Region specific characterization of the cuprizone model for Multiple Sclerosis and impairment of remyelination by corticosteroids
Year: 2011
Type: dissertation
Abstract: Multiple sclerosis is a widespread demyelinating disease where primary oligodendrocyte dysfunction represents a possible underlying mechanism of myelin loss. Cuprizone intoxication which causes primary oligodendrocyte apoptosis, mimics some aspects of this disease. In the first part of my thesis, the extent and pattern of demyelination in this MS animal model was analyzed. Additionally, the innate immune responses to the cuprizone challenge were investigated. Our results regarding the cerebellum were included in this thesis, and the different pattern of demyelination in the basal ganglia, hippocampus, and cerebellum was highlighted. Striking differences were found in the magnitude of demyelination between different white and grey matter areas. Distinct cerebellar white matter regions, the cerebellar cortical grey matter, the medial basal ganglia, and the hippocampal fimbria were resistant to the cuprizone challenge. In contrast, other regions displayed severe myelin loss and activation of microglia and astroglia. We discuss the advantages and limitations of this model with regard to regional differences and “protection”. In the second part of this work, we used the cuprizone model to investigate the impact of corticosteroid (CS) treatment on spontaneously remyelinating lesions and addressed the underlying mechanisms by several in vitro and in vivo approaches. We are able to demonstrate that while CS-treatment accelerates the differentiation of oligodendrocyte progenitors in vitro, it impairs endogenous remyelination in vivo. We additionally identified CS-induced changes in the growth factor expression profile of cultured astrocytes that might explain the impairment of repair processes in the brain. The importance of astrocytes for early and late repair processes was further highlighted by our finding that astrocytosis but not microgliosis persists after an acute demyelinating event. Our data clearly show that promotion of the intrinsic oligodendroyte differentiation program might negatively affect myelin repair in vivo. We speculate that CS treatment induces a preterm oligodendrocytes differentiation and, thus, might impair endogenous remyelination cascades. Furthermore, beneficial steroidal effects during inflammation have to be balaced against possible remyelination-inhibiting effects. In the third part of the presented thesis, we focused on astrocyte’s response during an acute demyelinating event. The amyloid precursor protein (APP) which is well known to be expressed in activated astroglia, microglia and stressed neurons in several disease models, was in the focus of the study. We found that the expression of APP is strongly induced during acute cuprizone-induced demyelination. Exclusively astrocytes express APP during cuprizone-induced demyelination. Our in vitro experiments using primary astrocyte cultures indicate that this is a highly specific response to toxic demyelination. The cuprizone model, therefore, is a suitable tool to study the role of astrocyte derived APP in a MS animal model. The results of my thesis significantly broaden the knowledge regarding the potential of the cuprizone model as a tool for studying underlying mechanisms of de- and remyelination.
Source: RWTH Publications (RWTH Aachen)
Authors: Tim Clarner, Cordian Beyer
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2610189326