| 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](/diseases/alzheimers-disease), [Frontotemporal Dementia](/diseases/frontotemporal-dementia), [Nasu-Hakola Disease](/diseases/nasu-hakola-disease) |
| Expression | Microglia, Cerebral cortex, Hippocampus |
| Key Mutations | |
| R47H, R62H, D87N, T66M, Y38C | |
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[1]. Discovered as a major risk factor for Alzheimer's disease, TREM2 has emerged as a central regulator of microglial function, amyloid clearance, and neuroinflammation[2].
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[3].
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 shows highly specific expression patterns in the brain:
Single-cell RNA-seq data from the Allen Brain Atlas Cell Types dataset shows:
| Region | Expression Level | Data Source |
|---|---|---|
| Cortex | High (Microglial) | Human MTG |
| Hippocampus | High (Microglial) | Mouse Brain |
| Substantia nigra | Medium | Mouse Brain |
| Cerebellum | Low | Mouse Brain |
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[5]:
Phagocytosis: TREM2 is essential for microglial phagocytosis of[@gratuze2018]:
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[6]
TREM2 recognizes several key ligands:
TREM2 interacts with several key proteins:
| Partner | Interaction Type | Functional Consequence |
|---|---|---|
| DAP12 (TYROBP) | Direct binding | ITAM-mediated signal transduction |
| DAP10 | Alternative adaptor | PI3K-mediated signaling |
| SYK | Kinase substrate | Signal propagation |
| PI3K | Phosphorylation | AKT pathway activation |
| PLCγ | Substrate | Calcium signaling |
| APOE | Lipid ligand | Aβ binding and clearance |
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[7].
Mechanisms linking TREM2 to AD:
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[3:1].
TREM2 variants may modify risk in Parkinson's disease, though evidence is less robust than for AD. Studies suggest TREM2 may be involved in:
TREM2 expression changes in motor neurons and may play a role in:
TREM2 is involved in microglial response to demyelination and may play a protective role in MS progression.
| 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[8].
Given TREM2's critical role in AD pathogenesis, several therapeutic approaches are being developed[9]:
Several TREM2-targeted therapies are in various stages of development:
Soluble TREM2 (sTREM2) in cerebrospinal fluid reflects microglial activity and[10]:
Jonsson T, et al. Variant in TREM2 associated with Alzheimer's disease. N Engl J Med. 2013. ↩︎
Guerreiro R, et al. TREM2 variants in Alzheimer's disease. N Engl J Med. 2013. ↩︎
Kleinberger G, et al. TREM2 mutations implicated in Nasu-Hakola disease and frontotemporal dementia. Nat Neurosci. 2014. ↩︎ ↩︎
Wang Y, et al. TREM2 deficiency eliminates the neuroprotective function of resolving microglia. Nat Neurosci. 2015. ↩︎
Zhao Y, et al. TREM2 is a receptor for beta-amyloid that mediates microglial function. Cell Rep. 2018. ↩︎
Painter MM, et al. TREM2 deficiency impairs complement activation. J Exp Med. 2015. ↩︎
Ulrich JD, et al. A decade of TREM2 in Alzheimer's disease: a new therapeutic target. Neuron. 2017. ↩︎
Elahi FM, et al. TREM2 variant associated with early-onset Alzheimer's disease. Neurology. 2020. ↩︎
Xiang X, et al. TREM2 agonist for Alzheimer's disease: current status and future directions. Brain. 2024. ↩︎
Schneck ME, et al. Soluble TREM2 as a biomarker for Alzheimer's disease. Nat Rev Neurol. 2021. ↩︎