Trends in Neurosciences
Volume 24, Issue 12, 1 December 2001, Pages 719-725
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Review
Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier

https://doi.org/10.1016/S0166-2236(00)02004-XGet rights and content

Abstract

Disruption of the tight junctions (TJs) of the blood–brain barrier (BBB) is a hallmark of many CNS pathologies, including stroke, HIV encephalitis, Alzheimer's disease, multiple sclerosis and bacterial meningitis. Furthermore, systemic-derived inflammation has recently been shown to cause BBB tight junctional disruption and increased paracellular permeability. The BBB is capable of rapid modulation in response to physiological stimuli at the cytoskeletal level, which enables it to protect the brain parenchyma and maintain a homeostatic environment. By allowing the ‘loosening’ of TJs and an increase in paracellular permeability, the BBB is able to ‘bend without breaking’; thereby, maintaining structural integrity.

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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