title: Antibody-Mediated Oligodendrocyte Remyelination Promotes Axon Health in Progressive Demyelinating Disease.
abstract: Demyelination underlies early neurological symptoms in multiple sclerosis (MS); however, axonal damage is considered critical for permanent chronic deficits. The precise mechanisms by which axonal injury occurs in MS are unclear; one hypothesis is the absence or failure of remyelination, suggesting that promoting remyelination may protect axons from death. This report provides direct evidence that promoting oligodendrocyte remyelination protects axons and maintains transport function. Persistent Theiler's virus infection of Swiss Jim Lambert (SJL)/J mice was used as a model of MS to assess the effects of remyelination on axonal injury following demyelination in the spinal cord. Remyelination was induced using an oligodendrocyte/myelin-specific recombinant human monoclonal IgM, rHIgM22. The antibody is endowed with strong anti-apoptotic and pro-proliferative effects on oligodendrocyte progenitor cells. We used (1)H-magnetic resonance spectroscopy (MRS) at the brainstem to measure N-acetyl-aspartate (NAA) as a surrogate of neuronal health and spinal cord integrity. We found increased brainstem NAA concentrations at 5 weeks post-treatment with rHIgM22, which remained stable out to 10 weeks. Detailed spinal cord morphology studies revealed enhanced remyelination in the rHIgM22-treated group but not in the isotype control antibody- or saline-treated groups. Importantly, we found rHIgM22-mediated remyelination protected small- and medium-caliber mid-thoracic spinal cord axons from damage despite similar demyelination and inflammation across all experimental groups. The most direct confirmation of remyelination-mediated protection of descending neurons was an improvement in retrograde transport. Treatment with rHIgM22 significantly increased the number of retrograde-labeled neurons in the brainstem, indicating that preserved axons are functionally competent. This is direct validation that remyelination preserves spinal cord axons and protects functional axon integrity.
authors.affiliation: Departments of Neurology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA.|Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.|Center for Regenerative Medicine, Neuroregeneration, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Bharath
authors.initials: B
authors.lastname: Wootla
authors.affiliation: Departments of Neurology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA.|Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Denic
authors.affiliation: Departments of Neurology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA.|Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.|Center for Regenerative Medicine, Neuroregeneration, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Jens O
authors.initials: JO
authors.lastname: Watzlawik
authors.affiliation: Departments of Neurology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA.|Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Warrington
authors.affiliation: Departments of Neurology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA. Rodriguez.Moses@mayo.edu.|Departments of Immunology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA. Rodriguez.Moses@mayo.edu.|Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. Rodriguez.Moses@mayo.edu.
authors.forename: Moses
authors.identifier: 0000-0001-6328-6497
authors.initials: M
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology; D018188:Cardiovirus Infections / Q000473:pathology / Q000821:virology; D003711:Demyelinating Diseases / Q000473:pathology*; D051379:Mice; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D000074586:Remyelination / Q000187:drug effects*; D013116:Spinal Cord / Q000473:pathology; D017945:Theilovirus / Q000187:drug effects / Q000502:physiology
chemical_list: D000906:Antibodies; D001224:Aspartic Acid; C000179:N-acetylaspartate
keywords: Antibody; Axons; Brainstem; Magnetic resonance spectroscopy; Multiple sclerosis; N-acetyl-aspartate; Protection; Remyelination; Theiler’s murine encephalomyelitis virus