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Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction
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Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 32866

Special Issue Editors

Dr. Julie E. Simpson

E-Mail Website
Guest Editor
Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield S10 2HQ, UK
Interests: vascular dementia; Alzheimer’s disease; neuroinflammation; neuropathology
Special Issues, Collections and Topics in MDPI journals
Dr. Claire J. Garwood

E-Mail Website
Guest Editor
Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK
Interests: Alzheimer’s disease; astrocytes; insulin/IGF1 signalling

Special Issue Information

Dear Colleagues,

The blood–brain barrier comprises a highly specialised complex of cells within the neurovascular unit, and is responsible for tightly regulating homeostasis within the central nervous system, which is critical to maintain neuronal function.  Dysfunction of the blood–brain barrier is a key pathological feature of a range of neurodegenerative diseases including Alzheimer’s Disease, cerebrovascular disorders including stroke and vascular dementia, and neuroinflammatory diseases including multiple sclerosis. Loss of blood–brain barrier integrity can result in pathological permeability resulting in the entry of immune cells and/or molecules into the central nervous system which stimulate a neuroinflammatory response, as well as ion dysregulation and altered signalling homeostasis, processes that contribute to neuronal dysfunction and neurodegeneration.  Deciphering the mechanisms underlying dysfunction of the blood-brain barrier is an important area to identify and develop potential disease-modifying treatments. 

This Special Issue of IJMS provides a comprehensive synopsis of current blood–brain barrier research from cellular to molecular mechanisms, the relationship between blood–brain barrier dysfunction and the neuroinflammatory response, and animal/cell models to study the molecular mechanisms underlying the pathophysiology of blood–brain barrier disruption.

You are warmly invited to submit original research and review articles related to any of these aspects.

Prof. Dr. Julie E. Simpson
Dr. Claire J. Garwood
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Ageing
  • Alzheimer’s disease
  • Astrocytes
  • Blood–brain barrier
  • Endothelial dysfunction
  • Microglia
  • Multiple sclerosis
  • Neurodegeneration
  • Neuroinflammation
  • Permeability
  • Stroke
  • Tight junction proteins
  • Vascular dementia

Published Papers (5 papers)

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Research

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20 pages, 3352 KiB  
Article
Ketone Bodies Promote Amyloid-β1–40 Clearance in a Human in Vitro Blood–Brain Barrier Model
by Romain Versele, Mariangela Corsi, Andrea Fuso, Emmanuel Sevin, Rita Businaro, Fabien Gosselet, Laurence Fenart and Pietra Candela
Int. J. Mol. Sci. 2020, 21(3), 934; https://doi.org/10.3390/ijms21030934 - 31 Jan 2020
Cited by 40 | Viewed by 8151
Abstract
Alzheimer’s disease (AD) is characterized by the abnormal accumulation of amyloid-β (Aβ) peptides in the brain. The pathological process has not yet been clarified, although dysfunctional transport of Aβ across the blood–brain barrier (BBB) appears to be integral to disease development. At present, [...] Read more.
Alzheimer’s disease (AD) is characterized by the abnormal accumulation of amyloid-β (Aβ) peptides in the brain. The pathological process has not yet been clarified, although dysfunctional transport of Aβ across the blood–brain barrier (BBB) appears to be integral to disease development. At present, no effective therapeutic treatment against AD exists, and the adoption of a ketogenic diet (KD) or ketone body (KB) supplements have been investigated as potential new therapeutic approaches. Despite experimental evidence supporting the hypothesis that KBs reduce the Aβ load in the AD brain, little information is available about the effect of KBs on BBB and their effect on Aβ transport. Therefore, we used a human in vitro BBB model, brain-like endothelial cells (BLECs), to investigate the effect of KBs on the BBB and on Aβ transport. Our results show that KBs do not modify BBB integrity and do not cause toxicity to BLECs. Furthermore, the presence of KBs in the culture media was combined with higher MCT1 and GLUT1 protein levels in BLECs. In addition, KBs significantly enhanced the protein levels of LRP1, P-gp, and PICALM, described to be involved in Aβ clearance. Finally, the combined use of KBs promotes Aβ efflux across the BBB. Inhibition experiments demonstrated the involvement of LRP1 and P-gp in the efflux. This work provides evidence that KBs promote Aβ clearance from the brain to blood in addition to exciting perspectives for studying the use of KBs in therapeutic approaches. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction)
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17 pages, 1510 KiB  
Article
Neutrophil-Derived Microvesicle Induced Dysfunction of Brain Microvascular Endothelial Cells In Vitro
by Anjana Ajikumar, Merete B. Long, Paul R. Heath, Stephen B. Wharton, Paul G. Ince, Victoria C. Ridger and Julie E. Simpson
Int. J. Mol. Sci. 2019, 20(20), 5227; https://doi.org/10.3390/ijms20205227 - 22 Oct 2019
Cited by 37 | Viewed by 4777
Abstract
The blood-brain barrier (BBB), composed of brain microvascular endothelial cells (BMEC) that are tightly linked by tight junction (TJ) proteins, restricts the movement of molecules between the periphery and the central nervous system. Elevated systemic levels of neutrophils have been detected in patients [...] Read more.
The blood-brain barrier (BBB), composed of brain microvascular endothelial cells (BMEC) that are tightly linked by tight junction (TJ) proteins, restricts the movement of molecules between the periphery and the central nervous system. Elevated systemic levels of neutrophils have been detected in patients with altered BBB function, but the role of neutrophils in BMEC dysfunction is unknown. Neutrophils are key players of the immune response and, when activated, produce neutrophil-derived microvesicles (NMV). NMV have been shown to impact the integrity of endothelial cells throughout the body and we hypothesize that NMV released from circulating neutrophils interact with BMEC and induce endothelial cell dysfunction. Therefore, the current study investigated the interaction of NMV with human BMEC and determined whether they altered gene expression and function in vitro. Using flow cytometry and confocal imaging, NMV were shown to be internalized by the human cerebral microvascular endothelial cell line hCMEC/D3 via a variety of energy-dependent mechanisms, including endocytosis and macropinocytosis. The internalization of NMV significantly altered the transcriptomic profile of hCMEC/D3, specifically inducing the dysregulation of genes associated with TJ, ubiquitin-mediated proteolysis and vesicular transport. Functional studies confirmed NMV significantly increased permeability and decreased the transendothelial electrical resistance (TEER) of a confluent monolayer of hCMEC/D3. These findings indicate that NMV interact with and affect gene expression of BMEC as well as impacting their integrity. We conclude that NMV may play an important role in modulating the permeability of BBB during an infection. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction)
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20 pages, 3373 KiB  
Article
Age-Associated mRNA and miRNA Expression Changes in the Blood-Brain Barrier
by Emily F. Goodall, Vicki Leach, Chunfang Wang, Johnathan Cooper-Knock, Paul R. Heath, David Baker, David R. Drew, M. Jill Saffrey, Julie E. Simpson, Ignacio A. Romero and Stephen B. Wharton
Int. J. Mol. Sci. 2019, 20(12), 3097; https://doi.org/10.3390/ijms20123097 - 25 Jun 2019
Cited by 18 | Viewed by 5847
Abstract
Functional and structural age-associated changes in the blood-brain barrier (BBB) may affect the neurovascular unit and contribute to the onset and progression of age-associated neurodegenerative pathologies, including Alzheimer’s disease. The current study interrogated the RNA profile of the BBB in an ageing human [...] Read more.
Functional and structural age-associated changes in the blood-brain barrier (BBB) may affect the neurovascular unit and contribute to the onset and progression of age-associated neurodegenerative pathologies, including Alzheimer’s disease. The current study interrogated the RNA profile of the BBB in an ageing human autopsy brain cohort and an ageing mouse model using combined laser capture microdissection and expression profiling. Only 12 overlapping genes were altered in the same direction in the BBB of both ageing human and mouse cohorts. These included genes with roles in regulating vascular tone, tight junction protein expression and cell adhesion, all processes prone to dysregulation with advancing age. Integrated mRNA and miRNA network and pathway enrichment analysis of the datasets identified 15 overlapping miRNAs that showed altered expression. In addition to targeting genes related to DNA binding and/or autophagy, many of the miRNAs identified play a role in age-relevant processes, including BBB dysfunction and regulating the neuroinflammatory response. Future studies have the potential to develop targeted therapeutic approaches against these candidates to prevent vascular dysfunction in the ageing brain. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction)
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16 pages, 2253 KiB  
Article
MRI Relaxometry for Quantitative Analysis of USPIO Uptake in Cerebral Small Vessel Disease
by Michael J. Thrippleton, Gordon W. Blair, Maria C. Valdes-Hernandez, Andreas Glatz, Scott I. K. Semple, Fergus Doubal, Alex Vesey, Ian Marshall, David E. Newby and Joanna M. Wardlaw
Int. J. Mol. Sci. 2019, 20(3), 776; https://doi.org/10.3390/ijms20030776 - 12 Feb 2019
Cited by 11 | Viewed by 3823
Abstract
A protocol for evaluating ultrasmall superparamagnetic particles of iron oxide (USPIO) uptake and elimination in cerebral small vessel disease patients was developed and piloted. B1-insensitive R1 measurement was evaluated in vitro. Twelve participants with history of minor stroke were scanned [...] Read more.
A protocol for evaluating ultrasmall superparamagnetic particles of iron oxide (USPIO) uptake and elimination in cerebral small vessel disease patients was developed and piloted. B1-insensitive R1 measurement was evaluated in vitro. Twelve participants with history of minor stroke were scanned at 3-T MRI including structural imaging, and R1 and R2* mapping. Participants were scanned (i) before and (ii) after USPIO (ferumoxytol) infusion, and again at (iii) 24–30 h and (iv) one month. Absolute and blood-normalised changes in R1 and R2* were measured in white matter (WM), deep grey matter (GM), white matter hyperintensity (WMH) and stroke lesion regions. R1 measurements were accurate across a wide range of values. R1 (p < 0.05) and R2* (p < 0.01) mapping detected increases in relaxation rate in all tissues immediately post-USPIO and at 24–30 h. R2* returned to baseline at one month. Blood-normalised R1 and R2* changes post-infusion and at 24–30 h were similar, and were greater in GM versus WM (p < 0.001). Narrower distributions were seen with R2* than for R1 mapping. R1 and R2* changes were correlated at 24–30 h (p < 0.01). MRI relaxometry permits quantitative evaluation of USPIO uptake; R2* appears to be more sensitive to USPIO than R1. Our data are explained by intravascular uptake alone, yielding estimates of cerebral blood volume, and did not support parenchymal uptake. Ferumoxytol appears to be eliminated at 1 month. The approach should be valuable in future studies to quantify both blood-pool USPIO and parenchymal uptake associated with inflammatory cells or blood-brain barrier leak. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction)
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Review

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27 pages, 426 KiB  
Review
Mechanisms of Blood–Brain Barrier Dysfunction in Traumatic Brain Injury
by Alison Cash and Michelle H. Theus
Int. J. Mol. Sci. 2020, 21(9), 3344; https://doi.org/10.3390/ijms21093344 - 08 May 2020
Cited by 113 | Viewed by 9699
Abstract
Traumatic brain injuries (TBIs) account for the majority of injury-related deaths in the United States with roughly two million TBIs occurring annually. Due to the spectrum of severity and heterogeneity in TBIs, investigation into the secondary injury is necessary in order to formulate [...] Read more.
Traumatic brain injuries (TBIs) account for the majority of injury-related deaths in the United States with roughly two million TBIs occurring annually. Due to the spectrum of severity and heterogeneity in TBIs, investigation into the secondary injury is necessary in order to formulate an effective treatment. A mechanical consequence of trauma involves dysregulation of the blood–brain barrier (BBB) which contributes to secondary injury and exposure of peripheral components to the brain parenchyma. Recent studies have shed light on the mechanisms of BBB breakdown in TBI including novel intracellular signaling and cell–cell interactions within the BBB niche. The current review provides an overview of the BBB, novel detection methods for disruption, and the cellular and molecular mechanisms implicated in regulating its stability following TBI. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction)
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