Are claudin-5 tight-junction proteins in the blood-brain barrier porous?

Fisher, David; Mentor, Shireen

doi:10.4103/1673-5374.280308

Cited by 12 publications

(18 citation statements)

References 12 publications

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“…In this study, we observe the "secretion" of an amorphous BM which allowed BEC consolidation into a perfectly orientated monolayer, an essential prerequisite for proper expression of domain-specific BBB ultrastructures and protein expression during its development and subsequent angiogenesis (Figure 1). We postulate that this feature is central to the functional orientation of BECs and the TJ enabled sealing of the PC space, a key component of BBB regulation (Fisher and Mentor, 2019).…”

Section: Discussionmentioning

confidence: 98%

“…It is established in the literature that BECs seal their PC spaces by aligning the apicolateral zones so precisely that the TJs on the adjacent cells could align and be closely juxtaposed to each other, for inter-TJ molecular bonding to occur and seal off the PC spaces. Hitherto, it has been unclear as to how these "apicolateral" zones of TJs between two adjacent cells are aligned to allow TJs from adjacent membranes to molecularly bond to each other, creating an impermeable PC seal (Fisher and Mentor, 2019). Thus, both TENT and TUNTs play an integral role in aligning juxtaposed lateral sides of BECs and in the establishing of PC occlusion between the neighboring BECs by approximating adjacent zones of TJs so closely that molecular bonding occurs between TJs of adjacent cells (Figures 6, 7).…”

Section: Tethering Nanotubesmentioning

confidence: 99%

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High-Resolution Insights Into the in vitro Developing Blood-Brain Barrier: Novel Morphological Features of Endothelial Nanotube Function

Mentor

Fisher

2021

Front. Neuroanat.

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High-resolution electron microscopy (HREM) imaging of the in vitro blood-brain barrier (BBB), is a promising modality for investigating the dynamic morphological interplay underpinning BBB development. The successful establishment of BBB integrity is grounded in the brain endothelial cells (BEC’s) ability to occlude its paracellular spaces of brain capillaries through the expression of the intercellular tight junction (TJ) proteins. The impermeability of these paracellular spaces are crucial in the regulation of transcellular transport systems to achieve homeostasis of the central nervous system. To-date research describing morphologically, the dynamics by which TJ interaction is orchestrated to successfully construct a specialized barrier remains undescribed. In this study, the application of HREM illuminates the novel, dynamic and highly restrictive BEC paracellular pathway which is founded based on lateral membrane alignment which is the functional imperative for the mechanical juxtapositioning of TJ zones that underpin molecular bonding and sealing of the paracellular space. For the first time, we report on the secretion of a basement membrane in vitro, which allow BECs to orientate themselves into distinct basolateral and apicolateral domains and establish a 3-dimensional BEC construct. We report for the first time, on the expression of nanovesicles bound to the plasma membrane surfaces of the BECs. These membrane-bound vesicles are reported to possess an array of DNA/RNA constituents and chemotaxic properties affecting the formation of nanotubes that span the paracellular space between BECs, facilitating BBB construction, alluding to a functional role in mediating cell-to-cell communication. This study suggests that novel, ultrathin nanotubular (NT) structures are involved in functional roles in bringing into alignment the paracellular space of BECs. Immortalized mouse BECs (b.End3, b.End5) and primary rat cardiac microvascular ECs were used to further validate the in vitro BBB model by profiling variances in peripheral EC monolayer development. These cardiac capillary ECs presented with an opposite topographical profile: large fenestra and intercellular spaces, devoid of morphological ultrastructures. This comparative study alludes to the role of NT facilitation in TJ-induced hemifusion of apicolateral BEC membranes, as a structural event forming the basis for establishing a polarized BBB.

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Section: Discussionmentioning

confidence: 98%

Section: Tethering Nanotubesmentioning

confidence: 99%

High-Resolution Insights Into the in vitro Developing Blood-Brain Barrier: Novel Morphological Features of Endothelial Nanotube Function

Mentor

Fisher

2021

Front. Neuroanat.

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“…Steiner et al (2011) also reported that bEnd5 cells lacked the localization of occludin to cellular junctions; however, Findley and Koval (2009) established that occludin‐deficient mice are viable and exhibit normal barrier function. Furthermore, the bEnd5 cells used in this study have successfully expressed one of the critical proteins of brain endothelial cell TJs, claudin‐5 (Fisher and Mentor, 2020). In BECs, claudin‐5 mRNA is almost 600‐fold greater than claudin‐3 (Günzel and Yu, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…In BECs, claudin‐5 mRNA is almost 600‐fold greater than claudin‐3 (Günzel and Yu, 2013). Furthermore, the importance of claudin‐5 TJ proteins to the brain function is illustrated in that claudin‐5‐knockout mice never survive for more than 10 hours after birth (Fisher and Mentor, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…It serves as a vascular interface protecting the central nervous system (CNS), by preventing the entry of toxic blood‐borne substances into the brain microenvironment (Colgan et al, 2008), and regulates the movement of molecules and ions between the blood and the brain’s parenchyma. The transport of these substances across the capillary endothelial cells (ECs) of the brain is mostly regulated via transcellular pathways, and in general, the paracellular pathways are sealed using tight junctions (TJs), which are located apically on the lateral walls of adjacent ECs (Fisher and Mentor, 2020). Small molecules that are nonpolar and lipophilic are able to transverse across the BBB with ease along their concentration gradients, and influence the physiological function of the endothelial component of the BBB.…”

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confidence: 99%

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The Synergistic and Neuroprotective Effects of Alcohol–Antioxidant Treatment on Blood–Brain Barrier Endothelial Cells

Fisher

Thomas

Abdul-Rasool

2020

Alcoholism Clin & Exp Res

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Background: Alcohol (EtOH) is reported to adversely affect one of the most crucial roles of the blood-brain barrier (BBB), the regulation of its permeability, thereby compromising the stability of the homeostatic environment of the brain. The central component of the BBB, endothelial cells (ECs), regulates BBB transcellular transport, while their paracellular pathways are made virtually impermeable by molecular structures called tight junctions (TJs). These TJs are composed of proteins, such as claudin-5, a protein involved in the regulation of paracellular permeability and of key interest in this study. Methods and Results: The working hypothesis of this study postulated that the high levels of antioxidants (AOs) in the fermented Aspalathus linearis (Rooibos; Rf) tincture may protect the ECs of the BBB against oxidative stress induced by EtOH exposure. Cells were exposed for 24 hours to selected concentrations of EtOH (25 and 100 mM), Rf (containing an antioxidant equivalence of 1.9 nM Aspalathin), and cotreatments of EtOH and Rf. Cell viability, live cell number, and toxicity were analyzed using the trypan blue exclusion assay. RT-qPCR was implemented to quantify claudin-5 transcription. In addition, permeability (Transepithelial Electrical Resistance) of bEnd5 monolayers was measured. The experimental timeline for the above-mentioned parameters was 24 and 48 hours. Conclusions: Our study showed that simultaneous exposure of Rf and EtOH was able to negate the effects of EtOH on cell viability and cell proliferation, but was not able to reverse or reduce the effects of EtOH on claudin-5 transcription and paracellular permeability. Furthermore, a novel finding in this study suggests that very low concentrations of AOs in tinctures such as Rooibos tea could profoundly alter the redox status of brain ECs.

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