The importance of tight junctions in the blood-brain barrier

Tight junctions (TJs) between blood-brain barrier (BBB) endothelial cells construct a robust physical barrier, whose damage underlies BBB dysfunctions related to several neurodegenerative diseases. What makes these highly specialized BBB-TJs extremely restrictive remains unknown. Here, we use super-resolution microscopy (dSTORM) to uncover new structural and functional properties of BBB TJs. Focusing on three major components, Nano-scale resolution revealed sparse (occludin) vs. clustered (ZO1/claudin-5) molecular architecture. In mouse development, permeable TJs become first restrictive to large molecules, and only later to small molecules, with claudin-5 proteins arrangement compacting during this maturation process. Mechanistically, we reveal that ZO1 clustering is independent of claudin-5 in-vivo. In contrast to accepted knowledge, we found that in the developmental context, total levels of claudin-5 inversely correlate with TJ functionality. Our super-resolution studies provide a unique perspective of BBB TJs and open new directions for understanding TJ functionality in biological barriers, ultimately enabling restoration in disease or modulation for drug delivery.

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Modulating the Blood-Brain Barrier by Light Stimulation of Molecular-Targeted Nanoparticles

10.1101/2020.10.05.326843 ◽

2020 ◽

Author(s):

Xiaoqing Li ◽

Vamsidhara Vemireddy ◽

Qi Cai ◽

Hejian Xiong ◽

Peiyuan Kang ◽

...

Keyword(s):

Tight Junction ◽

Tight Junctions ◽

Blood Brain Barrier ◽

Therapeutic Interventions ◽

Brain Barrier ◽

Light Stimulation ◽

Targeted Nanoparticles ◽

Blood Brain ◽

The Brain ◽

Stimulation Of

AbstractThe blood-brain barrier (BBB) tightly regulates the entry of molecules into the brain by tight junctions that seals the paracellular space and receptor-mediated transcytosis. It remains elusive to selectively modulate these mechanisms and to overcome BBB without significant neurotoxicity. Here we report that light stimulation of tight junction-targeted plasmonic nanoparticles selectively opens up the paracellular route to allow diffusion through the compromised tight junction and into the brain parenchyma. The BBB modulation does not impair vascular dynamics and associated neurovascular coupling, or cause significant neural injury. It further allows antibody and adeno-associated virus delivery into local brain regions. This novel method offers the first evidence of selectively modulating BBB tight junctions and opens new avenues for therapeutic interventions in the central nervous system.One Sentence SummaryGentle stimulation of molecular-targeted nanoparticles selectively opens up the paracellular pathway and allows macromolecules and gene therapy vectors into the brain.

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Blood-Brain Barrier Breakdown after Embolic Stroke in Rats Occurs without Ultrastructural Evidence for Disrupting Tight Junctions

PLoS ONE ◽

10.1371/journal.pone.0056419 ◽

2013 ◽

Vol 8 (2) ◽

pp. e56419 ◽

Cited By ~ 103

Author(s):

Martin Krueger ◽

Wolfgang Härtig ◽

Andreas Reichenbach ◽

Ingo Bechmann ◽

Dominik Michalski

Keyword(s):

Tight Junctions ◽

Blood Brain Barrier ◽

Embolic Stroke ◽

Brain Barrier ◽

Ultrastructural Evidence ◽

Blood Brain ◽

Barrier Breakdown ◽

Blood Brain Barrier Breakdown

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Modulation of tight junction structure in blood-brain barrier endothelial cells. Effects of tissue culture, second messengers and cocultured astrocytes

Journal of Cell Science ◽

10.1242/jcs.107.5.1347 ◽

1994 ◽

Vol 107 (5) ◽

pp. 1347-1357 ◽

Cited By ~ 6

Author(s):

H. Wolburg ◽

J. Neuhaus ◽

U. Kniesel ◽

B. Krauss ◽

E.M. Schmid ◽

...

Keyword(s):

Endothelial Cells ◽

Tight Junction ◽

Tight Junctions ◽

Blood Brain Barrier ◽

Barrier Function ◽

Primary Cultures ◽

Brain Barrier ◽

Brain Endothelial Cells ◽

Blood Brain ◽

Camp Levels

Tight junctions between endothelial cells of brain capillaries are the most important structural elements of the blood-brain barrier. Cultured brain endothelial cells are known to loose tight junction-dependent blood-brain barrier characteristics such as macromolecular impermeability and high electrical resistance. We have directly analyzed the structure and function of tight junctions in primary cultures of bovine brain endothelial cells using quantitative freeze-fracture electron microscopy, and ion and inulin permeability. The complexity of tight junctions, defined as the number of branch points per unit length of tight junctional strands, decreased 5 hours after culture but thereafter remained almost constant. In contrast, the association of tight junction particles with the cytoplasmic leaflet of the endothelial membrane bilayer (P-face) decreased continuously with a major drop between 16 hours and 24 hours. The complexity of tight junctions could be increased by elevation of intracellular cAMP levels while phorbol esters had the opposite effect. On the other hand, the P-face association of tight junction particles was enhanced by elevation of cAMP levels and by coculture of endothelial cells with astrocytes or exposure to astrocyte-conditioned medium. The latter effect on P-face association was induced by astrocytes but not fibroblasts. Elevation of cAMP levels together with astrocyte-conditioned medium synergistically increased transendothelial electrical resistance and decreased inulin permeability of primary cultures, thus confirming the effects on tight junction structure and barrier function. P-face association of tight junction particles in brain endothelial cells may therefore be a critical feature of blood-brain barrier function that can be specifically modulated by astrocytes and cAMP levels. Our results suggest an important functional role for the cytoplasmic anchorage of tight junction particles for brain endothelial barrier function in particular and probably paracellular permeability in general.

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