| TREM2 — Triggering Receptor Expressed on Myeloid Cells 2 | |
|---|---|
| Symbol | TREM2 |
| Full Name | Triggering Receptor Expressed on Myeloid Cells 2 |
| Chromosome | 6p21.1 |
| NCBI Gene | 54209 |
| Ensembl | ENSG00000095970 |
| OMIM | 605086 |
| UniProt | Q9NZC2 |
| Diseases | Alzheimer's Disease, Frontotemporal Dementia, Nasu-Hakola Disease |
| Expression | Microglia, Cerebral cortex, Hippocampus |
| Key Mutations | |
| R47H R62H D87N T66M Y38C |
|
Trem2 — Triggering Receptor Expressed On Myeloid Cells 2 plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a gene located on chromosome 6p21.1 that encodes a critical receptor protein expressed primarily on microglia in the central nervous system. Discovered as a major risk factor for Alzheimer's disease, TREM2 has emerged as a central regulator of microglial function, amyloid clearance, and neuroinflammation. This page provides comprehensive information about TREM2's structure, function, signaling pathways, disease associations, and therapeutic implications.
Key takeaway: TREM2 is a microglial receptor that when mutated (particularly R47H) significantly increases Alzheimer's disease risk by impairing microglial phagocytosis and amyloid clearance.
The TREM2 gene spans approximately 7.5 kb on chromosome 6p21.1 within the major histocompatibility complex (MHC) class III region. The gene consists of 5 exons encoding a type I transmembrane receptor protein. TREM2 is part of a gene family that includes TREM1, TREM3 (pseudogene), and TREML1-4.
TREM2 is predominantly expressed in:
Expression data is available from the Allen Human Brain Atlas and single-cell transcriptomic databases showing microglial-specific expression.
TREM2 expression is regulated by:
TREM2 functions as an activating receptor on microglia that triggers intracellular signaling cascades through its association with the adaptor protein DAP12 (TYROBP). Upon ligand binding:
Phagocytosis: TREM2 is essential for microglial phagocytosis of:
Microglial Survival: TREM2 signaling promotes microglial survival through AKT and mTOR pathways
Metabolic Reprogramming: TREM2 activation induces glycolytic shift necessary for active phagocytosis
Cytokine Production: TREM2 signaling modulates production of anti-inflammatory cytokines (IL-10, TGF-β) while limiting pro-inflammatory responses
Synaptic Pruning: During development and in disease states, TREM2 mediates appropriate synaptic elimination
TREM2 interacts with several key proteins:
| Partner | Interaction Type | Functional Consequence |
|---|---|---|
| [DAP12/TYROBP[/entities/[dap12[/entities/[dap12[/entities/[dap12--TEMP--/entities)--FIX-- | Direct binding | ITAM-mediated signal transduction |
| [DAP10[/entities/[dap10[/entities/[dap10[/entities/[dap10--TEMP--/entities)--FIX-- | Alternative adaptor | PI3K-mediated signaling |
| [TREM2-Ligand[/entities/[trem2-ligand[/entities/[trem2-ligand[/entities/[trem2-ligand--TEMP--/entities)--FIX-- | Receptor activation | Ligand-induced signaling |
| [CSF1R[/entities/[csf1r[/entities/[csf1r[/entities/[csf1r--TEMP--/entities)--FIX-- | Co-expression | Synergistic microglial activation |
| [TLRs[/entities/[toll-like-receptors[/entities/[toll-like-receptors[/entities/[toll-like-receptors--TEMP--/entities)--FIX-- | Synergistic signaling | Enhanced inflammatory response |
| [APOE[/genes/[apoe[/genes/[apoe[/genes/[apoe--TEMP--/genes)--FIX-- | Lipid ligand | Aβ binding and clearance |
| [SYP[/proteins/[synaptophysin[/proteins/[synaptophysin[/proteins/[synaptophysin--TEMP--/proteins)--FIX-- | Presynaptic target | Synaptic pruning regulation |
See the [TREM2 protein page[/proteins/[trem2-protein[/proteins/[trem2-protein[/proteins/[trem2-protein--TEMP--/proteins)--FIX-- for detailed structural information.
TREM2 variants represent one of the strongest genetic risk factors for late-onset Alzheimer's disease (LOAD) after APOE. The R47H variant increases AD risk by approximately 3-fold, similar to the effect of one APOE4 allele.
Mechanisms linking TREM2 to AD:
See [TREM2 Variants in Alzheimer's Disease[/diseases/[trem2-variants-in-ad[/diseases/[trem2-variants-in-ad[/diseases/[trem2-variants-in-ad--TEMP--/diseases)--FIX-- for detailed mechanisms.
TREM2 variants are associated with increased risk for frontotemporal dementia, particularly in cases with:
Homozygous loss-of-function mutations in TREM2 cause Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy - PLOSL), characterized by:
This demonstrates the critical role of TREM2 in neuronal function.
| Variant | Risk | Effect | Population Frequency |
|---|---|---|---|
| R47H | ~3x AD risk | Loss of ligand binding | ~0.5% European |
| R62H | ~1.5x AD risk | Partial loss of function | ~1% European |
| D87N | ~2x AD risk | Reduced signaling | Rare |
| T66M | Pathogenic (NHD) | Complete loss of function | Very rare |
| Y38C | Pathogenic (NHD) | Misfolding | Very rare |
The R47H variant specifically impairs binding to amyloid-beta and lipid ligands, explaining its strong effect on AD risk.
Given TREM2's critical role in AD pathogenesis, several therapeutic approaches are being developed:
See [TREM2 Agonist Therapies for Alzheimer's Disease[/treatments/[trem2-agonist-therapies-alzheimers[/treatments/[trem2-agonist-therapies-alzheimers[/treatments/[trem2-agonist-therapies-alzheimers--TEMP--/treatments)--FIX-- for current clinical trial status.
Soluble TREM2 (sTREM2) in cerebrospinal fluid reflects microglial activity and:
See [sTREM2 Biomarker[/biomarkers/[strem2[/biomarkers/[strem2[/biomarkers/[strem2--TEMP--/biomarkers)--FIX-- for details.
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.
Trem2 — Triggering Receptor Expressed On Myeloid Cells 2 plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
Page auto-generated from NeuroWiki gene database. Last updated: 2026-02-26.