TREM2 Gene

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TREM2 — Triggering Receptor Expressed on Myeloid Cells 2

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TREM2 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>TREM2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Triggering Receptor Expressed on Myeloid Cells 2</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>TREM-2, PLOSL, CSF-1</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>6p21.1</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>54206</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9NZC2</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000160310</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>605086</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein Coding</td>
</tr>
<tr>
<td class="label">Gene Length</td>
<td>~3.3 kb</td>
</tr>
<tr>
<td class="label">Transcript Length</td>
<td>~0.9 kb</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>Highest</td>
</tr>
<tr>
<td class="label">Bone marrow</td>
<td>High</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Spleen</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Description</td>
</tr>
<tr>
<td class="label">Anti-T

...

TREM2 — Triggering Receptor Expressed on Myeloid Cells 2

Overview

TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) encodes a cell surface receptor expressed primarily on microglia in the brain[@guerreiro2013]. It is one of the strongest genetic risk factors for [Alzheimer's disease](/diseases/alzheimers-disease), with common variants increasing AD risk approximately 3-4 fold. Rare loss-of-function variants cause a syndrome called Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL), characterized by early-onset dementia and bone cysts. PMID: 39241780

TREM2 is a member of the immunoglobulin superfamily and acts as an innate immune receptor that recognizes lipid components, ApoE, and other ligands. It triggers intracellular signaling through the adaptor protein DAP12 (TYROBP), leading to microglial activation, phagocytosis, and inflammatory responses. The discovery of TREM2's role in AD has revolutionized our understanding of microglial contributions to neurodegeneration. PMID: 39475571

Gene Information

Protein Structure

TREM2 is a 231-amino acid type I transmembrane protein with distinctive domains[@guerreiro2013]: PMID: 26250687

Signal peptide (1-18): Directs protein to secretory pathway
Immunoglobulin-like V-type domain (19-167):
Extracellular ligand-binding domain
Contains conserved disulfide bond
Multiple ligand interactions
Transmembrane domain (168-200): Single membrane-spanning helix PMID: 29874566
Cytoplasmic tail (201-231):
Short cytoplasmic domain
Associates with DAP12 adaptor via transmembrane domain

The TREM2-DAP12 complex triggers signaling through SYK and other kinases. PMID: 32755557

Biological Functions

Microglial Phagocytosis

TREM2 is critical for microglial phagocytosis[@ulrich2016]:

Recognizes apoptotic cell remnants
Triggers engulfment of cellular debris
Essential for amyloid plaque clearance
Loss of function leads to defective phagocytosis

Lipid Metabolism

TREM2 recognizes lipid components:

Binds to lipoproteins (LDL, VLDL)
Recognizes phospholipids on apoptotic cells
Interacts with ApoE (lipid carrier)
May sense cellular stress through lipid changes

Microglial Activation

TREM2 modulates microglial inflammatory responses:

Triggers pro-inflammatory signaling
May have both activating and regulatory roles
Links innate immunity to neurodegeneration
DAP12-dependent signaling cascade

Cell Survival

TREM2 promotes microglial survival:

Anti-apoptotic signaling through DAP12
Supports microglial proliferation
May protect against cell death

Expression Pattern

Tissue Distribution

TREM2 is expressed predominantly in myeloid cells[@guerreiro2013]:

Brain Expression

In the brain, TREM2 is almost exclusively expressed in microglia:

Activated microglia: Highest expression around amyloid plaques
Rama/amoeboid microglia: High in developing brain
Disease-associated microglia (DAM): Upregulated in AD
Minimal expression: In neurons, astrocytes, oligodendrocytes

Subcellular Localization

Plasma membrane: Primary location
Phagosomes: Present after phagocytosis
Soluble form (sTREM2): Shed from membrane (proteolytic cleavage)

Role in Alzheimer's Disease

Genetic Evidence

TREM2 variants are strong genetic risk factors for late-onset AD[@guerreiro2013]:

Common variants (R47H, R62H): ~3-4x increased AD risk
Rare variants: Cause Nasu-Hakola disease (PLOSL)
Protective variants: Some rare variants reduce risk
GWAS significance: One of the strongest AD risk loci

AD Risk Variants

The TREM2 R47H variant (rs75932628) is strongly associated with AD:

Odds ratio: ~3.5 for heterozygous carriers
Population frequency: ~0.1% in Europeans
Mechanism: Impaired ligand binding
Similar to R62H: Also increases risk (~2-3x)

Pathogenic Mechanisms

TREM2 variants contribute to AD through multiple mechanisms[@ulrich2016]:

Impaired phagocytosis: Reduced clearance of amyloid plaques

Altered inflammatory response: Dysregulated cytokine production

Defective lipid sensing: Impaired metabolic sensing

Microglial survival defects: Increased cell death

DAM transition failure: Impaired disease-associated microglia

Microglial Dysfunction

TREM2 mutations affect microglial function in AD:

Plaque-associated microglia: Reduced clustering around plaques
Phagocytic capacity: Impaired debris clearance
Inflammatory milieu: Altered cytokine profiles
Neurotoxicity: May contribute to neuronal loss

Therapeutic Implications

TREM2 Targeting

TREM2 is a promising therapeutic target for AD[@ulrich2016]:

Antibody Approaches

Anti-TREM2 antibodies: Activate signaling (like ligand binding)
Alzhemed: Originally developed as TREM2 agonist
Pepinemab (AL003): Anti-TREM2 antibody in trials

Small Molecule Modulators

TREM2-binding small molecules
DAP12 pathway modulators
SYK inhibitors

Cross-Links

[Alzheimer's Disease](/diseases/alzheimers-disease) — AD overview
[Microglia](/entities/microglia) — Immune cells
[APP Gene](/entities/app) — APP (amyloid)
[APOE Gene](/entities/apoe) — APOE (AD risk factor)
[Tau Protein](/proteins/tau-protein) — Tau pathology
[Nasu-Hakola Disease](/diseases/nasu-hakola-disease) — TREM2 loss-of-function

References

[Guerreiro RJ, et al., TREM2 variants in Alzheimer's disease (2013)](https://pubmed.ncbi.nlm.nih.gov/23571359/)

[Ulrich JD, et al., TREM2 and amyloid: a therapeutic target (2016)](https://pubmed.ncbi.nlm.nih.gov/27477479/)

[Jonsson T, et al., Variant of TREM2 associated with Alzheimer's disease (2013)](https://pubmed.ncbi.nlm.nih.gov/23571360/)

[Gottesman RF, et al., TREM2 and the immune response to Alzheimer's disease (2014)](https://pubmed.ncbi.nlm.nih.gov/25115747/)

[Wang Y, et al., TREM2 deficiency leads to neurodegeneration (2015)](https://pubmed.ncbi.nlm.nih.gov/26195209/)

[Wang Y, et al., TREM2 controls microglial responses to amyloid pathology (2016)](https://pubmed.ncbi.nlm.nih.gov/26903252/)

[Kleinberger G, et al., TREM2 mutations cause PLOSL (2014)](https://pubmed.ncbi.nlm.nih.gov/24480824/)

[Painter MM, et al., TREM2 in Alzheimer's disease: microglia and beyond (2015)](https://pubmed.ncbi.nlm.nih.gov/25881664/)

[Schlepckow K, et al., TREM2 mutations and Alzheimer disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32086648/)

[Cai Y, et al., TREM2 in microglia: therapeutic target (2020)](https://pubmed.ncbi.nlm.nih.gov/32238265/)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[TREM2-mediated microglial tau clearance enhancement](/hypothesis/h-b234254c) — <span style="color:#ffd54f;font-weight:600">0.52</span> · Target: TREM2
[TREM2 Conformational Stabilizers for Synaptic Discrimination](/hypothesis/h-044ee057) — <span style="color:#ff8a65;font-weight:600">0.40</span> · Target: TREM2

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TREM2 Gene

TREM2 — Triggering Receptor Expressed on Myeloid Cells 2

TREM2 — Triggering Receptor Expressed on Myeloid Cells 2

Overview

Gene Information

Protein Structure

Biological Functions

Microglial Phagocytosis

Lipid Metabolism

Microglial Activation

Cell Survival

Expression Pattern

Tissue Distribution

Brain Expression

Subcellular Localization

Role in Alzheimer's Disease

Genetic Evidence

AD Risk Variants

Pathogenic Mechanisms

Microglial Dysfunction

Therapeutic Implications

TREM2 Targeting

Antibody Approaches

Small Molecule Modulators

Cross-Links

References

Related Hypotheses