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Antibody-mediated oligodendrocyte remyelination protects axons and restores axonal transport in progressive demyelinating disease

      Background: The precise mechanisms by which axonal injury occurs in multiple sclerosis are unclear; one hypothesis is absence or failure of remyelination, suggesting that promoting remyelination may protect axons from death.
      Objective: The objective of the present work is to investigate whether promoting remyelination protects axons and restores transport function.
      Methods: Remyelination was induced in Theiler's virus-infected SJL/J mice using an oligodendrocyte/myelin-specific recombinant human monoclonal IgM, rHIgM22. As an indirect measure of spinal cord integrity, brainstem magnetic resonance spectroscopy was performed across treatment groups. At the completion of the experiment, spinal cord morphology (inflammation, demyelination, remyelination and mid-thoracic axon density) was assessed in detail. Retrograde labeling studies were performed on the spinal cord to provide direct evidence that remyelination protected axons.
      Results: Brainstem N-acetyl aspartate concentrations were increased at 5 weeks post-treatment with rHIgM22, which remained stable out to 10 weeks. Spinal cord morphology studies revealed enhanced remyelination in the rHIgM22-treated group compared to isotype control antibody- or saline-treated groups. Importantly, rHIgM22-mediated remyelination appeared to protect small- and medium-caliber mid-thoracic spinal cord axons from damage despite similar demyelination and inflammation across experimental groups. The most direct confirmation of remyelination-mediated protection of descending neurons was an improvement in retrograde labeling. Treatment with rHIgM22 significantly increased the number of retrograde labeled neurons in the brainstem, indicating that preserved axons are functionally competent.
      Conclusion: Our work provides direct evidence that remyelination preserves spinal cord axons, and protects molecular axon trafficking in a chronic murine demyelination model of human multiple sclerosis.