Tight junction proteins at the blood–brain barrier: far more than claudin-5

Berndt, Philipp; Winkler, Lars; Cording, Jimmi; Breitkreuz-Korff, Olga; Rex, André; Dithmer, Sophie; Rausch, Valentina; Blasig, Rosel; Richter, Matthias; Sporbert, Anje; Wolburg, Hartwig; Blasig, Ingolf E.; Haseloff, Reiner F.

doi:10.1007/s00018-019-03030-7

Cited by 159 publications

(156 citation statements)

References 73 publications

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“…While the importance of claudin-5 as a tight junction protein at the cerebral endothelium is widely recognized [59], the potential role of other claudins [60] is more contentious. Uchida et al [61] recently provided evidence in multiple sclerosis that claudin-11 is decreased at the BBB (and the blood-spinal cord and the blood-arachnoid barriers) contributing to barrier leakiness.…”

Section: Claudins At the Cerebral Endotheliummentioning

confidence: 99%

This was the year that was: brain barriers and brain fluid research in 2019

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Jones²,

Drewes

2020

Fluids Barriers CNS

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This editorial highlights advances in brain barrier and brain fluid research published in 2019, as well as addressing current controversies and pressing needs. Topics include recent advances related to: the cerebral endothelium and the neurovascular unit; the choroid plexus, arachnoid membrane; cerebrospinal fluid and the glymphatic hypothesis; the impact of disease states on brain barriers and brain fluids; drug delivery to the brain; and translation of preclinical data to the clinic. This editorial also mourns the loss of two important figures in the field, Malcolm B. Segal and Edward G. Stopa.

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Section: Claudins At the Cerebral Endotheliummentioning

confidence: 99%

This was the year that was: brain barriers and brain fluid research in 2019

Keep

Jones²,

Drewes

2020

Fluids Barriers CNS

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“…Myelin was removed by adding dextran (60-70 kDa, 16% (w/v) final concentration; Sigma-Aldrich) and centrifugation (15 min, 4,500×g, 4 °C). The resuspended pellet was filtered (40 µm nylon mesh, Merck Millipore) and the remaining capillaries were rinsed off with DMEM and 1% (v/v) fetal calf serum (Life Technologies) (Berndt et al, 2019).…”

Section: Permeability Of the Bnb (Endoneurial Vessels)mentioning

confidence: 99%

Claudin-12 deficiency causes nerve barrier breakdown, mechanical hypersensitivity and painfulness in polyneuropathy

Chen

Doppler

et al. 2019

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Running title: Loss of claudin-12 results in mechanical hypersensitivity. AbstractPeripheral nerves and their axons are shielded by the blood-nerve and the myelin barrier, but understanding of how these barriers impact nociception is limited. Here, we identified a regulatory axis of the tight junction protein claudin-12, sex-dependently controlling perineurial and myelin barrier integrity. In nerve biopsies, claudin-12 in Schwann cells was lost in male and postmenopausal female patients with painful but not painless polyneuropathy. Global Cldn12 gene-knockout selectively increased perineurial/myelin barrier leakage, damaged tight junction protein expression and morphology, increased proinflammatory cytokines and induced mechanical hypersensitivity in naïve and neuropathic male mice, respectively. Other barriers and neurological function remained intact. In vitro transfection studies documented claudin-12 plasma membrane localisation without interaction with other tight junction proteins or intrinsic sealing properties. Rather, claudin-12 had a regulatory tight junction protein function on the myelin barrier via the morphogen SHH in vivo in Cldn12-KO and after local siRNA knockdown. Fertile female mice were completely protected. Collectively, these studies reveal the critical role of claudin-12 maintaining the myelin barrier and highlight restoration of the claudin-12/SHH pathway as a potential target for painful neuropathy. 5

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“…For example, it was recently shown that the claudins-3 and -12 in the BBB of the mouse do not have the previously believed importance for BBB function [7,8]. In addition, there are postulated species differences that make it difficult to get a clear picture of which claudins are present in the human BBB and which function they fulfill [3]. Previous studies have in common that they prove the essential role of claudin-5 in all species.…”

Section: Introductionmentioning

confidence: 99%

The pivotal role of micro-environmental cells in a human blood–brain barrier in vitro model of cerebral ischemia: functional and transcriptomic analysis

Gerhartl

Pracser

Vladetic

et al. 2020

Fluids Barriers CNS

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Background: The blood-brain barrier (BBB) is altered in several diseases of the central nervous system. For example, the breakdown of the BBB during cerebral ischemia in stroke or traumatic brain injury is a hallmark of the diseases' progression. This functional damage is one key event which is attempted to be mimicked in in vitro models. Recent studies showed the pivotal role of micro-environmental cells such as astrocytes for this barrier damage in mouse stroke in vitro models. The aim of this study was to evaluate the role of micro-environmental cells for the functional, paracellular breakdown in a human BBB cerebral ischemia in vitro model accompanied by a transcriptional analysis. Methods: Transwell models with human brain endothelial cell line hCMEC/D3 in mono-culture or co-culture with human primary astrocytes and pericytes or rat glioma cell line C6 were subjected to oxygen/glucose deprivation (OGD). Changes of transendothelial electrical resistance (TEER) and FITC-dextran 4000 permeability were recorded as measures for paracellular tightness. In addition, qPCR and high-throughput qPCR Barrier chips were applied to investigate the changes of the mRNA expression of 38 relevant, expressed barrier targets (tight junctions, ABC-transporters) by different treatments. Results: In contrast to the mono-culture, the co-cultivation with human primary astrocytes/pericytes or glioma C6 cells resulted in a significantly increased paracellular permeability after 5 h OGD. This indicated the pivotal role of micro-environmental cells for BBB breakdown in the human model. Hierarchical cluster analysis of qPCR data revealed differently, but also commonly regulated clustered targets dependent on medium exchange, serum reduction, hydrocortisone addition and co-cultivations. Conclusions: The co-cultivation with micro-environmental cells is necessary to achieve a functional breakdown of the BBB in the cerebral ischemia model within an in vivo relevant time window. Comprehensive studies by qPCR revealed that distinct expression clusters of barrier markers exist and that these are regulated by different treatments (even by growth medium change) indicating that controls for single cell culture manipulation steps are crucial to understand the observed effects properly.

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Tight junction proteins at the blood–brain barrier: far more than claudin-5

Cited by 159 publications

References 73 publications

This was the year that was: brain barriers and brain fluid research in 2019

This was the year that was: brain barriers and brain fluid research in 2019

Claudin-12 deficiency causes nerve barrier breakdown, mechanical hypersensitivity and painfulness in polyneuropathy

The pivotal role of micro-environmental cells in a human blood–brain barrier in vitro model of cerebral ischemia: functional and transcriptomic analysis

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