Claudin-5: gatekeeper of neurological function

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.

Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

“…Only a handful of studies have explored molecular and epigenetic regulation of cldn5 despite its role in several inflammatory conditions and neurological disorders, including stroke (25), glioblastoma (26), multiple sclerosis, and Alzheimer's disease (27). In an elegant set of papers, Taddei et al showed that VE-cadherin mediates up-regulation of cldn5 and epigenetic regulation of endothelial gene expression (12,13).…”

Disruption of the Blood-Brain Barrier in 22q11.2 Deletion Syndrome

“…Remarkably, during adolescence and young adulthood roughly 25% of 22qDS patients develop SZ, a 25-fold increase in risk over the general population (Arinami, 2006;Karayiorgou & Gogos, 2004; Van, Boot, & Bassett, 2017). The 22q11.2 deletion includes junctional and mitochondrial genes that could influence barrier function (Arinami, 2006;Devaraju & Zakharenko, 2017;Greene et al, 2018;Greene, Hanley, & Campbell, 2019). However, the status of the blood brain barrier (BBB), the highly specialized central nervous system (CNS) endothelial cells, in 22qDS is unknown.…”

Neuroprotective Properties of Resveratrol and Its Derivatives—Influence on Potential Mechanisms Leading to the Development of Alzheimer’s Disease

“…A violation of BBB integrity disrupts Aβ transport contributing to the excessive accumulation of toxic Aβ in the brain and further aggravating pathology [60]. Matrix metalloprotein-9 (MMP-9) and tight junction protein Claudin-5 have been shown to regulate BBB permeability and play an important role in neuropathologies such as Alzheimer's disease [61,62]. In the rat Alzheimer's disease model, resveratrol defends BBB integrity by reducing advanced glycation end products (RAGE), matrix metalloprotein-9 (MMP-9) and increasing Claudin-5 but also reduces neuroinflammation by affecting nuclear factor NF-κB expression [63].…”