Tight Junctions of the Neurovascular Unit

Hudson, Natalie; Campbell, Matthew

doi:10.3389/fnmol.2021.752781

Cited by 19 publications

(22 citation statements)

References 108 publications

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“…Unique to the BBB are well-evolved endothelial tight junctions, which, as the name suggests, seal the paracellular cleft between two contacting cells. 4 The density of these tight junctions is due in a large part to the presence of high levels of the barrier-forming tight junction protein claudin-5. Indeed, the levels of claudin-5 dominate any other claudin at the BBB and recent single cell RNA-sequencing studies in mice suggest that claudin-5 is amongst the highest expressed protein in cerebrovascular endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

Recurrent de novo mutations in CLDN5 induce an anion-selective blood–brain barrier and alternating hemiplegia

Poirier

Boddaert

Hubert

et al. 2022

Brain

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Claudin-5 is the most enriched tight junction protein at the blood brain barrier (BBB). Perturbations in its levels of expression have been observed across numerous neurological and neuropsychiatric conditions; however, pathogenic variants in the coding sequence of the gene have never previously been reported. Here, we report the identification of a novel de novo mutation (c.178G > A) in the CLDN5 gene in two un-related cases of alternating hemiplegia with microcephaly. This mutation (G60R) lies within the first extracellular loop of claudin-5 and based on protein modelling and sequence alignment, we predicted it would modify claudin-5 to become an anion selective junctional component as opposed to a purely barrier forming protein. Generation of stably transfected cell lines expressing wild-type or G60R claudin-5 showed that the tight junctions could still form in the presence of the G60R mutation but that the barrier against small molecules was clearly attenuated and displayed higher Cl- ion permeability and lower Na+ permeability. While this study strongly suggests that CLDN5 associated alternating hemiplegia is a channelopathy, it is also the first study to identify the conversion of the BBB to an anion selective channel mediated by a dominant acting variant in CLDN5.

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Section: Introductionmentioning

confidence: 99%

Recurrent de novo mutations in CLDN5 induce an anion-selective blood–brain barrier and alternating hemiplegia

Poirier

Boddaert

Hubert

et al. 2022

Brain

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“…The integrity of the BBB is maintained by tight junctions between endothelial cells, which are complexes consisting of occludin and members of the claudin family, with Claudin-5 being the most abundant [47]. The Zonula occludens family members (ZO-1 and ZO-2) are localized in the cytoplasm and link the actin cytoskeleton with tight junctions via binding occludin.…”

Section: Resultsmentioning

confidence: 99%

Reactive astrocytes associated with prion disease impair the blood brain barrier

Kushwaha

Makarava

et al. 2023

Preprint

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Background. Impairment of the blood-brain barrier (BBB) is considered to be a common feature among neurodegenerative diseases, including Alzheimer's, Parkinso'n s and prion diseases. In prion disease, increased BBB permeability was reported 40 years ago, yet the mechanisms behind the loss of BBB integrity have never been explored. Recently, we showed that reactive astrocytes associated with prion diseases are neurotoxic. The current work examines the potential link between astrocyte reactivity and BBB breakdown. Results. In prion-infected mice, the loss of BBB integrity and aberrant localization of aquaporin 4 (AQP4), a sign of retraction of astrocytic endfeet from blood vessels, were noticeable prior to disease onset. Gaps in cell-to-cell junctions along blood vessels, together with downregulation of Occludin, Claudin-5 and VE-cadherin, which constitute tight and adherens junctions, suggested that loss of BBB integrity is linked with degeneration of vascular endothelial cells. In contrast to cells isolated from non-infected adult mice, endothelial cells originating from prion-infected mice displayed disease-associated changes, including lower levels of Occludin, Claudin-5 and VE-cadherin expression, impaired tight and adherens junctions, and reduced trans-endothelial electrical resistance (TEER). Endothelial cells isolated from non-infected mice, when co-cultured with reactive astrocytes isolated from prion-infected animals or treated with media conditioned by the reactive astrocytes, developed the disease-associated phenotype observed in the endothelial cells from prion-infected mice. Reactive astrocytes were found to produce high levels of secreted IL-6, and treatment of endothelial monolayers originating from non-infected animals with recombinant IL-6 alone reduced their TEER. Remarkably, treatment with extracellular vesicles produced by normal astrocytes partially reversed the disease phenotype of endothelial cells isolated from prion-infected animals. Conclusions. To our knowledge, the current work is the first to illustrate early BBB breakdown in prion disease and to document that reactive astrocytes associated with prion disease are detrimental to BBB integrity. Moreover, our findings suggest that the harmful effects are linked to proinflammatory factors secreted by reactive astrocytes.

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“…All this molecular framework is associated with cytoplasmic proteins, including the zonula occludens −1, −2, and −3 (ZO-1, ZO-2, and ZO-3), cingulin, and others. These cytoplasmic proteins bind to membrane proteins of the endothelial cytoskeleton, which favours the structural and functional integrity of the luminal surface of the capillary [ 46 , 47 , 48 ].…”

Section: Bbb Structure and Functionmentioning

confidence: 99%

Need for a Paradigm Shift in the Treatment of Ischemic Stroke: The Blood-Brain Barrier

Alonso-Alonso¹,

Sampedro-Viana²,

Fernández-Rodicio³

et al. 2022

IJMS

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Blood-brain barrier (BBB) integrity is essential to maintaining brain health. Aging-related alterations could lead to chronic progressive leakiness of the BBB, which is directly correlated with cerebrovascular diseases. Indeed, the BBB breakdown during acute ischemic stroke is critical. It remains unclear, however, whether BBB dysfunction is one of the first events that leads to brain disease or a down-stream consequence. This review will focus on the BBB dysfunction associated with cerebrovascular disease. An added difficulty is its association with the deleterious or reparative effect, which depends on the stroke phase. We will first outline the BBB structure and function. Then, we will focus on the spatiotemporal chronic, slow, and progressive BBB alteration related to ischemic stroke. Finally, we will propose a new perspective on preventive therapeutic strategies associated with brain aging based on targeting specific components of the BBB. Understanding BBB age-evolutions will be beneficial for new drug development and the identification of the best performance window times. This could have a direct impact on clinical translation and personalised medicine.

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Tight Junctions of the Neurovascular Unit

Cited by 19 publications

References 108 publications

Recurrent de novo mutations in CLDN5 induce an anion-selective blood–brain barrier and alternating hemiplegia

Recurrent de novo mutations in CLDN5 induce an anion-selective blood–brain barrier and alternating hemiplegia

Reactive astrocytes associated with prion disease impair the blood brain barrier

Need for a Paradigm Shift in the Treatment of Ischemic Stroke: The Blood-Brain Barrier

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