TREM2 (Triggering Receptor Expressed on Myeloid Cells 2), located on chromosome 6p21.1, encodes a cell-surface receptor on microglia that plays critical roles in brain immune surveillance, phagocytosis, and inflammatory responses. Rare coding variants in TREM2 significantly increase the risk for Alzheimer's disease (AD), with the R47H variant conferring approximately 3-fold increased risk, similar to APOE4. TREM2 has emerged as a key therapeutic target for AD and other neurodegenerative diseases.
The TREM2 gene encodes TREM2 protein, a 234-amino acid type I transmembrane receptor:
- Microglial phagocytosis: Critical receptor for ApoE and lipid clearance; mediates phagocytosis of apoptotic cells, myelin debris, and amyloid-beta
- Inflammatory signaling: Activates SYK and downstream signaling cascades; modulates cytokine production
- Cell survival: Provides pro-survival signals through DAP12 adapter protein
- Metabolic regulation: Supports microglial metabolic fitness and adaptation to brain environment
- Amyloid response: Required for microglial clustering around amyloid plaques; regulates plaque compaction
- Tau pathology: Modulates tau spreading and microglial-mediated neurotoxicity
TREM2 undergoes proteolytic cleavage, releasing a soluble fragment (sTREM2) that may have immunomodulatory functions.
| Feature |
Details |
| Molecular weight |
~26 kDa (membrane-bound), ~20 kDa (soluble) |
| Structure |
Ig-like V-type extracellular domain; transmembrane helix |
| Ligands |
Lipids, ApoE, amyloid-beta, bacterial components |
| Signaling |
Associates with DAP12 (TYROBP) adapter protein |
| Crystal structure |
PDB: 1OMZ, 5W2F |
- Risk factor: R47H, R62H, R64H variants significantly increase AD risk (~3x)
- Mechanism: Impaired microglial phagocytosis and lipid sensing
- Neuropathology: Reduced microglial clustering around plaques; more diffuse plaques
| Variant |
AD Risk |
Function |
| R47H |
3x increased |
Impaired ligand binding |
| R62H |
~2x increased |
Partial loss of function |
| R64H |
~2x increased |
Partial loss of function |
| Q33X |
5x increased |
Truncated protein (loss of function) |
| Y38C |
Pathogenic |
Impaired trafficking |
- Nasu-Hakola disease: Biallelic TREM2 mutations cause presenile dementia with bone cysts
- Frontotemporal dementia: Some TREM2 variants associated
- Parkinson's disease: Possible association under investigation
- Amyotrophic lateral sclerosis: TREM2 microglial activation observed
- Brain: Microglia-specific expression; highest in white matter microglia
- Cell types: Primarily microglia; low expression in monocytes, macrophages, dendritic cells
- Subcellular: Cell membrane; undergoes constitutive shedding
- Regulation: Upregulated by ApoE, amyloid-beta, and inflammatory signals
- sTREM2: Detectable in CSF; levels correlate with disease stage
- Guerreiro et al., TREM2 variants in Alzheimer's disease (2013)
- Jonsson et al., TREM2 and Alzheimer's disease (2013)
- Ulrich et al., TREM2 function in microglia (2014)
- Wang et al., TREM2 in amyloid pathology (2015)
- Zhao et al., TREM2 and tau pathology (2018)
- Schneider et al., TREM2 therapeutic strategies (2020)
- Deczkowska et al., TREM2 in brain immune surveillance (2021)
- Felsky et al., TREM2 expression and AD neuroimaging (2022)
- Anti-TREM2 antibodies: AL002, AL003 (phase 1/2 clinical trials)
- Small molecule agonists: Under development
- AAV-TREM2 delivery approaches in preclinical development
- sTREM2 as potential biomarker
- sTREM2 replacement strategies under investigation
- Microglial activation modulation
- Lipid metabolism restoration
- Plaque containment improvement
- Neuroinflammation regulation