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
References (67)
Induction of blood–brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors
Neurosci. Res.
(1999)Inflammatory pain alters blood–brain barrier permeability and tight junctional protein expression
Am. J. Physiol. Heart. Circ. Physiol.
(2001)Amyloid-beta induces chemokine secretion and monocyte migration across a human blood–brain barrier model
Mol. Med.
(1998)β-amyloid-induced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1
Am. J. Physiol. Cell. Physiol.
(2000)Structural alterations of tight junctions are associated with loss of polarity in stroke-prone spontaneously hypertensive rat blood–brain barrier endothelial cells
Brain Res.
(2000)Occludin as a possible determinant of tight junction permeability in endothelial cells
J. Cell Sci.
(1997)The Ras target AF-6 interacts with ZO-1 and serves as a peripheral component of tight junctions in epithelial cells
J. Cell Biol.
(1997)Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins
J. Cell Biol.
(1999)- et al.
Concentration-dependent effects of cytochalasin D on tight junctions and actin filaments in MDCK epithelial cells
J. Cell Sci.
(1994) - et al.
The caveolin triad: caveolae biogenesis, cholesterol trafficking, and signal transduction
Cytokine Growth Factor Rev.
(2001)
Dependence of epithelial intercellular junction biogenesis on thapsigargin-sensitive intracellular calcium stores
J. Biol. Chem.
Occludin proteolysis and increased permeability in endothelial cells through tyrosine phosphatase inhibition
J. Cell Sci.
The tight junction protein ZO-1 is homologous to the Drosophila discs-large tumor suppressor protein of septate junctions
Proc. Natl. Acad. Sci. U. S. A.
Protein kinase C-ζ mediates TNF-α-induced ICAM-1 gene transcription in endothelial cells
Am. J. Physiol. Cell Physiol.
Assembly and sealing of tight junctions: possible participation of G-proteins, phospholipase C, protein kinase C and calmodulin
J. Membr. Biol.
Neutrophil transendothelial migration is independent of tight junctions and occurs preferentially at tricellular corners
J. Immunol.
VEGF increases BMEC monolayer permeability by affecting occludin expression and tight junction assembly
Am. J. Physiol. Heart Circ. Physiol.
Kinetics and polarization of the membrane expression of cytokine-induced ICAM-1 on rat brain endothelial cells
J. Neuropathol. Exp. Neurol.
Electrical resistance across the blood–brain barrier in anaesthetized rats: a developmental study
J. Physiol.
Protein expression of brain endothelial cell E-cadherin after hypoxia/aglycemia: influence of astrocyte contact
Brain Res.
Faulty indication of blood–brain barrier functions by astrocytes isolated from stroke-prone spontaneously hypertensive rates
Clin. Exp. Pharmacol. Physiol.
Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis. Gadolinium MRI Meta-analysis Group
Lancet
Role of chemokines, neuronal projections, and the blood–brain barrier in the enhancement of cerebral EAE following focal brain damage
J. Neuropathol. Exp. Neurol.
Agrin and microvascular damage in Alzheimer's disease
Neurobiol. Aging
Development of intercellular junctions in the pulmonary epithelium of the foetal lamb
J. Cell Sci.
Morphological factors influencing transepithelial permeability: a model for the resistance of the zonula occludens
J. Membr. Biol.
Establishment of a pure vascular endothelial cell line from human placenta
Placenta
Barrier function of epithelia
Am. J. Physiol.
Manner of interaction of heterogeneous claudin species within and between tight junction strands
J. Cell Biol.
Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration
J. Cell Biol.
ZO-3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO-1 and occludin
J. Cell Biol.
Localization of 7H6 tight junction-associated antigen along the cell border of vascular endothelial cells correlates with paracellular barrier function against ions, large molecules, and cancer cells
Exp. Cell Res.
Molecular structure and assembly of the tight junction
Am. J. Physiol.
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