S100B as a Potential Biomarker and Therapeutic Target in Multiple Sclerosis Andreia Barateiro 1 & Vera Afonso 1 & Gisela Santos 1 & João José Cerqueira 2,3 & Dora Brites 1,4 & Jack van Horssen 5 & Adelaide Fernandes 1,4 Received: 19 February 2015 /Accepted: 1 July 2015 # Springer Science+Business Media New York 2015 Abstract Multiple sclerosis (MS) pathology is characterized by neuroinflammation and demyelination. Recently, the inflammatory molecule S100B was identified in cerebrospinal fluid (CSF) and serum of MS patients. Although seen as an astrogliosis marker, lower/physiological levels of S100B are involved in oligodendrocyte differentiation/maturation. Nevertheless, increased S100B levels released upon injury may induce glial reactivity and oligodendrocyte demise, exacerbating tissue damage during an MS episode or delaying the following remyelination. Here, we aimed to unravel the functional role of S100B in the pathogenesis of MS. Elevated S100B levels were detected in the CSF of relapsing-remitting MS patients at diagnosis. Active demyelinating MS lesions showed increased expression of S100B and its receptor, the receptor for advanced glycation end products (RAGE), in the lesion area, while chronic active lesions displayed increased S100B in demyelinated areas with lower expression of RAGE in the rim. Interestingly, reactive astrocytes were identified as the predominant cellular source of S100B, whereas RAGE was expressed by activated microglia/macrophages. Using an ex vivo demyelinating model, cerebral organotypic slice cultures treated with lysophosphatidylcholine (LPC), we observed a marked elevation of S100B upon demyelination, which co-localized mostly with astrocytes. Inhibition of S100B action using a directed antibody reduced LPC-induced demyelination, prevented astrocyte reactivity and abrogated the expression of inflammatory and inflammasome-related molecules. Overall, high S100B expression in MS patient samples suggests its usefulness as a diagnostic biomarker for MS, while the beneficial outcome of its inhibition in our demyelinating model indicates S100B as an emerging therapeutic target in MS. Keywords Cerebellar organotypic slice cultures . Demyelination . Glial inflammatory response . Human samples . Multiple sclerosis . S100B Introduction Multiple sclerosis (MS) is a primary inflammatory demyelinat- ing autoimmune disorder of the central nervous system (CNS) affecting mainly young people aged between 20 and 40 years at disease onset. In early stages of the disease, it is characterized by infiltration and activation of T cells and accumulation of monocyte-derived macrophages, which promote destruction of the myelin sheath leading to the formation of focal demyelinated lesions [1]. Diagnosis and follow-up in MS are usually based on as- sessment of clinical symptoms, in particular the presentation Electronic supplementary material The online version of this article (doi:10.1007/s12035-015-9336-6) contains supplementary material, which is available to authorized users. * Adelaide Fernandes amaf@ff.ulisboa.pt 1 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal 2 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal 3 ICVS/3B’ s—PT Government Associate Laboratory, Braga Guimarães, Portugal 4 Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal 5 Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands Mol Neurobiol DOI 10.1007/s12035-015-9336-6