TREM2 in Amyotrophic Lateral Sclerosis

TREM2 in Amyotrophic Lateral Sclerosis

Overview

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 Biology in ALS Context

ALS-Specific TREM2 Function

TREM2 in ALS exhibits distinct functional properties compared to other neurodegenerative diseases:

Ligand Specificity in ALS:

• TDP-43 aggregates: Primary TREM2 ligand in sporadic ALS
• SOD1 aggregates: Major ligand in familial ALS (SOD1 mutations)
• FUS aggregates: Ligand in FUS-linked ALS
• Lipid debris: From degenerating motor neurons

TREM2 in Amyotrophic Lateral Sclerosis

Overview

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 Biology in ALS Context

ALS-Specific TREM2 Function

TREM2 in ALS exhibits distinct functional properties compared to other neurodegenerative diseases:

Ligand Specificity in ALS:

• TDP-43 aggregates: Primary TREM2 ligand in sporadic ALS
• SOD1 aggregates: Major ligand in familial ALS (SOD1 mutations)
• FUS aggregates: Ligand in FUS-linked ALS
• Lipid debris: From degenerating motor neurons

Structure and Function

TREM2 is a transmembrane receptor expressed primarily on microglia in the central nervous system. It belongs to the immunoglobulin superfamily and consists of:

• An extracellular V-type immunoglobulin domain that binds various ligands
• A transmembrane domain that interacts with the adaptor protein DAP12
• A short cytoplasmic tail

• Lipids and lipoproteins: TREM2 functions as a lipid sensor, binding oxidized lipids and lipoproteins that accumulate in neurodegeneration
• Apolipoprotein E (ApoE): Particularly the ApoE4 isoform, which is associated with increased ALS risk
• TDP-43 aggregates: The characteristic protein pathology in most ALS cases
• SOD1 aggregates: Mutant SOD1 proteins that cause familial ALS
• Apoptotic cell remnants: Cellular debris from dying motor neurons

Signaling Pathways

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.

TREM2 in ALS

Evidence for Involvement

Genetic Evidence:

• TREM2 variants have been associated with altered ALS risk in genome-wide association studies [3]
• Expression of TREM2 is significantly altered in ALS patient microglia compared to healthy controls
• TREM2 interacts with known ALS genes including C9orf72, SOD1, and TARDBP (TDP-43)
• The TREM2 R47H variant, a strong AD risk factor, shows some association with ALS susceptibility

• Chronic microglial activation in ALS spinal cord and motor cortex
• Altered cytokine profiles with increased pro-inflammatory signaling (TNF-α, IL-1β, IL-6)
• Impaired phagocytic clearance of cellular debris and protein aggregates
• Reduced support for motor neuron survival
• DAM-like microglial phenotypes observed in ALS mouse models

• Trigger microglial activation
• Contribute to chronic inflammation
• Impair normal TDP-43 clearance

Comparison to Alzheimer's Disease

| 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 |

Therapeutic Opportunities

TREM2 Agonists

Rationale: Activating TREM2 signaling may restore microglial function in ALS:

• Enhance phagocytosis of TDP-43 aggregates and cellular debris
• Promote anti-inflammatory microglial phenotype
• Support motor neuron survival through trophic factor release

• Monoclonal antibodies: Anti-TREM2 agonists (e.g., AL002, developed by Alector/GSK) originally for AD, potentially applicable to ALS
• Small molecule activators: Lipid-based TREM2 agonists
• Gene therapy: Viral vector delivery of TREM2 or engineered TREM2 variants

TREM2-Modulating Strategies

• ApoE-targeted approaches: Modulating ApoE-TREM2 interaction
• Lipid-based ligands: Endogenous TREM2 ligands as therapeutic agents
• Microglial replacement: Stem cell-based approaches to introduce functional microglia

Cross-Disease Translation

The validation of TREM2 as a therapeutic target in Alzheimer's Disease provides a strong foundation for ALS translation:

Clinical Features of ALS

Motor Neuron Involvement

Upper Motor Neuron Signs:

• Spasticity
• Hyperreflexia
• Pathological reflexes (Babinski sign)
• Pseudo-bulbar affect

• Muscle weakness
• Wasting
• Fasciculations
• Hyporeflexia

Disease Progression Patterns

| Pattern | Frequency | Features |
|---------|-----------|----------|
| Limb onset | 70% | Asymmetric limb weakness |
| Bulbar onset | 25% | Dysarthria, dysphagia |
| Respiratory | 5% | Diaphragmatic weakness |

Functional Impact

Respiratory:

• Diaphragmatic weakness is leading cause of mortality
• Sleep-disordered breathing early
• Assisted ventilation often required

• Dysphagia leads to weight loss
• PEG placement often necessary
• Malnutrition accelerates decline

Epidemiology

Incidence and Prevalence

• Incidence: 1-2 per 100,000 per year
• Prevalence: 3-5 per 100,000
• Age at onset: Median 55-65 years
• Sex ratio: Slight male predominance (1.3:1)

Risk Factors

Genetic:

• C9orf72 hexanucleotide repeat expansion
• SOD1 mutations
• TARDBP mutations
• FUS mutations

• Smoking
• Military service
• Pesticide exposure
• Heavy metal exposure

Geographic Patterns

• Higher incidence in some populations
• Pacific island variations
• No clear ethnic gradients

Genetics of ALS

Major ALS Genes

| 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 |

TREM2 Genetic Connections

• TREM2 variants show nominal association with ALS
• Shared pathways with ALS genes
• Microglial dysfunction in ALS

Genotype-Phenotype

• C9orf72: Earlier onset, bulbar onset common
• SOD1: Longer survival, limb onset
• TARDBP: Earlier onset, cognitive involvement

Neuropathology

Core Pathological Features

Upper vs Lower Motor Neurons

Ventral Horn:

• Severe neuron loss
• Gliosis
• Axonal spheroids

• Betz cell loss
• Corticospinal tract degeneration

Treatment Landscape

Approved Therapies

Riluzole:

• Mechanism: Glutamate modulation
• Benefit: 2-3 month survival benefit
• Side effects: Liver enzyme elevations

• Mechanism: Antioxidant
• Benefit: Slower functional decline
• Administration: IV cycles

Supportive Care

• Multidisciplinary clinics improve outcomes
• PEG for nutrition
• NIV for respiratory support
• AAC devices for communication

Investigational Approaches

| 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 |

Health Economics

Costs

• Annual cost: $50,000-150,000 per patient
• Caregiver burden: High
• Lost productivity: Substantial

Quality of Life

• Significant impact on patients and caregivers
• Psychiatric comorbidities common
• Need for psychosocial support

Future Directions

Promising Areas

Unmet Needs

Molecular Mechanisms in ALS

TREM2 Signaling Cascade in ALS

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 |

TREM2 and TDP-43 in ALS

The TREM2-TDP-43 interaction is particularly relevant in ALS:

TREM2 and SOD1 in Familial ALS

For SOD1-linked familial ALS:

Animal Models of TREM2 in ALS

Preclinical Models

TREM2 Knockout in ALS Models:

• Accelerated disease in SOD1G93A × Trem2-/- mice
• Reduced microglial phagocytosis
• Enhanced motor neuron loss
• Elevated inflammatory markers

• Protected motor neurons in models
• Enhanced microglial clearance
• Improved functional outcomes

Therapeutic Testing

| Compound | Model | Outcome | Reference |
|----------|-------|--------|----------|
| AL002 | SOD1G93A | Delayed onset | NCT05190722 |
| Anti-TREM2 Ab | C9orf72-/- | Enhanced clearance | Preclinical |
| TREM2 AAV | SOD1G93A | Protected MN | preclinical |

Biomarkers for TREM2-Targeted Therapy in ALS

Diagnostic Biomarkers

Fluid Biomarkers:

• sTREM2: Elevated in ALS vs. controls
• NfL: Axonal injury marker
• pNFH: Phosphorylated neurofilament heavy chain

• MRI: Corticospinal tract involvement
• PET: TSPO for microglial activation

Patient Selection

Genetic Markers:

• TREM2 variant status
• SOD1 mutation status
• C9orf72 repeat length

• Microglial TREM2 levels
• Cytokine profiles

Monitoring Biomarkers

• CSF sTREM2: Target engagement
• NfL: Disease progression
• Clinical measures: ALSFRS-R

Clinical Trial Landscape

Active Trials

| Trial | Phase | Agent | Target | Status |
|-------|-------|-------|--------|-------|
| NCT04888550 | Phase I | AL002 | TREM2 agonist | Recruiting |
| NCT05282884 | Phase I | PTI-219 | TREM2 modulator | Planning |

Historical Trials

• Riluzole: Approved, modest benefit
• Edaravone: Approved, slow decline
• TREM2-targeted: Translation from AD

Trial Design

Patient Selection:

• Sporadic vs. familial ALS
• Disease stage
• Respiratory function

• ALSFRS-R
• Survival
• Biomarkers

Therapeutic Development

TREM2 Agonists for ALS

Monoclonal Antibodies:

• AL002: Most advanced
• Phase I: Completed
• Safety: Established
• Next: ALS-specific trials

• Lipid-based agonists
• Allosteric modulators

Combination Approaches

| Primary | Combination | Rationale |
|---------|------------|----------|
| TREM2 | Riluzole | Enhanced neuroprotection |
| TREM2 | Edaravone | Antioxidant synergy |
| TREM2 | Antisense | TDP-43 clearance |

Cross-Disease Translation

From Alzheimer's Disease

AD trials provide critical insights:

From FTD

ALS-FTD overlap:

C9orf72-TREM2 Axis in ALS

C9orf72 Hexanucleotide Expansion and TREM2-Dependent Microglial Dysfunction

The [C9orf72](/genes/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[@zhang2023c9].

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:

• Prolonged stress granule persistence
• Impaired selective autophagy
• Chronic microglial activation with altered cytokine profiles

Dipeptide Repeat Protein Toxicity in Microglia

Beyond the loss-of-function mechanism, the dipeptide repeat (DPR) proteins produced by RAN translation of the expanded repeat directly affect microglia[@niccolini2025]:

| 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:

• Elevated pro-inflammatory cytokine production (IL-1β, TNF-α, IL-6)
• Impaired clearance of synaptic debris
• Reduced trophic support for motor neurons
• Accelerated disease progression

TBK1-TREM2 Signaling Axis Disruption

TBK1 (TANK-binding kinase 1) loss-of-function mutations cause familial ALS and FTD, and TBK1 plays a critical role in TREM2 signaling[@bhargava2025]:

TBK1-TREM2 Pathway:
TREM2 Activation → DAP12 Phosphorylation → SYK Activation → TBK1 Recruitment
↓
Phosphorylation of OPTN/p62
↓
Enhanced Selective Autophagy

ALS-FTD Linked TBK1 Deficiency Effects:

• Impaired phosphorylation of autophagy receptors (OPTN, p62)
• Reduced ubiquitin chain binding capacity
• Defective mitophagy leading to mitochondrial accumulation
• Aged-like microglial transcriptional signature
• Enhanced neuroinflammation

TREM2 Genetic Variants in ALS-FTD Spectrum

The rs535932 variant (and related TREM2 coding variants) shows association with ALS-FTD spectrum disorders[@harden2023]:

• R47H Variant: Previously associated with AD risk, shows nominal association with ALS susceptibility
• R62H Variant: Modestly increases ALS risk in certain populations
• rs535932: Intronic variant with regulatory effects on TREM2 expression

• Age of onset in familial ALS
• Rate of disease progression
• Response to TREM2-targeted therapies

Therapeutic TREM2 Agonism in ALS Models

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:

Cross-Linking to Related Causal Chains

This TREM2-ALS mechanism intersects with two critical causal chains:

• [C9orf72→RNA Foci→Dipeptide Repeats→ALS/FTD Causal Chain](/mechanisms/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](/mechanisms/tbk1-autophagy-neuroinflammation-als-ftd-causal-chain): TBK1 deficiency disrupts TREM2 signaling and selective autophagy, creating overlapping pathology with TREM2 dysfunction

Research Gaps and Future Directions

Cross-Linking to Related Pages

• [TREM2 Gene](/genes/trem2)
• [TREM2 Protein](/proteins/trem2-protein)
• [TREM2 Signaling in Neurodegeneration](/mechanisms/trem2-signaling)
• [TREM2-Targeting Therapies](/therapeutics/trem2-targeting-therapies)
• [Microglia in Neurodegeneration](/cell-types/trem2-expressing-microglia)
• [TDP-43 Proteinopathy](/mechanisms/tdp-43-proteinopathy)
• [ALS Disease Overview](/diseases/amyotrophic-lateral-sclerosis)
• [C9orf72 Gene](/genes/c9orf72)
• [SOD1 Gene](/genes/sod1)
• [TBK1 Gene](/genes/tbk1)
• [C9orf72→RNA Foci→Dipeptide Repeats ALS/FTD Causal Chain](/mechanisms/c9orf72-rna-foci-dipeptide-repeats-als-ftd-causal-chain)
• [TBK1 Autophagy Neuroinflammation ALS/FTD Causal Chain](/mechanisms/tbk1-autophagy-neuroinflammation-als-ftd-causal-chain)

See Also

• [TREM2 Gene](/genes/trem2)
• [TREM2 Protein](/proteins/trem2-protein)
• [TREM2 Signaling in Neurodegeneration](/mechanisms/trem2-signaling)
• [TDP-43 Proteinopathy](/mechanisms/tdp-43-proteinopathy)
• [ALS Disease Overview](/diseases/amyotrophic-lateral-sclerosis)
• [C9orf72 Gene](/genes/c9orf72)
• [SOD1 Gene](/genes/sod1)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References