Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation

The present review summarizes our current understanding of the structure and functional regulation of endothelial TJs at the BBB. Accumulating evidence points to a correlation between BBB dysfunction, alteration of TJ complexes and progression of a variety of CNS diseases, such as stroke, multiple sclerosis and brain tumors, as well as neurodegenerative diseases like Parkinson’s and Alzheimer’s diseases. Understanding how TJ integrity is controlled may thus help improve drug delivery across the BBB and the design of therapeutic strategies for neurological disorders.The BBB maintains the homeostasis of the central nervous system (CNS) by (i) strictly limiting the passive diffusion of polar substances from the blood to the brain, (ii) mediating the transport of nutrients to the brain parenchyma as well as the efflux from the brain of toxic metabolites and xenobiotics, (iii) regulating the migration of circulating immune cells [1-3]. Formed by specialized vascular endothelial cells, the BBB is tightly controlled by pericytes, embedded in the vascular basement membrane, perivascular microglial cells, astrocytes and neurons which altogether constitute the neurovascular unit (NVU), a concept highlighting the functional cell-cell interactions supporting BBB function.BBB endothelial cells display a unique phenotype characterized by the presence of TJs and the expression of specific polarized transport systems. TJs constitute the most apical intercellular junctional complex in polarized epithelium and endothelium, with three key biological functions: a barrier to paracellular diffusion of blood-borne polar substances [4], a fence preventing the lateral diffusion of lipids and integral membrane proteins, thus maintaining cell polarization [5-7] and an intracellular signaling platform which will be described below.Brain endothelial TJ strands, like epithelial TJs, are composed of integral membrane proteins (occludin, claudins and junctional adhesion molecules (JAMs)) involved