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Proc Natl Acad Sci U S A. 2019 Nov 5;116(45):22710-22720. doi: 10.1073/pnas.1915141116. Epub 2019 Oct 22.

Aged hind-limb clasping experimental autoimmune encephalomyelitis models aspects of the neurodegenerative process seen in multiple sclerosis.

Author information

1
Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON M5T 3H7, Canada.
2
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
3
Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
4
Toronto General Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
5
Institute of Anatomy and Cell Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
6
Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
7
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Shannon.Dunn@unityhealth.to.
8
Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
9
Women's College Research Institute, Women's College Hospital, Toronto, ON M5S 1B2, Canada.

Abstract

Experimental autoimmune encephalomyelitis (EAE) is the most common model of multiple sclerosis (MS). This model has been instrumental in understanding the events that lead to the initiation of central nervous system (CNS) autoimmunity. Though EAE has been an effective screening tool for identifying novel therapies for relapsing-remitting MS, it has proven to be less successful in identifying therapies for progressive forms of this disease. Though axon injury occurs in EAE, it is rapid and acute, making it difficult to intervene for the purpose of evaluating neuroprotective therapies. Here, we describe a variant of spontaneous EAE in the 2D2 T cell receptor transgenic mouse (2D2+ mouse) that presents with hind-limb clasping upon tail suspension and is associated with T cell-mediated inflammation in the posterior spinal cord and spinal nerve roots. Due to the mild nature of clinical signs in this model, we were able to maintain cohorts of mice into middle age. Over 9 mo, these mice exhibited a relapsing-remitting course of hind-limb clasping with the development of progressive motor deficits. Using a combined approach of ex vivo magnetic resonance (MR) imaging and histopathological analysis, we observed neurological progression to associate with spinal cord atrophy, synapse degradation, and neuron loss in the gray matter, as well as ongoing axon injury in the white matter of the spinal cord. These findings suggest that mild EAE coupled with natural aging may be a solution to better modeling the neurodegenerative processes seen in MS.

KEYWORDS:

multiple sclerosis model; neurodegeneration; progressive

PMID:
31641069
PMCID:
PMC6842635
[Available on 2020-04-22]
DOI:
10.1073/pnas.1915141116

Conflict of interest statement

The authors declare no competing interest.

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