| TREM2 | |
|---|---|
| Gene | TREM2 |
| UniProt | Q9NZC2 |
| PDB | 5ELI, 5UD7 |
| Mol. Weight | 25 kDa (transmembrane), 17 kDa (soluble sTREM2) |
| Localization | Cell surface (microglia), shed as soluble sTREM2 |
| Family | TREM family (Ig superfamily) |
| Diseases | Alzheimer's Disease, Frontotemporal Dementia, Nasu-Hakola Disease |
Trem2 (Triggering Receptor Expressed On Myeloid Cells 2) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a cell surface receptor expressed primarily on microglia in the central nervous system. It belongs to the TREM family of immunoglobulin-like receptors and plays a critical role in modulating microglial function, phagocytosis, and neuroinflammation. TREM2 has emerged as a key player in Alzheimer's disease pathogenesis, with rare coding variants conferring approximately 3-5x increased risk for late-onset AD.
TREM2 is a type I transmembrane protein consisting of an extracellular immunoglobulin-like V-type domain, a transmembrane region, and a short cytoplasmic tail. The protein is encoded by the [TREM2--TEMP--/genes)--FIX-- gene located on chromosome 6p21.1.
The extracellular domain mediates ligand binding, while the transmembrane domain contains a positively charged lysine residue that associates with the adaptor protein DAP12 (TYROBP) for signal transduction. TREM2 undergoes proteolytic shedding by ADAM10/ADAM17, releasing soluble sTREM2 into the cerebrospinal fluid, which serves as a potential biomarker.
Crystal structures of the TREM2 extracellular domain have been solved (PDB: 5ELI, 5UD7), revealing a typical Ig-like fold with a ligand-binding pocket. The AlphaFold model provides additional insight into the full-length protein structure.
TREM2 recognizes multiple ligands including:
Upon ligand binding, TREM2 recruits the adaptor protein DAP12 (DNAX-activating protein of 12 kDa) through charged transmembrane residues. DAP12 contains an immunoreceptor tyrosine-based activation motif (ITAM) that becomes phosphorylated by Src family kinases, leading to recruitment of SYK and activation of downstream signaling pathways:
Rare TREM2 coding variants (R47H, R62H, D87N, Y38C) significantly increase AD risk, comparable to APOE ε4. These variants impair ligand binding and TREM2 function, highlighting the importance of microglial activation in AD pathogenesis.
TREM2 is essential for the transition of microglia to a disease-associated microglia (DAM) or neurodegenerative phenotype. TREM2-deficient mice show:
Soluble TREM2 (sTREM2) in CSF reflects microglial activity:
Agonistic antibodies or small molecules aim to enhance TREM2 signaling, promoting:
The study of Trem2 (Triggering Receptor Expressed On Myeloid Cells 2) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.