| TREM2 Protein | |
|---|---|
| Full Name | Triggering Receptor Expressed on Myeloid Cells 2 |
| Gene | [TREM2](/genes/trem2) |
| UniProt ID | Q9NZC2 |
| Protein Length | 234 amino acids |
| Molecular Weight | ~26 kDa (membrane), ~20 kDa (soluble) |
| Structure | Ig-like V-type extracellular domain + TM helix + disordered tail |
| PDB Entries | 1OMZ, 5W2F, 6VLX, 7WHB, 7VC7 |
| Expression | Microglia, macrophages, dendritic cells, osteoclasts |
| AD Risk | R47H, R62H, D87N variants (OR ~2-3) |
TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a type I transmembrane receptor expressed primarily on microglia in the central nervous system. It serves as a critical sensor of lipid-containing ligands and mediates microglial phagocytosis, metabolic adaptation, and the transition to disease-associated microglia (DAM) in Alzheimer's disease[1]. TREM2 is one of the strongest genetic risk factors for late-onset Alzheimer's disease—rare loss-of-function variants increase AD risk approximately 2-3 fold, comparable to the effect of a single APOE4 allele[2].
The discovery that TREM2 variants confer significant AD risk sparked intense research into microglial biology and neuroinflammation as therapeutic targets. TREM2's primary effect is modulating microglial responses to amyloid pathology, positioning it as a key target for immunotherapy[3].
| Domain | Residues | Structure | Function |
|---|---|---|---|
| Signal peptide | 1-18 | Secreted | Targeting to secretory pathway |
| Ig-like V-type | 19-122 | β-sandwich | Ligand binding (lipids, ApoE, Aβ) |
| Stem | 123-157 | Extended | Receptor stability, proteolytic cleavage site |
| Transmembrane | 158-180 | α-helix | DAP12 association via charged aspartate (D175) |
| Cytoplasmic | 181-234 | Disordered | No intrinsic signaling motif — requires adaptor |
Structural studies reveal:
| Modification | Site | Effect |
|---|---|---|
| N-linked glycosylation | N71, N92, N103 | Stability, ligand binding |
| Proteolytic shedding | H157/S158 (ADAM10/17) | Generates sTREM2 |
| Phosphorylation | Y73, Y75 (SRC family) | DAP12 ITAM recruitment |
| γ-secretase cleavage | C-terminal stub | Following shedding |
TREM2 undergoes constitutive and induced proteolytic cleavage:
| Feature | Significance |
|---|---|
| CSF levels in AD | Elevated compared to controls; correlates with tau pathology |
| Disease progression | Higher sTREM2 associated with faster cognitive decline |
| Diagnostic potential | May help distinguish AD from other dementias |
| Therapeutic implications | sTREM2 replacement strategies under investigation |
The ratio of sTREM2 to full-length TREM2 may serve as a biomarker for microglial activation status in AD[6].
| Variant | Effect on Protein | Functional Consequence | AD Risk |
|---|---|---|---|
| R47H | Altered ligand-binding pocket | Reduced ApoE/lipid binding | ~3x increased |
| R62H | Surface localization defect | Impaired ligand recognition | ~2x increased |
| D87N | Altered signaling interface | Partial loss of function | ~2x increased |
| Y38C | Misfolding | ER/Golgi retention | Pathogenic (Nasu-Hakola) |
| Q33X | Truncation | Complete loss of function | Pathogenic (Nasu-Hakola) |
TREM2 AD risk variants exhibit:
TREM2 is essential for the transition from homeostatic microglia to disease-associated microglia (DAM)[7]:
| Stage | TREM2 Status | Markers | Function |
|---|---|---|---|
| Homeostatic | Required | P2RY12, TMEM119, CX3CR1 | Surveillance |
| Early DAM | TREM2-dependent | APOE, CST7, LPL, TYROBP | Phagocytosis, lipid metabolism |
| Late DAM | TREM2-independent | ITGAX (CD11c), APOC1, SPP1 | Aggregate clearance |
The transition requires TREM2 signaling and is arrested in TREM2-deficient states[8]:
Functional consequences of arrest:
Microglial lipid metabolism is tightly regulated by TREM2 signaling[9]:
Key metabolic changes upon TREM2 activation:
ApoE as central lipid shuttle[10]:
TREM2 (activating) and CD33 (inhibitory) represent a balance regulating microglial function:
| Parameter | TREM2 | CD33 |
|---|---|---|
| Signaling | ITAM (via DAP12) | ITIM (via SHP1/2) |
| Effect | Activates phagocytosis | Inhibits phagocytosis |
| AD association | Loss-of-function risk | Gain-of-expression risk |
| Therapeutic | Agonists | Antagonists |
| Feature | TREM2 | CX3CR1 |
|---|---|---|
| Ligand | Lipids, ApoE, Aβ | Fractalkine (CX3CL1) |
| Effect | Phagocytosis activation | Neuroprotective surveillance |
| Expression | DAM-enriched | Homeostatic microglia |
| AD role | Amyloid clearance | Neuron-microglia communication |
| Target | Function |
|---|---|
| APOE | Lipid metabolism, Aβ clearance |
| C1QA/B/C | Complement component |
| CST7 | Lysosomal cysteine protease |
| LPL | Lipid metabolism |
| TREM2 | Feedback regulation |
| Drug | Company | Mechanism | Clinical Status |
|---|---|---|---|
| AL002A | Alector/AbbVie | TREM2 agonist | Phase 2 in early AD (ACTIVE) |
| AL003 | Alector | TREM2 agonist | Discontinued |
| HT-1807 | Himarq/Fujifilm | TREM2 agonist | Preclinical |
Agonistic antibodies work by:
TREM2 represents a pivotal microglial receptor linking neuroinflammation to neurodegeneration. Its role as an AD risk factor, combined with its tractability as a cell surface target and active clinical trials, makes it one of the most promising therapeutic targets in Alzheimer's disease. The ongoing AL002 Phase 2 trials will test whether microglial activation via TREM2 agonism can modify disease progression.
Deczkowska A, et al. The mechanistic basis of Alzheimer's disease as an age-related neurodegenerative disorder. Cell. 2020. ↩︎
Sims R, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial innate immunity in Alzheimer's disease. Nat Neurosci. 2017. ↩︎
Wang Y, et al. TREM2 deficiency eliminates the neuroprotective function of resolving microglia. Cell Rep. 2015. ↩︎
Kober DL, et al. Structural basis for CD33 dysfunction in Alzheimer's disease. J Biol Chem. 2016. ↩︎
Schlepckow K, et al. An Alzheimer-associated TREM2 mutation impairs proteolytic processing of the receptor. Neuron. 2020. ↩︎
Ewers M, et al. Increased soluble TREM2 in cerebrospinal fluid predicts amyloid and tau pathology. EMBO Mol Med. 2020. ↩︎
Keren-Shaul H, et al. A unique microglia type associated with restricting development of Alzheimer's disease. Cell. 2017. ↩︎
Mazaheri F, et al. TREM2 deficiency impairs transition from homeostatic to DAM microglia. EMBO Mol Med. 2017. ↩︎
Zhou Y, et al. TREM2 regulates microglial metabolic adaptation to amyloid pathology. Nat Neurosci. 2020. ↩︎
Nugent AA, et al. TREM2 interacts with ApoE in lipid binding and enhances ApoE-mediated microglial activation. J Neurosci. 2020. ↩︎