Modulation of the wnt/beta-Catenin signalling pathway to promote remyelination as therapeutic strategy in MS

• Applicant: Professorin Dr. Tanja Kuhlmann
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 256830997

Multiple sclerosis (MS) is the most frequent demyelinating disease in the central nervous system and a leading cause for clinical disability in young adults. The histopathological hallmarks of MS are inflammatory demyelinating lesions. Inflammation and permanent demyelination contribute to axonal damage and loss, the cause for the progressive neurological deficit observed in MS patients. Only aggressive ablation of the immune system is able to stop disease progression; however these treatment regimens are associated with severe side effects. Promotion of remyelination combined with immunomodulatory drugs represents an attractive treatment strategy to prevent disease progression and even improve clinical symptoms. Remyelination does occur in MS lesions; however maturation of oligodendroglial precursor cells (OPCs) to myelinating oligodendrocytes is often impaired, limiting remyelination especially in chronic MS lesions. One pathway implicated in impaired oligodendroglial differentiation and remyelination in MS is the wnt/beta-catenin signaling pathway. Our preliminary data demonstrate that indometacin, an non-steroidal anti-inflammatory drug as well as ICG001, a small molecule promote oligodendroglial differentiation in vitro; furthermore indometacin accelerates remyelination in a demyelinating animal model. Indometacin increases phosphorylation of beta-catenin and inhibition of GSK3beta abrogates increased oligodendroglial differentiation induced by indometacin. Based on these results we hypothesize that the remyelination promoting effects of indometacin are at least partly mediated by inhibition of the wnt/beta-catenin signaling pathway. Aim of the application is to determine whether indometacin and ICG001 represent potential drugs to promote remyelination in MS. Therefore we will a) further dissect the pathways by which the effects of indometacin and ICG001 mediate increased differentiation of oligodendrocytes, b) determine whether indometacin and ICG001 are able to promote remyelination also in an inflammatory demyelinating animal model and c) characterize the expression patterns of the wnt/beta-catenin pathway in early and chronic MS lesions with and without remyelination.

• DFG Programme: Research Grants