Claudin-5: gatekeeper of neurological function
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Fluids and Barriers of the CNS Open Access
REVIEW
Claudin‑5: gatekeeper of neurological function Chris Greene, Nicole Hanley and Matthew Campbell*
Abstract Tight junction proteins of the blood–brain barrier are vital for maintaining integrity of endothelial cells lining brain blood vessels. The presence of these protein complexes in the space between endothelial cells creates a dynamic, highly regulated and restrictive microenvironment that is vital for neural homeostasis. By limiting paracellular diffusion of material between blood and brain, tight junction proteins provide a protective barrier preventing the passage of unwanted and potentially damaging material. Simultaneously, this protective barrier hinders the therapeutic effectiveness of central nervous system acting drugs with over 95% of small molecule therapeutics unable to bypass the blood–brain barrier. At the blood–brain barrier, claudin-5 is the most enriched tight junction protein and its dysfunction has been implicated in neurodegenerative disorders such as Alzheimer’s disease, neuroinflammatory disorders such as multiple sclerosis as well as psychiatric disorders including depression and schizophrenia. By regulating levels of claudin-5, it is possible to abrogate disease symptoms in many of these disorders. This review will give an overview of the blood–brain barrier and the role of tight junction complexes in maintaining blood–brain barrier integrity before focusing on the role of claudin-5 and its regulation in homeostatic and pathological conditions. We will also summarise therapeutic strategies to restore integrity of cerebral vessels by targeting tight junction protein complexes. Keywords: Blood–brain barrier, Endothelial cell, Tight junction, Claudin-5 Introduction The blood–brain barrier (BBB) is formed by a tightly packed monolayer of non fenestrated endothelial cells lining the brain capillaries which are enveloped by pericytes and perivascular astrocytes. The BBB forms a protective layer in the central nervous system (CNS) strictly limiting molecular exchange between the circulating blood and brain microenvironment. This is to ensure a constant state of homeostasis for efficient neural signalling. Accounting for just 2% of bodily mass, the brain and neuronal functions consume as much as 20% of the body’s oxygen and glucose needs despite a lack of energy reserves in the brain [1]. Therefore, blood vessels in the brain provide vital energy and nutrients in response to the metabolic demands of neurons (a process known as hyperaemia) [2]. Cerebral capillaries account for 85% of vessel length in the brain, providing a surface area of ~ 12 m2 of the endothelial surface for molecular *Correspondence: [email protected] Trinity College Dublin, Smurfit Institute of Genetics, Dublin 2, Ireland
exchange and an approximate 1:1 ratio of capillaries to neurons [3–5]. Owing to the restrictive regenerative capacities of neurons, there is a vital need to limit the unrestricted movement of material between the blood and brain and vice versa to pre
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