Mechanisms of Ageing and Development 155 (2016) 48–54 Contents lists available at ScienceDirect Mechanisms of Ageing and Development jou rn al hom epage : www.elsevier.com/locat e/mechagedev Original article Novel insights in the dysfunction of human blood-brain barrier after glycation Maryam Hussain a , Kaya Bork a , Vinayaga S. Gnanapragassam a , Dorit Bennmann a , Kathleen Jacobs b , Alexander Navarette-Santos b , Britt Hofmann b , Andreas Simm b , Kerstin Danker c , Rüdiger Horstkorte a,∗ a Institute of Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Hollystr. 1, D-06114 Halle (Salle), Germany b Clinic and Policlinic for Cardiothoracic Surgery, University Hospital Halle, Ernst-Grube-Str. 40, D-06120 Halle (Saale), Germany c Institute of Biochemistry, Charite´ ı—Universit¨ atsmedizin Berlin, Charite´ ıplatz 1, 10117 Berlin, Germany a r t i c l e i n f o Article history: Received 11 December 2015 Received in revised form 8 March 2016 Accepted 9 March 2016 Available online 11 March 2016 Keywords: Advanced glycation endproducts (AGEs) Glycation Blood-brain barrier Interleukin Extracellular matrix a b s t r a c t The blood-brain barrier (BBB) provides a dynamic and complex interface consisting of endothelial cells, pericytes and astrocytes, which are embedded in a collagen and fibronectin-rich basement membrane. This complex structure restricts the diffusion of small hydrophilic solutes and macromolecules as well as the transmigration of leukocytes into the brain. It has been shown that carbonyl stress followed by the formation of advanced glycation endproducts (AGE = glycation) interfere with the BBB integrity and func- tion. Here, we present data that carbonyl stress induced by methylglyoxal leads to glycation of endothelial cells and the basement membrane, which interferes with the barrier-function and with the expression of RAGE, occludin and ZO-1. Furthermore, methylglyoxal induced carbonyl stress promotes the expression of the pro-inflammatory interleukins IL-6 and IL-8. In summary, this study provides new insights into the relationship between AGE formation by carbonyl stress and brain microvascular endothelial barrier dysfunction. © 2016 Elsevier Ireland Ltd. All rights reserved. 1. Introduction The essential function of the blood-brain barrier (BBB) is to protect the brain from uncontrolled cross of agents. Alongside its protective function, the BBB constantly supplies not only the brain with nutrients by specific transport systems but also organises removal of metabolites (Bernacki et al., 2008; Hawkins et al., 2006). Different types of cells define the complex structure of the BBB: microvascular endothelial cells, pericytes and astrocytes. Endothe- lial cells (Choi and Kim, 2008) and pericytes (Allt and Lawrenson, 2001) are embedded in a basement membrane consisting mainly of collagen IV, fibronectin and laminin (Baeten and Akassoglou, 2011). The basement membrane, which serves as a scaffold, is also cru- cial for the BBB functionality. It establishes contact sites for the surrounding neuronal cells (Carvey et al., 2009). Endothelial cells embody the main mediators between blood and the brain (Calabria and Shusta, 2008). They function as regulators for the selective transport and metabolism of substances from the luminal to ablu- ∗ Corresponding author. E-mail address: ruediger.horstkorte@medizin.uni-halle.de (R. Horstkorte). minal side as well as in the opposite direction (Zheng et al., 2003). As a consequence, the apical and basolateral plasma membranes have different protein compositions establishing a cellular polarity (Wolburg et al., 2009). Tight junctions represent protein complexes between endothe- lial cells, which restrict the passive diffusion of molecules toward a concentration gradient. These complexes include transmembrane and membrane-associated proteins, such as claudins or occludins, which tightly interact with each other (Begley and Brightman, 2003). The result of extensive tight junction formation is the rea- son for a high electrical resistance of brain capillaries of about 2000  × cm 2 and a low permeability (Stamatovic et al., 2008). The central nervous system is described as an immune- privileged region (Wekerle, 2006). The BBB plays an important role in maintaining the separation of central nervous system from the adaptive and the innate immune system (Carson et al., 2006; Francis et al., 2003). Pathological events, such as viral infections, severe brain injuries or chronic-inflammatory diseases promote transmigration of immune cells through the BBB, lead- ing to inflammation of the brain (Persidsky et al., 2006). Brain inflammation is characterised by activation of microglia, astro- cytes and endothelial cells, which leads to expression of different http://dx.doi.org/10.1016/j.mad.2016.03.004 0047-6374/© 2016 Elsevier Ireland Ltd. All rights reserved.