The cuprizone model and multiple sclerosis : disparities and similarities
Year: 2011
Type: dissertation
Abstract: Multiple sclerosis (MS) is a chronic, inflammatory and demyelinating disorder of the central nervous system. Although demyelination is still a characteristic entity, it has become increasingly apparent in recent years that substantial axonal destruction and neuronal loss are equally important features. The frequent involvement of grey matter structures has received new impetus. Studies on the pathogenesis of grey matter lesions suggest that its underlying disease mechanisms are unique. Less marked microglia activation in grey compared to white matter lesions is obvious but underlying mechanisms are poorly understood. Adequate animal models are a likewise powerful and irreplaceable tool to study disease pathogenesis. In order to serve as a useful model, it should be similar in its aetiology or phenotype. The recognition of the importance of grey matter pathology in MS did lead to the desire for animal models that display grey matter damage. Within the scope of the presented thesis, I characterized the toxic cuprizone model with a special focus on grey matter pathology. This work is not confined to descriptive changes but makes a comparison between the model itself and MS. In recent years the contribution of innate immune cells in mediating MS pathogenesis is being appreciated. We were able to show that histopathological hallmarks of MS are closely mirrored by the cuprizone model. Furthermore, our studies clearly demonstrate that the magnitude of microglia activation is related to the amount of myelin debris during a demyelination event. Thus, the lower inflammatory infiltrate of grey matter lesion is not related to a unique grey matter cytoarchitecture that makes it more resistant to inflammation. Differences in myelination account for observed regional differences. The second part of this thesis deals with one of the most effective repair mechanisms in the central nervous system, i.e. remyelination. A better understanding of the remyelination processes in MS and possible reasons for its failure is required. We created lesions with either robust or impaired endogenous remyelination capacity. Lesions were analyzed for mRNA expression levels by gene-chip arrays. One finding was the predominance of immune and stress response factors in the group of genes which were classified as remyelination-supporting factors. We further demonstrate that lesions with impaired remyelination capacity show weak expression of the radial-glia cell marker brain lipid binding protein (BLBP) whereas expression of this marker protein is high in lesions with marked remyelination. The expression of BLBP in activated astrocytes correlates with the presence of oligodendrocyte progenitor cells. Highest numbers of BLBP-expressing astrocytes were evident in lesions of early MS whereas significantly less are present in tissue samples from patients with long disease duration. Transfection experiments show that BLBP regulates growth factor expression in U87 astrocytoma cells. In conclusion, we provide evidence that expression of BLBP in activated astrocytes orchestrates remyelination.
Source: RWTH Publications (RWTH Aachen)
Authors: Markus Kipp, Werner Baumgärtner
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1023585792