Cuprizone Intoxication Results in Myelin Vacuole Formation.

Sarah Joost,Markus Kipp,Friederike Pfeiffer,Marcus Frank,Felix Schweiger,Carolin Ertl,Jonas Keiler

doi:10.3389/fncel.2022.709596

Abstract

Myelin damage is a histopathological hallmark of multiple sclerosis lesions. Results of post mortem studies suggest that impaired myelin-axon interaction characterized by focal myelin detachments is an early event during lesion genesis. In this study, we investigated the ultrastructural changes of the axon-myelin interface in the cuprizone model using serial block face scanning electron microscopy and immunohistochemistry. We show that non-inflammatory injury of oligodendrocytes by cuprizone intoxication results in myelin vacuole formation and axonal swellings, paralleled by early alterations of the node of Ranvier cytoarchitecture. This remarkable resemblance of ultrastructural myelin characteristics in multiple sclerosis and the cuprizone animal model suggests that the cuprizone model is a valuable tool to study early pathologies during lesion formation.

Highlights

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), leading to irreversible neuronal damage and, in consequence, clinical disability
To investigate whether demyelination was paralleled by functional deficits, electrically evoked Compound action potentials (CAPs) were recorded across the corpus callosum in control and 3 weeks cuprizone-intoxicated mice
We found a shift of the frequency of the affected axons toward smaller axonal diameters (Figure 2I, lower diagram, a significant difference was found using Kolmogorov–Smirnov testing to compare cumulative distributions, p = 0.0121), suggesting that not big-caliber but small-caliber axons are preferentially affected by the myelin detachments in this model

Summary

Introduction

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), leading to irreversible neuronal damage and, in consequence, clinical disability. On the histopathological level, such lesions are characterized by peripheral immune cell recruitment, destruction of oligodendrocytes and the myelin sheaths, glia cell activation (microglia and astrocytes) as well as acute axonal injury (Kipp et al, 2012). The histopathological hallmark which distinguishes MS from other CNS disorders is the formation of large confluent plaques of primary demyelination. For this reason, any concept of MS pathogenesis has to provide an explanation for this highly specific destruction of the oligodendrocyte-myelin-axonal unit. Oligodendrocytes provide nutritional support to neurons (Funfschilling et al, 2012), fast axonal transport depends on oligodendrocytes (Edgar et al, 2004), and mice deficient for mature myelin proteins display severe neurodegeneration (Uschkureit et al, 2000)

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