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The Blood-Brain Barrier in Health and Disease
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The Blood-Brain Barrier in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 33291

Special Issue Editors

Prof. Dr. Amal Kaddoumi

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Guest Editor
Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, 720 S Donahue Dr., Auburn, AL 36849, USA
Interests: Alzheimer’s disease; cerebral amyloid angiopathy; blood-brain barrier; neuroinflammation; drug development; translational therapeutics
Special Issues, Collections and Topics in MDPI journals
Dr. Yazan S. Batarseh

E-Mail
Guest Editor
Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman – Jordan
Interests: Neuroscience; Blood-brain barrier; Alzhiemer’s disease; Drug discovery; Clinical pharmacy; Pharmacology
Dr. Sweilem Baseem Al Rihani

E-Mail Website
Guest Editor
Precision Pharmacotherapy Research & Development Institute, Tabula Rasa HealthCare, Orlando, FL, USA
Interests: clinical pharmacology; aging; drug metabolism, pharmacokinetics and pharmacodynamics; blood-brain barrier; precision pharmacotherapy

Special Issue Information

Dear Colleagues,

The brain requires vascularization and tight regulation of nutrients and waste products. Therefore, the blood-brain barrier (BBB) tightly regulates the transport of molecules and ions between blood vasculature and brain parenchyma. The BBB sets the microenvironment in the brain to achieve homeostasis and to ensure efficient neuronal function and provide basic protection against pathogens and toxins. The BBB works hand in hand with other cellular bodies in the brain to create a neurovascular coupling unit. Brain endothelial cells interact with pericytes, astrocytes, and microglial cells to establish a highly effective network to provide neurons with the ability to function properly. Understanding the complex role of the BBB and neurovascular coupling, and evaluating how these heterogeneous cell populations interact with such harmony in regulating the barrier function is vital for answering questions about brain function during health and disease states, which is essential to develop therapeutic drugs to treat neurodegenerative disorders. 

This Special Issue is focused on role of the BBB in brain function/dysfunction and would include original and up-to-date review articles on topics related, but not limited to the following: the BBB function, BBB role in neurodegenerative diseases such as Alzheimer’s disease and related disorders, Amyotrophic lateral sclerosis, Parkinson disease, Huntington’s disease, and other brain diseases.

Prof. Dr. Amal Kaddoumi
Dr. Yazan S. Batarseh
Dr. Sweilem Baseem Al Rihani
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

  • Blood-brain barrier
  • Neurovascular unit
  • Neurodegeneration
  • Aging
  • Alzheimer’s Disease
  • Amyotrophic Lateral Sclerosis
  • Parkinson Disease
  • Huntington’s disease
  • Epilepsy
  • Stroke
  • BBB as a therapeutic target
  • Translational research

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 193 KiB  
Editorial
The Blood–Brain Barrier in Health and Disease
by Sweilem B. Al Rihani, Yazan S. Batarseh and Amal Kaddoumi
Int. J. Mol. Sci. 2023, 24(11), 9261; https://doi.org/10.3390/ijms24119261 - 25 May 2023
Viewed by 1220
Abstract
The blood–brain barrier (BBB) is a complex network of tightly regulated cells and transport proteins that separate the circulating blood from the brain tissue [...] Full article
(This article belongs to the Special Issue The Blood-Brain Barrier in Health and Disease)

Research

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15 pages, 1293 KiB  
Article
Sex-Related Differences in Regional Blood–Brain Barrier Integrity in Non-Demented Elderly Subjects
by Yeonsil Moon, Changmok Lim, Yeahoon Kim and Won-Jin Moon
Int. J. Mol. Sci. 2021, 22(6), 2860; https://doi.org/10.3390/ijms22062860 - 11 Mar 2021
Cited by 21 | Viewed by 2904
Abstract
The role of the blood–brain barrier (BBB) breakdown has been recognized as being important in Alzheimer’s disease pathogenesis. We aimed to evaluate whether regional BBB integrity differed according to sex and whether differences in BBB integrity changed as a consequence of aging or [...] Read more.
The role of the blood–brain barrier (BBB) breakdown has been recognized as being important in Alzheimer’s disease pathogenesis. We aimed to evaluate whether regional BBB integrity differed according to sex and whether differences in BBB integrity changed as a consequence of aging or cognitive decline, using dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI). In total, 75 participants with normal cognition (NC) or mild cognitive impairment (MCI) underwent cognitive assessments and MRI examination including DCE-MRI. Regional Ktrans was calculated in cortical regions and the Patlak permeability model was used to calculate BBB permeability (Ktrans, min−1). Females had a lower median Ktrans in the cingulate and occipital cortices. In the “older old” group, sex differences in Ktrans were only observed in the occipital cortex. In the MCI group, sex differences in Ktrans were only observed in the occipital cortex. Age was the only predictor of cognitive assessment scores in the male MCI group; however, educational years and Ktrans in the occipital cortex could predict cognitive scores in the female MCI group. Our study revealed that females may have better BBB integrity in cingulate and occipital cortices. We also found that sex-related differences in BBB integrity are attenuated with aging or cognitive decline. Full article
(This article belongs to the Special Issue The Blood-Brain Barrier in Health and Disease)
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18 pages, 3656 KiB  
Article
Blood-Brain Barrier Disruption Increases Amyloid-Related Pathology in TgSwDI Mice
by Ihab M. Abdallah, Kamal M. Al-Shami, Euitaek Yang and Amal Kaddoumi
Int. J. Mol. Sci. 2021, 22(3), 1231; https://doi.org/10.3390/ijms22031231 - 27 Jan 2021
Cited by 14 | Viewed by 3597
Abstract
In Alzheimer’s disease (AD), several studies have reported blood-brain barrier (BBB) breakdown with compromised function. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are transport proteins localized at the BBB luminal membrane and play an important role in the clearance of amyloid-β (Aβ). [...] Read more.
In Alzheimer’s disease (AD), several studies have reported blood-brain barrier (BBB) breakdown with compromised function. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are transport proteins localized at the BBB luminal membrane and play an important role in the clearance of amyloid-β (Aβ). The purpose of this study was to investigate the effect of pharmacological inhibition of Aβ efflux transporters on BBB function and Aβ accumulation and related pathology. Recently, we have developed an in vitro high-throughput screening assay to screen for compounds that modulate the integrity of a cell-based BBB model, which identified elacridar as a disruptor of the monolayer integrity. Elacridar, an investigational compound known for its P-gp and BCRP inhibitory effect and widely used in cancer research. Therefore, it was used as a model compound for further evaluation in a mouse model of AD, namely TgSwDI. TgSwDI mouse is also used as a model for cerebral amyloid angiopathy (CAA). Results showed that P-gp and BCRP inhibition by elacridar disrupted the BBB integrity as measured by increased IgG extravasation and reduced expression of tight junction proteins, increased amyloid deposition due to P-gp, and BCRP downregulation and receptor for advanced glycation end products (RAGE) upregulation, increased CAA and astrogliosis. Further studies revealed the effect was mediated by activation of NF-κB pathway. In conclusion, results suggest that BBB disruption by inhibiting P-gp and BCRP exacerbates AD pathology in a mouse model of AD, and indicate that therapeutic drugs that inhibit P-gp and BCRP could increase the risk for AD. Full article
(This article belongs to the Special Issue The Blood-Brain Barrier in Health and Disease)
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Review

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22 pages, 25519 KiB  
Review
Blood–Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration
by Alla B. Salmina, Ekaterina V. Kharitonova, Yana V. Gorina, Elena A. Teplyashina, Natalia A. Malinovskaya, Elena D. Khilazheva, Angelina I. Mosyagina, Andrey V. Morgun, Anton N. Shuvaev, Vladimir V. Salmin, Olga L. Lopatina and Yulia K. Komleva
Int. J. Mol. Sci. 2021, 22(9), 4661; https://doi.org/10.3390/ijms22094661 - 28 Apr 2021
Cited by 23 | Viewed by 5915
Abstract
Pathophysiology of chronic neurodegeneration is mainly based on complex mechanisms related to aberrant signal transduction, excitation/inhibition imbalance, excitotoxicity, synaptic dysfunction, oxidative stress, proteotoxicity and protein misfolding, local insulin resistance and metabolic dysfunction, excessive cell death, development of glia-supported neuroinflammation, and failure of neurogenesis. [...] Read more.
Pathophysiology of chronic neurodegeneration is mainly based on complex mechanisms related to aberrant signal transduction, excitation/inhibition imbalance, excitotoxicity, synaptic dysfunction, oxidative stress, proteotoxicity and protein misfolding, local insulin resistance and metabolic dysfunction, excessive cell death, development of glia-supported neuroinflammation, and failure of neurogenesis. These mechanisms tightly associate with dramatic alterations in the structure and activity of the neurovascular unit (NVU) and the blood–brain barrier (BBB). NVU is an ensemble of brain cells (brain microvessel endothelial cells (BMECs), astrocytes, pericytes, neurons, and microglia) serving for the adjustment of cell-to-cell interactions, metabolic coupling, local microcirculation, and neuronal excitability to the actual needs of the brain. The part of the NVU known as a BBB controls selective access of endogenous and exogenous molecules to the brain tissue and efflux of metabolites to the blood, thereby providing maintenance of brain chemical homeostasis critical for efficient signal transduction and brain plasticity. In Alzheimer’s disease, mitochondria are the target organelles for amyloid-induced neurodegeneration and alterations in NVU metabolic coupling or BBB breakdown. In this review we discuss understandings on mitochondria-driven NVU and BBB dysfunction, and how it might be studied in current and prospective NVU/BBB in vitro models for finding new approaches for the efficient pharmacotherapy of Alzheimer’s disease. Full article
(This article belongs to the Special Issue The Blood-Brain Barrier in Health and Disease)
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29 pages, 2080 KiB  
Review
Disease-Induced Modulation of Drug Transporters at the Blood–Brain Barrier Level
by Sweilem B. Al Rihani, Lucy I. Darakjian, Malavika Deodhar, Pamela Dow, Jacques Turgeon and Veronique Michaud
Int. J. Mol. Sci. 2021, 22(7), 3742; https://doi.org/10.3390/ijms22073742 - 03 Apr 2021
Cited by 20 | Viewed by 4857
Abstract
The blood–brain barrier (BBB) is a highly selective and restrictive semipermeable network of cells and blood vessel constituents. All components of the neurovascular unit give to the BBB its crucial and protective function, i.e., to regulate homeostasis in the central nervous system (CNS) [...] Read more.
The blood–brain barrier (BBB) is a highly selective and restrictive semipermeable network of cells and blood vessel constituents. All components of the neurovascular unit give to the BBB its crucial and protective function, i.e., to regulate homeostasis in the central nervous system (CNS) by removing substances from the endothelial compartment and supplying the brain with nutrients and other endogenous compounds. Many transporters have been identified that play a role in maintaining BBB integrity and homeostasis. As such, the restrictive nature of the BBB provides an obstacle for drug delivery to the CNS. Nevertheless, according to their physicochemical or pharmacological properties, drugs may reach the CNS by passive diffusion or be subjected to putative influx and/or efflux through BBB membrane transporters, allowing or limiting their distribution to the CNS. Drug transporters functionally expressed on various compartments of the BBB involve numerous proteins from either the ATP-binding cassette (ABC) or the solute carrier (SLC) superfamilies. Pathophysiological stressors, age, and age-associated disorders may alter the expression level and functionality of transporter protein elements that modulate drug distribution and accumulation into the brain, namely, drug efficacy and toxicity. This review focuses and sheds light on the influence of inflammatory conditions and diseases such as Alzheimer’s disease, epilepsy, and stroke on the expression and functionality of the BBB drug transporters, the consequential modulation of drug distribution to the brain, and their impact on drug efficacy and toxicity. Full article
(This article belongs to the Special Issue The Blood-Brain Barrier in Health and Disease)
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30 pages, 1327 KiB  
Review
SSAO/VAP-1 in Cerebrovascular Disorders: A Potential Therapeutic Target for Stroke and Alzheimer’s Disease
by Mercedes Unzeta, Mar Hernàndez-Guillamon, Ping Sun and Montse Solé
Int. J. Mol. Sci. 2021, 22(7), 3365; https://doi.org/10.3390/ijms22073365 - 25 Mar 2021
Cited by 15 | Viewed by 4071
Abstract
The semicarbazide-sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1) or primary amine oxidase (PrAO), is a deaminating enzyme highly expressed in vessels that generates harmful products as a result of its enzymatic activity. As a multifunctional enzyme, it is also [...] Read more.
The semicarbazide-sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1) or primary amine oxidase (PrAO), is a deaminating enzyme highly expressed in vessels that generates harmful products as a result of its enzymatic activity. As a multifunctional enzyme, it is also involved in inflammation through its ability to bind and promote the transmigration of circulating leukocytes into inflamed tissues. Inflammation is present in different systemic and cerebral diseases, including stroke and Alzheimer’s disease (AD). These pathologies show important affectations on cerebral vessels, together with increased SSAO levels. This review summarizes the main roles of SSAO/VAP-1 in human physiology and pathophysiology and discusses the mechanisms by which it can affect the onset and progression of both stroke and AD. As there is an evident interrelationship between stroke and AD, basically through the vascular system dysfunction, the possibility that SSAO/VAP-1 could be involved in the transition between these two pathologies is suggested. Hence, its inhibition is proposed to be an interesting therapeutical approach to the brain damage induced in these both cerebral pathologies. Full article
(This article belongs to the Special Issue The Blood-Brain Barrier in Health and Disease)
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28 pages, 1088 KiB  
Review
Interactions of SARS-CoV-2 with the Blood–Brain Barrier
by Michelle A. Erickson, Elizabeth M. Rhea, Rachel C. Knopp and William A. Banks
Int. J. Mol. Sci. 2021, 22(5), 2681; https://doi.org/10.3390/ijms22052681 - 06 Mar 2021
Cited by 104 | Viewed by 9506
Abstract
Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood–brain barrier (BBB) is a critical interface that regulates entry of circulating molecules into the CNS, and is regulated by signals that arise [...] Read more.
Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood–brain barrier (BBB) is a critical interface that regulates entry of circulating molecules into the CNS, and is regulated by signals that arise from the brain and blood compartments. In this review, we discuss mechanisms by which SARS-CoV-2 interactions with the BBB may contribute to neurological dysfunction associated with coronavirus disease of 2019 (COVID-19), which is caused by SARS-CoV-2. We consider aspects of peripheral disease, such as hypoxia and systemic inflammatory response syndrome/cytokine storm, as well as CNS infection and mechanisms of viral entry into the brain. We also discuss the contribution of risk factors for developing severe COVID-19 to BBB dysfunction that could increase viral entry or otherwise damage the brain. Full article
(This article belongs to the Special Issue The Blood-Brain Barrier in Health and Disease)
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