Chronic cortical pathology in multiple sclerosis : molecular studies on normal-appearing and demyelinated cortex and a novel animal model for chronic inflammatory demyelination

The chronic cortical pathology of multiple sclerosis (MS) composes of demyelination and neurodegeneration and has been studied since the early pathoanatomical descriptions of MS. Due to the technical difficulties in detecting the extent of cortical damage accumulating during the disease process it has only been recognized as a major aspect of MS pathology 20 years ago. The presented thesis comprises of three studies investigating the chronic cortical pathology of MS.
The first study describes gene expression changes between cortex from control cases and MS normal-appearing cortical grey matter without apparent signs of cortical pathology, id est no demyelination, inflammation or cell loss. HLA-DRB1 was detected as differentially upregulated within the MS cerebral cortex. This upregulation appeared in a bimodal distribution pattern, with its expression being either high or low within each case. Genotyping revealed that all carriers of the major MS risk allele HLA-DRB1*15:01 belonged to the high expressing group, irrespective of whether they had MS or were control cases. Immunofluorescent-colocalization revealed the expression of HLA-DRB1 by microglia within MS and control cases. The higher gene expression of HLA-DRB1 further associated with higher protein expression of HLA-DRB1 and with the extent of cortical demyelination, effectively demonstrating a link between the strongest genetic risk factor, ribonucleic acid and protein expression of HLA-DRB1 and cortical demyelination.
The second study describes gene expression changes between MS demyelinated cortical grey matter lesions and normal-appearing grey matter. Gene set enrichment analysis revealed a cluster of olfactory receptors to be differentially higher expressed within the lesions. Immunofluorescent-colocalization of three selected olfactory receptors revealed one to be expressed on neurons (OR5P2), another to be expressed on neurons and blood vessels (OR52I1/OR52I2) and a third one to be expressed on blood vessels (OR9K2). Closer investigation of the expression pattern revealed a higher number of neurons to be positive for the respective receptor in the area of the demyelinated lesion, whereas the blood vessels showed a higher number of positive vessels for the respective receptor throughout the cortex. Olfactory receptors have previously been shown to be differentially regulated in other neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, Creutzfeldt-Jakob disease and chronic schizophrenia, possibly linking MS chronic cortical pathology to more general mechanisms of neurodegenerative diseases.
The third study aimed to establish and investigate a novel animal model to study the effects of chronic cortical demyelination and meningeal inflammation. For this, rats were immunized-against myelin-oligodendrocyte glycoprotein and injected with lentiviruses overexpressing tumor necrosis factor alpha and interferon gamma, simulating the release of these cytokines in follicles located in the meninges and associated with cortical grey matter lesions in MS. The animals developed demyelination and meningeal inflammation stable for at least ten weeks and showed neuronal and oligodendrocyte loss, blood-brain barrier leakage and signs of remyelination, efficiently reproducing MS grey matter lesion phenotypes. This model will be of interest to study chronic adaptations of cortical grey matter to meningeal inflammation and demyelination as seen in MS.
In summary, this thesis gives novel insights into molecular changes within normal-appearing cortex and cortical grey matter lesions in MS, and describes a novel animal model to study chronic cortical changes caused by demyelination and meningeal inflammation.