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Aims: Cell matrix modulating protein SPARCL-1 is highly expressed by astrocytes during CNS development and following acute CNS damage. Applying NanoLC-MS/MS to CSF of RRMS and SPMS patients, we identified SPARCL-1 as differentially expressed between these two stages of MS, suggesting a potential as CSF biomarker to differentiate RRMS from SPMS and a role in MS pathogenesis., Methods: This study examines the potential of SPARCL-1 as CSF biomarker discriminating RRMS from SPMS in three independent cohorts (n = 249), analyses its expression pattern in MS lesions (n = 26), and studies its regulation in cultured human brain microvasculature endothelial cells (BEC) after exposure to MS-relevant inflammatory mediators., Results: SPARCL-1 expression in CSF was significantly higher in SPMS compared to RRMS in a Dutch cohort of 76 patients. This finding was not replicated in 2 additional cohorts of MS patients from Sweden (n = 81) and Switzerland (n = 92). In chronic MS lesions, but not active lesions or NAWM, a vessel expression pattern of SPARCL-1 was observed in addition to the expression by astrocytes. EC were found to express SPARCL-1 in chronic MS lesions, and SPARCL-1 expression was regulated by MS-relevant inflammatory mediators in cultured human BEC., Conclusions: Conflicting results of SPARCL-1's differential expression in CSF of three independent cohorts of RRMS and SPMS patients precludes its use as biomarker for disease progression. The expression of SPARCL-1 by BEC in chronic MS lesions together with its regulation by inflammatory mediators in vitro suggest a role for SPARCL-1 in MS neuropathology, possibly at the brain vascular level., (© 2017 British Neuropathological Society.)

The blood-brain barrier (BBB) assures brain homeostasis through the specialized function of brain endothelial cells (BECs). Dysfunction of the BBB due to inflammatory processes is associated with several neurological disorders, including multiple sclerosis (MS). Understanding the mechanisms that underlie these processes may ultimately lead to new therapeutic strategies to restore BBB function, thereby fighting disease progression. In this study, we demonstrate for the first time a critical role of the Notch signaling pathway in the function of the BBB under resting and inflammatory conditions. Inhibition of the Notch signaling, either by a γ-secretase inhibitor or by genetic ablation of endothelial NOTCH, led to BBB dysfunction in vitro as evidenced by reduced transendothelial electrical resistance (TEER), altered localization and loss of endothelial junction molecules and enhanced macromolecular permeability. Inflamed BECs showed impaired Notch signaling as indicated by reduced level of the downstream targets HES-1 and HES-5. Notably, barrier function was further reduced when the Notch signaling was inhibited under inflammatory conditions, suggesting an additive effect of the Notch signaling and inflammation in BECs. In contrast, inducible overexpression of Notch-intracellular domain 1 (NICD1) rescued the detrimental effect caused by inflammation. Furthermore, we provide evidence that inflammation reduced the expression of the glycosyltransferase Lunatic Fringe (LFNG), a known positive regulator of Notch glycosylation and signaling, thereby leading to disrupted barrier function of BECs. Together, our data demonstrate the functional importance of the conserved Notch signaling pathway in control of the brain endothelial barrier and shed light on the role of LFNG in the regulation of Notch glycosylation and signaling in the adult brain vasculature in both health and disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Impairment of the protective properties of the blood-brain barrier (BBB) is a key event during numerous neurological diseases, including multiple sclerosis (MS). Under these pathological conditions, the specialized brain endothelial cells (BECs) lose their protective function leading to neuroinflammation and neurodegeneration. To date, underlying mechanisms for this loss of function remain unclear. Endothelial to mesenchymal transition (EndoMT) is a dynamic process by which endothelial cells (ECs) dedifferentiate into mesenchymal cells and as a result lose their specific phenotype and function. As yet, little is known about the involvement of this process in the impaired function of the BECs under pathological conditions such as MS. Interestingly, several signaling pathways that can induce EndoMT are also involved in different central nervous system (CNS) pathologies associated with BBB dysfunction. In this review, we first discuss the structure and function of the BBB highlighting the changes that occur during MS. Next, we will summarize recent findings on the pathways underlying EndoMT, and finally, we will discuss the potential role of EndoMT during BBB dysfunction in neurological disorders. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger., (Copyright © 2015 Elsevier B.V. All rights reserved.)