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, 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.
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.
| Property |
Value |
| Gene Symbol |
TREM2 |
| Full Name |
Triggering Receptor Expressed on Myeloid Cells 2 |
| Aliases |
TREM-2, PLOSL, CSF-1 |
| Chromosomal Location |
6p21.1 |
| NCBI Gene ID |
54206 |
| UniProt ID |
Q9NZC2 |
| Ensembl ID |
ENSG00000160310 |
| OMIM ID |
605086 |
| Gene Type |
Protein Coding |
| Gene Length |
~3.3 kb |
| Transcript Length |
~0.9 kb |
TREM2 is a 231-amino acid type I transmembrane protein with distinctive domains[@guerreiro2013]:
- 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
- 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.
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
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
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
TREM2 promotes microglial survival:
- Anti-apoptotic signaling through DAP12
- Supports microglial proliferation
- May protect against cell death
TREM2 is expressed predominantly in myeloid cells[@guerreiro2013]:
| Tissue |
Expression Level |
Cell Types |
| Brain |
Highest |
Microglia |
| Bone marrow |
High |
Osteoclasts, macrophages |
| Lung |
Moderate |
Alveolar macrophages |
| Liver |
Moderate |
Kupffer cells |
| Spleen |
Moderate |
Macrophages |
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
- Plasma membrane: Primary location
- Phagosomes: Present after phagocytosis
- Soluble form (sTREM2): Shed from membrane (proteolytic cleavage)
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
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)
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
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
TREM2 is a promising therapeutic target for AD[@ulrich2016]:
| Approach |
Description |
Status |
| Anti-TREM2 antibodies |
Agonist antibodies to enhance function |
Phase 1/2 |
| TREM2 agonists |
Small molecule activators |
Research |
| Gene therapy |
Restore TREM2 expression |
Preclinical |
| sTREM2 replacement |
Soluble TREM2 protein |
Research |
¶ Antibody Approaches
- Anti-TREM2 antibodies: Activate signaling (like ligand binding)
- Alzhemed: Originally developed as TREM2 agonist
- Pepinemab (AL003): Anti-TREM2 antibody in trials
- TREM2-binding small molecules
- DAP12 pathway modulators
- SYK inhibitors
- Guerreiro RJ, et al., TREM2 variants in Alzheimer's disease (2013)
- Ulrich JD, et al., TREM2 and amyloid: a therapeutic target (2016)
- Jonsson T, et al., Variant of TREM2 associated with Alzheimer's disease (2013)
- Gottesman RF, et al., TREM2 and the immune response to Alzheimer's disease (2014)
- Wang Y, et al., TREM2 deficiency leads to neurodegeneration (2015)
- Wang Y, et al., TREM2 controls microglial responses to amyloid pathology (2016)
- Kleinberger G, et al., TREM2 mutations cause PLOSL (2014)
- Painter MM, et al., TREM2 in Alzheimer's disease: microglia and beyond (2015)
- Schlepckow K, et al., TREM2 mutations and Alzheimer disease (2020)
- Cai Y, et al., TREM2 in microglia: therapeutic target (2020)