Trends in Neurosciences
ReviewMolecular physiology and pathophysiology of tight junctions in the blood–brain barrier
Section snippets
Blood–brain barrier
The BBB is a physical and metabolic barrier between the CNS and the systemic circulation, which serves to regulate and protect the microenvironment of the brain. The BBB is characterized by the presence of TJs, which result in high transendothelial electrical resistance (1500–2000 Ω*cm 2) and decreased paracellular permeability 1. The cerebral microvasculature is ensheathed by astrocytic end feet, which play an essential role in maintaining BBB phenotype 2. Astrocytes confer a protective role
Tight junctions
TJs of the BBB create a rate-limiting barrier to paracellular diffusion of solutes between endothelial cells. They are the most apical element of the junctional complex, which includes both tight and adherens junctions. Structurally, TJs form a continuous network of parallel, interconnected, intramembrane strands of protein arranged as a series of multiple barriers 11. Studies using TJs from different tissues with varying transendothelial and transepithelial electrical resistances show a
Signaling molecules
TJs are localized at cholesterol-enriched regions along the plasma membrane associated with caveolin 1 (Ref. 29). Caveolin 1 interacts with and regulates the activity of several signal transduction pathways and downstream targets 30. Several cytoplasmic signaling molecules are concentrated at TJ complexes and are involved in signaling cascades that control assembly and disassembly of TJs (Ref. 31).
Hypoxic or ischemic insult
An ATP depletion–repletion in vitro model of TJ reassembly has been used to study ischemia–reperfusion and hypoxia–reoxygenation. After a hypoxic or ischemic insult, re-establishing the actin cytoarchitecture is crucial for TJ reassembly. Disruption of the cytoskeleton leads to altered polarity of membrane proteins and loss of the permeability barrier between adjacent endothelial cells. ATP depletion is associated with marked reorganization of the actin cytoskeleton. After 30 min of ATP
Concluding remarks
The BBB plays a crucial role in maintaining brain homeostasis by maintaining brain extracellular fluid within a precise physiological range, independent of fluctuations within the blood, in order to maintain optimal conditions for neuronal function. Presence of ‘epithelial-like’ TJs is necessary for BBB formation and function. Rapid progress has been made in elucidating the functional and molecular properties of TJs in the BBB, as recent studies clearly indicate the dynamic nature of the TJ
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