their utility for mechanistic studies of microglial immunobiology^[1][7].