TREM2 Protein — Triggering Receptor Expressed on Myeloid Cells 2

TREM2 Protein — Triggering Receptor Expressed on Myeloid Cells 2

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#f0f0f0;">TREM2 Protein</th></tr>
<tr><td><b>Full Name</b></td><td>Triggering Receptor Expressed on Myeloid Cells 2</td></tr>
<tr><td><b>Gene</b></td><td>[TREM2](/genes/trem2)</td></tr>
<tr><td><b>UniProt ID</b></td><td>Q9NZC2</td></tr>
<tr><td><b>Protein Length</b></td><td>234 amino acids</td></tr>
<tr><td><b>Molecular Weight</b></td><td>~26 kDa (membrane), ~20 kDa (soluble)</td></tr>
<tr><td><b>Structure</b></td><td>Ig-like V-type extracellular domain + TM helix + disordered tail</td></tr>
<tr><td><b>PDB Entries</b></td><td>1OMZ, 5W2F, 6VLX, 7WHB, 7VC7</td></tr>
<tr><td><b>Expression</b></td><td>Microglia, macrophages, dendritic cells, osteoclasts</td></tr>
<tr><td><b>AD Risk</b></td><td>R47H, R62H, D87N variants (OR ~2-3)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als-therapeutic-landscape-—-programs-by-phase-and-modality" style="color:#ef9a9a">ALS Therapeutic Landscape — Programs by Phase and Modality</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer-disease" style="color:#ef9a9a">ALZHEIMER DISEASE</a>, <a href="/wiki/alzheimer's" style="color:#ef9a9a">ALZHEIMER'S</a></td>
</tr>
<tr>
<td class="label">SciDEX Hypotheses</td>
<td><a href="/hypothesis/h-seaad-51323624" style="color:#ce93d8" title="Score: 0.73">Cell-Type Specific TREM2

TREM2 Protein — Triggering Receptor Expressed on Myeloid Cells 2

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#f0f0f0;">TREM2 Protein</th></tr>
<tr><td><b>Full Name</b></td><td>Triggering Receptor Expressed on Myeloid Cells 2</td></tr>
<tr><td><b>Gene</b></td><td>[TREM2](/genes/trem2)</td></tr>
<tr><td><b>UniProt ID</b></td><td>Q9NZC2</td></tr>
<tr><td><b>Protein Length</b></td><td>234 amino acids</td></tr>
<tr><td><b>Molecular Weight</b></td><td>~26 kDa (membrane), ~20 kDa (soluble)</td></tr>
<tr><td><b>Structure</b></td><td>Ig-like V-type extracellular domain + TM helix + disordered tail</td></tr>
<tr><td><b>PDB Entries</b></td><td>1OMZ, 5W2F, 6VLX, 7WHB, 7VC7</td></tr>
<tr><td><b>Expression</b></td><td>Microglia, macrophages, dendritic cells, osteoclasts</td></tr>
<tr><td><b>AD Risk</b></td><td>R47H, R62H, D87N variants (OR ~2-3)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als-therapeutic-landscape-—-programs-by-phase-and-modality" style="color:#ef9a9a">ALS Therapeutic Landscape — Programs by Phase and Modality</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer-disease" style="color:#ef9a9a">ALZHEIMER DISEASE</a>, <a href="/wiki/alzheimer's" style="color:#ef9a9a">ALZHEIMER'S</a></td>
</tr>
<tr>
<td class="label">SciDEX Hypotheses</td>
<td><a href="/hypothesis/h-seaad-51323624" style="color:#ce93d8" title="Score: 0.73">Cell-Type Specific TREM2 Upregulation in...</a><br><a href="/hypothesis/h-180807e5" style="color:#ce93d8" title="Score: 0.70">APOE-TREM2 Interaction Modulation...</a><br><a href="/hypothesis/h-3460f820" style="color:#ce93d8" title="Score: 0.58">TREM2-Mediated Selective Aggregate Clear...</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1914 edges</a></td>
</tr>
</table>
</div>

Overview

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[@deczkowska2020]. 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[@sims2017].

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[@wang2015].

Protein Structure

Domain Architecture

| 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](/genes/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 Features

• Ig-like V-type domain: Classic immunoglobulin beta-sandwich fold with a hydrophobic binding groove enriched in aromatic residues. The pocket accommodates lipid ligands, apolipoproteins, and amyloid-beta oligomers[@kober2016].
• Transmembrane helix: Contains a charged aspartate residue (D175) that pairs with a lysine in DAP12's transmembrane domain, forming a stable receptor-adaptor complex.
• Proteolytic cleavage site: ADAM10/17 cleavage at position H157/S158 releases soluble TREM2 (sTREM2) constitutively. This shedding is upregulated under inflammatory conditions[@schlepckow2020].

Crystal Structure Insights

Structural studies reveal:

• Ligand-binding pocket: A hydrophobic groove accommodating phosphatidylserine, lipidated ApoE, and Aβ oligomers
• Dimerization interface: TREM2 forms side-by-side dimers, which may be important for high-affinity ligand binding and signaling
• Antibody epitopes: Therapeutic antibodies bind the Ig-like domain, often near the ligand-binding region

Post-Translational Modifications

| 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 |

Soluble TREM2 (sTREM2)

Proteolytic Processing

TREM2 undergoes constitutive and induced proteolytic cleavage:

• Shedases: ADAM10 and ADAM17 mediate cleavage at the stem domain (H157)
• sTREM2: Released extracellular fragment (~20 kDa) detectable in cerebrospinal fluid
• γ-secretase: Following shedding, the remaining membrane stub is cleaved by γ-secretase

sTREM2 as Biomarker

| 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[@ewers2020].

TREM2 Variants and Alzheimer's Risk

Risk Variants

| 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) |

Mechanism of Risk

TREM2 AD risk variants exhibit:

• Reduced ligand binding: Impaired recognition of lipidated ApoE and Aβ
• Defective signaling: Reduced microglial activation in response to ligands
• Altered sTREM2: Some variants affect shedding and sTREM2 levels
• DAM deficiency: Failure to transition to disease-associated microglia

Disease-Associated Microglia (DAM)

TREM2 is essential for the transition from homeostatic microglia to disease-associated microglia (DAM)[@kerenshaul2017]:

| 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 |

DAM Transition Pathway

The transition requires TREM2 signaling and is arrested in TREM2-deficient states[@mazaheri2017]:

Functional consequences of arrest:

• Impaired Abeta phagocytosis and clearance
• Reduced lipid droplet accumulation for phagocytic energy
• Altered inflammatory response to amyloid
• Increased neuronal death around plaques

TREM2 and Lipid Metabolism

Microglial lipid metabolism is tightly regulated by TREM2 signaling[@zhou2020]:

Key metabolic changes upon TREM2 activation:

• Glycolysis upregulation: Increased glucose metabolism to fuel phagocytosis
• Lipid droplet formation: Accumulation of lipid droplets for energy storage
• Cholesterol efflux: Regulation of intracellular cholesterol levels
• Phospholipid remodeling: Membrane composition changes for phagocytosis

• TREM2 recognizes lipidated ApoE particles as primary ligands
• ApoE4 shows reduced TREM2 binding (Kd ~ 300 nM vs ~ 100 nM for ApoE3)
• This partially explains ApoE4's increased AD risk through impaired microglial activation

Cross-Talk with Other Microglial Receptors

TREM2-CD33 Balance

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 |

TREM2-CX3CR1 Interaction

| 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 |

Signaling Pathways

Core Signaling Cascade

• PI3K/AKT → cell survival, metabolism
• MAPK/ERK → gene transcription, proliferation
• NF-κB → inflammatory gene expression
• mTOR → metabolic adaptation

Transcriptional Targets

| Target | Function |
|--------|----------|
| APOE | Lipid metabolism, Aβ clearance |
| C1QA/B/C | Complement component |
| CST7 | Lysosomal cysteine protease |
| LPL | Lipid metabolism |
| TREM2 | Feedback regulation |

Therapeutic Targeting

Agonist Antibodies in Clinical Development

| 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 |

Mechanism of Antibody Therapy

Agonistic antibodies work by:

• Binding the TREM2 extracellular domain
• Inducing receptor clustering (mimicking ligand binding)
• Activating downstream signaling in the absence of ligand
• Promoting microglial DAM transition

Summary

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.

See Also

• [TREM2 Gene](/genes/trem2) — Gene page with genetics and biology
• [CD33 Protein](/proteins/cd33-protein) — Complementary microglial receptor
• [DAP12 Protein](/proteins/dap12-protein) — Signaling adaptor
• [Microglia](/cell-types/microglia) — Cell type where TREM2 is expressed
• [Alzheimer's Disease](/diseases/alzheimers-disease) — Primary disease association
• [Microglial Phagocytosis](/mechanisms/microglial-phagocytosis) — Process TREM2 enhances