Delayed Demyelination and Impaired Remyelination in Aged Mice in the Cuprizone Model.

Stefan Gingele,Thomas Skripuletz,Sandra Heckers,Florian Henkel,Viktoria Gudi,Martin Stangel,Thiemo M Moellenkamp,Martin W Hümmert

doi:10.3390/cells9040945

Abstract

To unravel the failure of remyelination in multiple sclerosis (MS) and to test promising remyelinating treatments, suitable animal models like the well-established cuprizone model are required. However, this model is only standardized in young mice. This does not represent the typical age of MS patients. Furthermore, remyelination is very fast in young mice, hindering the examination of effects of remyelination-promoting agents. Thus, there is the need for a better animal model to study remyelination. We therefore aimed to establish the cuprizone model in aged mice. 6-month-old C57BL6 mice were fed with different concentrations of cuprizone (0.2–0.6%) for 5–6.5 weeks. De- and remyelination in the medial and lateral parts of the corpus callosum were analyzed by immunohistochemistry. Feeding aged mice 0.4% cuprizone for 6.5 weeks resulted in the best and most reliable administration scheme with virtually complete demyelination of the corpus callosum. This was accompanied by a strong accumulation of microglia and near absolute loss of mature oligodendrocytes. Subsequent remyelination was initially robust but remained incomplete. The remyelination process in mature adult mice better represents the age of MS patients and offers a better model for the examination of regenerative therapies.

Highlights

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS).Destruction and loss of oligodendrocytes resulting in demyelination represent the pathological core characteristics of multiple sclerosis (MS) [1]
Usually young mice are fed with the copper chelator cuprizone which leads to highly reproducible oligodendrocyte apoptosis followed by demyelination
0.2% cuprizone did not lead to significant demyelination (Figure 1 and Figure S2)

Summary

Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS).Destruction and loss of oligodendrocytes resulting in demyelination represent the pathological core characteristics of MS [1]. Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Remyelination is a naturally occurring and highly effective repair mechanism after demyelination that can restore rapid axonal conduction velocity [2] and lead to functional recovery and neuroprotection [3,4,5]. It was suggested that remyelination might prevent axonal injury and chronic clinical disability [6,7]. Remyelination varies considerably between individual patients and lesion location and is often incomplete or fails, in chronic MS lesions [8,9]. Usually young mice are fed with the copper chelator cuprizone (bis-cyclohexanone oxaldihydrazone) which leads to highly reproducible oligodendrocyte apoptosis followed by demyelination. C57BL6 mice aged 8–10 weeks are fed a diet containing

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