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

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...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 45; pp. 22710 - 22720
Main Authors:	Cahill, Lindsay S., Zhang, Monan Angela, Ramaglia, Valeria, Whetstone, Heather, Sabbagh, Melika Pahlevan, Yi, Tae Joon, Woo, Laura, Przybycien, Thomas S., Moshkova, Marina, Zhao, Fei Linda, Rojas, Olga L., Gomes, Josephine, Kuerten, Stefanie, Gommerman, Jennifer L., Sled, John G., Dunn, Shannon E.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 05-11-2019
Subjects:	Aging Aging (natural) Aging - immunology Animals Atrophy Autoimmunity Biological Sciences Central nervous system Encephalomyelitis, Autoimmune, Experimental - immunology Experimental allergic encephalomyelitis Gray Matter - pathology Hindlimb Lymphocytes Lymphocytes T Magnetic resonance imaging Mice Mice, Inbred C57BL Mice, Transgenic Multiple sclerosis Multiple Sclerosis - immunology Multiple Sclerosis - pathology Neuroprotection PPAR alpha - genetics Spinal cord Spinal cord injuries Spinal nerves Substantia alba Substantia grisea T cell receptors Transgenic mice White Matter - pathology neurodegeneration progressive multiple sclerosis model
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 1L.S.C. and M.A.Z. contributed equally to this work. Author contributions: L.S.C., V.R., O.L.R., J.L.G., J.G.S., and S.E.D. designed research; L.S.C., M.A.Z., V.R., H.W., M.P.S., T.J.Y., L.W., T.S.P., M.M., F.L.Z., O.L.R., J.G., and S.E.D. performed research; J.G.S. contributed new reagents/analytic tools; L.S.C., M.A.Z., V.R., T.J.Y., L.W., S.K., and S.E.D. analyzed data; and L.S.C., T.J.Y., J.L.G., and S.E.D. wrote the paper. Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved October 3, 2019 (received for review August 30, 2019)
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1915141116