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.

Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood–brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog. Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.

The blood–retina barrier (BRB) is the term used to define the properties of the retinal capillaries and the retinal pigment epithelium (RPE), which separate the systemic circulation from the retina. More specifically, the inner blood–retina barrier (iBRB) is used to describe the properties of the endothelial cells that line the microvasculature of the inner retina, while the outer blood–retina barrier (oBRB) refers to the properties of the RPE cells that separate the fenestrated choriocapillaris from the retina. The BRB is not a fixed structure; rather, it is dynamic, with its components making unique contributions to its function and structural integrity, and therefore the retina. For example, while tight junction (TJ) proteins between retinal endothelial cells are the key molecular structures in the maintenance of the iBRB, other cell types surrounding endothelial cells are also important. In fact, this overall structure is termed the neurovascular unit (NVU). The integrity of the BRB is crucial in the maintenance of a ‘dry’, tightly regulated retinal microenvironment through the regulation of transcellular and paracellular transport. Specifically, breakdown of TJs can result in oedema formation, a hallmark feature of many retinal diseases. Here, we will describe the oBRB briefly, with a more in‐depth focus on the structure and function of the iBRB in health and diseased states. Finally, the contribution of the BRB to the pathophysiology of age‐related macular degeneration (AMD), diabetic retinopathy (DR) and other rarer retinal diseases will be discussed.

Prevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice; however, this association is unclear in females. Here, we report that chronic social and subchronic variable stress promotes blood-brain barrier (BBB) alterations in mood-related brain regions of female mice. Targeted disruption of the BBB in the female prefrontal cortex (PFC) induces anxiety- and depression-like behaviours. By comparing the endothelium cell-specific transcriptomic profiling of the mouse male and female PFC, we identify several pathways and genes involved in maladaptive stress responses and resilience to stress. Furthermore, we confirm that the BBB in the PFC of stressed female mice is leaky. Then, we identify circulating vascular biomarkers of chronic stress, such as soluble E-selectin. Similar changes in circulating soluble E-selectin, BBB gene expression and morphology can be found in blood serum and postmortem brain samples from women diagnosed with MDD. Altogether, we propose that BBB dysfunction plays an important role in modulating stress responses in female mice and possibly MDD.