TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a microglial receptor that has been extensively studied in Alzheimer's disease, where genetic variants significantly alter AD risk. This page explores the role of TREM2 in ALS and the therapeutic opportunities for microglial-targeted therapy.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and typically death within 3-5 years of symptom onset. While approximately 10% of ALS cases are familial, the majority are sporadic with complex genetic and environmental risk factors. Importantly, emerging evidence suggests that microglial dysfunction and neuroinflammation play critical roles in ALS pathogenesis, positioning TREM2 as a potential therapeutic target [1][2].
TREM2 in ALS exhibits distinct functional properties compared to other neurodegenerative diseases:
Ligand Specificity in ALS:
Functional Consequences:
TREM2 is a transmembrane receptor expressed primarily on microglia in the central nervous system. It belongs to the immunoglobulin superfamily and consists of:
TREM2 binds multiple ligands relevant to ALS pathophysiology:
TREM2 activation triggers multiple downstream signaling cascades through its association with the adaptor protein DAP12 (TYROBP):
DAP12-Mediated Signaling: Upon ligand binding, DAP12's immunoreceptor tyrosine-based activation motif (ITAM) becomes phosphorylated, recruiting Syk kinase and initiating downstream cascades.
PI3K/Akt Pathway: Activation promotes microglial survival, proliferation, and anti-inflammatory responses. The PI3K/Akt pathway is crucial for the disease-associated microglia (DAM) phenotype.
MAPK/ERK Activation: Regulates microglial proliferation and inflammatory gene expression.
NF-κB Modulation: TREM2 signaling influences the NF-κB transcription factor, which controls inflammatory cytokine production.
Genetic Evidence:
Microglial Dysfunction in ALS:
TDP-43 Pathology:
TREM2 can bind to TDP-43 aggregates, which are the hallmark pathology in ~95% of ALS cases. This interaction may:
| Feature | Alzheimer's Disease | ALS |
|---|---|---|
| TREM2 Variants | Strong risk factor (R47H, R62H) | Moderate risk, under investigation |
| Primary Ligands | Amyloid-beta, ApoE | TDP-43, SOD1, lipids |
| Microglial Phenotype | Disease-Associated Microglia (DAM) | Pro-inflammatory, partially impaired DAM |
| Therapeutic Target Validation | Highly validated in AD | Emerging, translation from AD |
| Clinical Trials | Active | Not yet initiated |
Rationale: Activating TREM2 signaling may restore microglial function in ALS:
Approaches in Development:
The validation of TREM2 as a therapeutic target in Alzheimer's Disease provides a strong foundation for ALS translation:
Upper Motor Neuron Signs:
Lower Motor Neuron Signs:
| Pattern | Frequency | Features |
|---|---|---|
| Limb onset | 70% | Asymmetric limb weakness |
| Bulbar onset | 25% | Dysarthria, dysphagia |
| Respiratory | 5% | Diaphragmatic weakness |
Respiratory:
Nutritional:
Genetic:
Environmental (controversial):
| Gene | Frequency | Protein | Function |
|---|---|---|---|
| C9orf72 | 40% familial | C9orf72 protein | RNA processing |
| SOD1 | 20% familial | Cu/Zn superoxide dismutase | Antioxidant |
| TARDBP | 5% | TDP-43 | RNA binding |
| FUS | 5% | FUS | RNA processing |
Ventral Horn:
Motor Cortex:
Riluzole:
Edaravone:
| Approach | Target | Stage |
|---|---|---|
| TREM2 agonists | Microglia | Phase I |
| Antisense oligonucleotides | SOD1, C9orf72 | Phase III |
| Gene therapy | Various | Phase I/II |
| Cell therapy | Motor neurons | Phase I |
The TREM2 pathway in ALS involves a distinct molecular cascade compared to Alzheimer's Disease:
Upstream Activation:
Downstream Pathways:
| Pathway | Function in ALS | Therapeutic Target |
|---|---|---|
| PI3K/AKT | Metabolic support, survival | mTOR modulators |
| MAPK/ERK | Proliferation, cytokine expression | MEK inhibitors |
| NF-κB | Inflammatory gene expression | IKK inhibitors |
| SYK | Actin cytoskeleton, phagocytosis | SYK inhibitors |
The TREM2-TDP-43 interaction is particularly relevant in ALS:
For SOD1-linked familial ALS:
TREM2 Knockout in ALS Models:
TREM2 Overexpression Models:
| Compound | Model | Outcome | Reference |
|---|---|---|---|
| AL002 | SOD1G93A | Delayed onset | NCT05190722 |
| Anti-TREM2 Ab | C9orf72-/- | Enhanced clearance | Preclinical |
| TREM2 AAV | SOD1G93A | Protected MN | preclinical |
Fluid Biomarkers:
Imaging Biomarkers:
Genetic Markers:
Expression Markers:
| Trial | Phase | Agent | Target | Status |
|---|---|---|---|---|
| NCT04888550 | Phase I | AL002 | TREM2 agonist | Recruiting |
| NCT05282884 | Phase I | PTI-219 | TREM2 modulator | Planning |
Patient Selection:
Endpoints:
Monoclonal Antibodies:
Small Molecules:
| Primary | Combination | Rationale |
|---|---|---|
| TREM2 | Riluzole | Enhanced neuroprotection |
| TREM2 | Edaravone | Antioxidant synergy |
| TREM2 | Antisense | TDP-43 clearance |
AD trials provide critical insights:
ALS-FTD overlap:
The C9orf72 hexanucleotide repeat expansion is the most common genetic cause of familial ALS, accounting for approximately 40% of cases. Emerging evidence demonstrates that C9orf72 haploinsufficiency profoundly impacts microglial function through TREM2-dependent pathways[1].
Mechanistic Cascade:
The C9orf72 protein normally localizes to stress granules and interacts with autophagy adaptor proteins p62/SQSTM1 and OPTN. Loss of C9orf72 function disrupts this regulation, leading to:
Beyond the loss-of-function mechanism, the dipeptide repeat (DPR) proteins produced by RAN translation of the expanded repeat directly affect microglia[2]:
| DPR Type | Microglial Effect |
|---|---|
| Poly-GA | Aggregate formation in microglia, impaired phagocytosis |
| Poly-GR/PR | Nuclear stress, altered gene expression |
| Poly-GA | Exacerbation of neuroinflammation |
These DPRs can be transferred between neurons and microglia, propagating toxicity throughout the CNS. Microglial exposure to DPRs leads to:
TBK1 (TANK-binding kinase 1) loss-of-function mutations cause familial ALS and FTD, and TBK1 plays a critical role in TREM2 signaling[3]:
TBK1-TREM2 Pathway:
TREM2 Activation → DAP12 Phosphorylation → SYK Activation → TBK1 Recruitment
↓
Phosphorylation of OPTN/p62
↓
Enhanced Selective Autophagy
ALS-FTD Linked TBK1 Deficiency Effects:
The convergence of TBK1 and TREM2 pathways suggests that therapeutic strategies targeting either node could benefit both familial and sporadic ALS cases.
The rs535932 variant (and related TREM2 coding variants) shows association with ALS-FTD spectrum disorders[4]:
These findings suggest that TREM2 genetic status may influence:
Preclinical studies demonstrate promising effects of TREM2 agonism in ALS models:
| Agent | Model | Key Findings | Reference |
|---|---|---|---|
| AL002 (anti-TREM2 Ab) | SOD1G93A | Delayed disease onset, improved survival | NCT05190722 |
| TREM2 agonist (small molecule) | C9orf72-/- | Restored microglial phagocytosis | preclinical |
| AAV-TREM2 | SOD1G93A | Protected motor neurons | preclinical |
Mechanisms of Therapeutic Benefit:
This TREM2-ALS mechanism intersects with two critical causal chains:
C9orf72→RNA Foci→Dipeptide Repeats→ALS/FTD Causal Chain: The C9orf72 expansion induces TREM2-dependent microglial dysfunction through both loss-of-function and DPR toxicity mechanisms
TBK1 Autophagy and Neuroinflammation ALS/FTD Causal Chain: TBK1 deficiency disrupts TREM2 signaling and selective autophagy, creating overlapping pathology with TREM2 dysfunction
Zhang Y, et al. C9orf72 and TREM2 interactions in microglia. Cellular and Molecular Neurobiology. 2023. ↩︎
Niccolini F, et al. Dipeptide repeat proteins toxicity in microglia. Acta Neuropathol. 2025. ↩︎
Bhargava P, et al. ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature. Nat Commun. 2025. ↩︎
Harden JL, et al. TREM2 rs535932 association with ALS-FTD. Neurology. 2023. ↩︎