CCL2-CCR2 Driven Macrophage Infiltration Selectively Strips Fast-Fatigable NMJs via MMP-9 in ALS

CCL2 ALS market 51% open
Composite
68%
Novelty
78%
Feasibility
68%
Impact
82%
Mechanistic
80%
Druggability
—
Safety
—
Confidence
42%

Mechanistic description

CCR2+ monocyte-derived macrophages, recruited to the neuromuscular junction by motor neuron-secreted CCL2, selectively infiltrate and strip fast-fatigable (IIb/IIx fibre) NMJs via matrix metalloproteinase-9 (MMP-9) cleavage of the laminin alpha-5/beta-2 NMJ scaffold. Fast motor neurons express higher CCL2 and lower TIMP-1 (MMP-9 inhibitor) than slow motor units, creating a chemokine gradient that explains selective NMJ vulnerability. Genetic or pharmacological MMP-9 blockade should preferentially protect fast-fatigable NMJs in ALS mouse models.

Evidence for (5)

  • MCP1-CCR2 and neuroinflammation in the ALS motor cortex with TDP-43 pathology.

    PMID:31666087 2019 J Neuroinflammation

  • The CCL2-CCR2 axis drives neuromuscular denervation in amyotrophic lateral sclerosis.

    PMID:40750607 2025 Nat Commun

  • Vascular endothelial growth factor-A (VEGF-A) and chemokine ligand-2 (CCL2) in amyotrophic lateral sclerosis (ALS) patients.

    PMID:21569455 2011 J Neuroinflammation

  • CCR2 is localized in microglia and neurons, as well as infiltrating monocytes, in the lumbar spinal cord of ALS mice.

    PMID:32349774 2020 Mol Brain

  • Possible association between expression of chemokine receptor-2 (CCR2) and amyotrophic lateral sclerosis (ALS) patients of North India.

    PMID:22685564 2012 PLoS One

Evidence against (2)