Modulation of bone morphogenic protein signalling alters demyelination and myelin repair in the corpus callosum of adult mice

© 2012 Dr. Jennifer Kristin SaboMultiple Sclerosis (MS) is the most common progressive neurodegenerative disease of young adults. A key pathological event in MS is oligodendrocyte apoptosis, which leads to axons losing their myelin sheaths throughout the central nervous system (CNS). Therefore, enhancement of oligodendrocyte regeneration by endogenous progenitor cells is a promising strategy for remyelination. Bone morphogenic proteins (BMPs) are a family of growth factors which have been shown to inhibit oligodendrocyte production in the healthy CNS. This thesis describes the role for BMP signalling in demyelination and remyelination in the adult brain. Firstly, the cellular changes in the subventricular zone (SVZ) are examined during cuprizone-induced demyelination and in response to BMP signalling modulation. BMP signalling is active in the SVZ during demyelination, and infusion of the BMP4 antagonist, Noggin, decreased the number of astrocytes and increased the number of oligodendroglial cells. Work from this thesis has also identified that BMP signalling is active in the demyelinated corpus callosum. BMP4 infusion increased oligodendrocyte progenitor cell (OPC) numbers in the demyelinated corpus callosum, while infusion of Noggin increased numbers of mature oligodendrocytes and remyelinated axons following recovery from cuprizone challenge. Furthermore, sequential infusions of BMP4 and Noggin or BMP4 and insulin-like growth factor-1 (IGF-1) were performed during demyelination to determine whether myelin repair could be further enhanced by delivery of BMP4, to increase the pool of OPCs, followed by Noggin or IGF-1 to increase either differentiation or survival of the OPCs. Sequential delivery of BMP4 and Noggin or IGF-1 does not further enhance myelin repair above what occurs with Noggin infusion alone. The results in this thesis indicate an important role for BMP signalling in modulating oligodendrogliogenesis and remyelination. The research described here has identified BMPs as potential therapeutic targets to enhance myelin repair in MS