NDLI: Antibody-Mediated Oligodendrocyte Remyelination Promotes Axon Health in Progressive Demyelinating Disease

Content Provider	Springer Nature Link
Author	Wootla, Bharath Denic, Aleksandar Watzlawik, Jens O. Warrington, Arthur E. Rodriguez, Moses
Copyright Year	2015
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.
Starting Page	5217
Ending Page	5228
Page Count	12
File Format	PDF
ISSN	08937648
Journal	Molecular Neurobiology
Volume Number	53
Issue Number	8
e-ISSN	15591182
Language	English
Publisher	Springer US
Publisher Date	2015-09-26
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Antibody Remyelination Multiple sclerosis Theiler’s murine encephalomyelitis virus Magnetic resonance spectroscopy N-acetyl-aspartate Brainstem Axons Protection Neurosciences Neurobiology Cell Biology Neurology
Content Type	Text
Resource Type	Article
Subject	Neurology Cellular and Molecular Neuroscience

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Antibody-Mediated Oligodendrocyte Remyelination Promotes Axon Health in Progressive Demyelinating Disease

A single dose of a neuron-binding human monoclonal antibody improves brainstem NAA concentrations, a biomarker for density of spinal cord axons, in a model of progressive multiple sclerosis

A monoclonal natural human IgM protects axons in the absence of remyelination

Anti-CCL2 treatment inhibits Theiler’s murine encephalomyelitis virus-induced demyelinating disease

Depletion of Olig2 in oligodendrocyte progenitor cells infected by Theiler’s murine encephalomyelitis virus

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

Possible role of interleukin-17 in a prime/challenge model of multiple sclerosis

Blockade of sustained tumor necrosis factor in a transgenic model of progressive autoimmune encephalomyelitis limits oligodendrocyte apoptosis and promotes oligodendrocyte maturation

Interferon-stimulated genes—essential antiviral effectors implicated in resistance to Theiler’s virus-induced demyelinating disease

Antibody-Mediated Oligodendrocyte Remyelination Promotes Axon Health in Progressive Demyelinating Disease

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Antibody-Mediated Oligodendrocyte Remyelination Promotes Axon Health in Progressive Demyelinating Disease

A single dose of a neuron-binding human monoclonal antibody improves brainstem NAA concentrations, a biomarker for density of spinal cord axons, in a model of progressive multiple sclerosis

A monoclonal natural human IgM protects axons in the absence of remyelination

Anti-CCL2 treatment inhibits Theiler’s murine encephalomyelitis virus-induced demyelinating disease

Depletion of Olig2 in oligodendrocyte progenitor cells infected by Theiler’s murine encephalomyelitis virus

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

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Blockade of sustained tumor necrosis factor in a transgenic model of progressive autoimmune encephalomyelitis limits oligodendrocyte apoptosis and promotes oligodendrocyte maturation

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Antibody-Mediated Oligodendrocyte Remyelination Promotes Axon Health in Progressive Demyelinating Disease