Abstract
NOD mice represent a unique strain that recapitulates some aspects of progressive MS when subjected to experimental autoimmune encephalomyelitis (EAE). It is unknown, however, whether a proneness to demyelination and/or defect in remyelination contribute to disease progression in NOD mice. Answering to this question might help deciphering the molecular and cellular events underpinning disease evolution in progressive MS. Here, we compared the cuprizone-dependent demyelination and remyelination responses, as well as their functional correlates, in NOD, C57BL/6, and SJL mice typically adopted to model progressive, chronic or relapsing EAE. We report that demyelination occurred to a similar extent in the three mice strains, and that in none of them there was evidence of axonal degeneration during prolonged demyelination. Moreover, immunostaining for GFAP+ astrocytes, Iba1+ microglia, and NG2+ oligodendrocyte precursor cells similarly increased in the 3 mouse strains after cuprizone exposure. The mice underwent concomitant and complete remyelination 2 weeks after cuprizone withdrawal. On a functional level, NOD mice showed the earliest reduction of spontaneous motility and full recovery, but no impairment of motor skill. Conversely, C57BL/6 animals showed phasic reduction of both spontaneous motility and motor skill. Lastly, SJL mice presented the most severe neurological impairment with long-lasting reduction of spontaneous motility and motor skill. Overall, data suggest that the unique feature of EAE progression in NOD mice is not due to proneness to demyelination or intrinsic defects in myelin formation. Findings also unravel important functional differences in the response of the three mouse stains to cuprizone that can be harnessed to design and interpret future experiments.
Highlights
Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system that affects about 2.3 million people worldwide and the leading cause of disability among young individuals (Thompson et al 2018)
Brains were collected after 6 weeks of cuprizone diet (n = 4 per strain), 10 μm thin sections were blocked with 5% normal goat serum (Thermo Fisher Scientific, Waltham, MA, USA) containing 0.3% Triton X-100 (Sigma, Milan, Italy)
We found that 6 weeks after the cuprizone diet immunostaining for glial fibrillary acidic protein (GFAP)+ astrocytes, ionized calcium-binding adapter molecule 1 (Iba1)+ microglia as well as N G2+ OPCs dramatically increased in the corpus callosum of the mice, showing no difference among the strains (Fig. 2)
Summary
Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system that affects about 2.3 million people worldwide and the leading cause of disability among young individuals (Thompson et al 2018). We reported that whereas progression of EAE in NOD mice is insensitive to immune suppression (Buonvicino et al 2019), it can be counteracted by the bioenergetic-boosting drug dexpramipexole (Buonvicino et al 2020) These findings, on the one hand are consistent with the hypothesis that virtual hypoxia, rather than autoimmune processes, contribute to neurodegeneration during disease progression (Trapp and Stys 2009), and on the other strengthen the reliability of EAE in NOD mice as a model of PMS. In these three mouse strains, we the compared the neurological correlates during cuprizone exposure and subsequent withdrawal
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