S100B IN CENTRAL NERVOUS SYSTEM DEMYELINATION AND REMYELINATION: LOOKING AT CYTOSKELETON

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Deciphering the involvement of S100B-rage axis in imflammation-associated myelin damage

Publication . Santos, Gisela Filipa Assunção, 1988-; Borralho, Adelaide Maria Afonso Fernandes; Brites, Dora, 1951-

Oligodendrocytes (OL) are responsible for the production of the myelin sheath involving the neuronal axons, providing nutritional support and fastening the transmission of electrical signals. Oligodendrogenesis impairment or myelin damage, either during neurodevelopment or later in life, may result in impaired brain functions leading to cognitive and/or motor deficits. Increased levels of S100B have been described in several conditions associated with both OL and myelin damage, being associated with a poorer disease prognosis. Moreover, S100B toxic effects have been mainly correlated with engagement of its receptor for advanced glycation end-products (RAGE), which is also highly expressed under these conditions. Thus, the major goal of this thesis was to decipher the involvement of the S100B-RAGE axis in the inflammatory-associated myelin damage, both during neurodevelopmental white matter damage, and upon demyelinating disorders. First, we showed that excessive S100B levels impaired oligodendrogenesis, either in primary cultures of OL, or in maturating organotypic cultures of cerebellar slices. Indeed, high S100B levels impaired OL differentiation and promoted morphological maturation arrest in pure cultures that was corroborated by deficient myelination in cerebellar slices. Additionally, S100B also compromised neuronal and synaptic integrity, while inducing astrogliosis, nuclear factor (NF)-kB activation and inflammation. Interestingly, the use of the RAGE antagonist FPS-ZM1 prevented S100B effects, indicating that RAGE engagement is necessary for this S100B detrimental role during neurodevelopment. We next observed that demyelination of mature organotypic cultures of cerebellar slices with lysophosphatidylcholine (LPC) markedly enhanced the expression of S100B and RAGE. In parallel, there was an elevation of markers of immature oligodendrocytes, compromised neuronal networks, and a marked gliosis with augmented inflammatory response also via NF-kB induction. Once again the use of the RAGE antagonist FPS-ZM1 prevented LPC effects, suggesting that S100B-RAGE axis have as well an injurious action during demyelination. Finally, we observed that the S100B-RAGE axis was highly expressed in the in vivo animal model of multiple sclerosis, the experimental autoimmune encephalomyelitis. These animals, besides showing a chronic elevated clinical score also displayed a great loss of myelin, downregulation of OL and synaptic specific markers, in addition to a potentiated expression of proinflammatory cytokines and inhibition of anti-inflammatory response. Interestingly, when the animals where treated with dimethyl fumarate (DMF), a drug used in clinical practice for multiple sclerosis treatment, although no changes were observed in their clinical score, there was a mild improvement in their cognitive performance. In addition, we observed a marked improvement in myelination, a restoration of oligodendrocyte and synaptic markers, as well as a reduction of inflammation, including a decreased expression of S100B and RAGE. Our studies imply a toxic role of S100B-RAGE axis in oligodendrogenesis, either during myelin formation, or following demyelination, along with impaired neuronal and synaptic integrity, glia activation and establishment of an inflammatory milieu. Most importantly, this work supports that S100B-RAGE interaction may constitute a new and more specific target for therapeutic intervention strategies to reduce brain injury associated with inflammation-associated myelin diseases.

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Fundação para a Ciência e a Tecnologia

Número da atribuição

SFRH/BD/91437/2012