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Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 2.0

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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 October 2022) | Viewed by 28011

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Dr. Julie E. Simpson

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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

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.

Dr. Julie E. Simpson
Guest Editor

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 (10 papers)

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Editorial

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2 pages, 173 KiB

Open AccessEditorial

Potential Mechanisms Underlying the Dysfunction of the Blood–Brain Barrier

by Julie E. Simpson

Int. J. Mol. Sci. 2023, 24(9), 8184; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24098184 - 03 May 2023

Cited by 2 | Viewed by 914

Abstract

The blood–brain barrier (BBB) 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 for maintaining neuronal function [...] Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 2.0)

Research

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6 pages, 718 KiB

Open AccessCommunication

Time of Day Influences Concentrations of Total Protein and Albumin in Cerebrospinal Fluid in HIV

by Visesha Kakarla, Scott L. Letendre and Ronald J. Ellis

Int. J. Mol. Sci. 2023, 24(3), 2832; https://doi.org/10.3390/ijms24032832 - 01 Feb 2023

Viewed by 1477

Abstract

The accumulation of soluble proteins and metabolites during wakefulness and their clearance during sleep via the glymphatic system occurs in healthy adults and is disturbed in some neurological conditions. Such diurnal variations in the cerebrospinal fluid (CSF) proteins produced outside the central nervous system and entering via the blood–brain barrier (BBB) have not been evaluated in people with HIV (PWH). CSF and blood were collected in 165 PWH at six US centers between 2003 and 2007. The time of collection was compared to CSF albumin, globulin, and total protein concentrations using bivariate and multivariate regression. Participants all took antiretroviral therapy (ART) and were mostly middle-aged (median age 44.0 years) men (78.8%), with AIDS (77.0%), plasma HIV RNA ≤ 200 copies/mL (75.8%), and immune recovery (median CD4+ T-cell count 414/µL). CSF was collected at median 1:10 p.m. (range 9:00 a.m. to 5:20 p.m.) and within a median of 15 min of blood collection. A later time of CSF collection was associated with higher total protein (p = 0.0077) and albumin (p = 0.057) in CSF but not in serum, and was additionally associated with higher CSF globulin (p = 0.013). The glymphatic clearance of albumin, globulin, and total protein is preserved in PWH. The analyses of soluble biomarkers in CSF should account for the time of collection. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 2.0)

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22 pages, 4236 KiB

Open AccessArticle

TNF-α and IL-1β Modulate Blood-Brain Barrier Permeability and Decrease Amyloid-β Peptide Efflux in a Human Blood-Brain Barrier Model

by Romain Versele, Emmanuel Sevin, Fabien Gosselet, Laurence Fenart and Pietra Candela

Int. J. Mol. Sci. 2022, 23(18), 10235; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810235 - 06 Sep 2022

Cited by 25 | Viewed by 2964

Abstract

The blood-brain barrier (BBB) is a selective barrier and a functional gatekeeper for the central nervous system (CNS), essential for maintaining brain homeostasis. The BBB is composed of specialized brain endothelial cells (BECs) lining the brain capillaries. The tight junctions formed by BECs regulate paracellular transport, whereas transcellular transport is regulated by specialized transporters, pumps and receptors. Cytokine-induced neuroinflammation, such as the tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), appear to play a role in BBB dysfunction and contribute to the progression of Alzheimer’s disease (AD) by contributing to amyloid-β (Aβ) peptide accumulation. Here, we investigated whether TNF-α and IL-1β modulate the permeability of the BBB and alter Aβ peptide transport across BECs. We used a human BBB in vitro model based on the use of brain-like endothelial cells (BLECs) obtained from endothelial cells derived from CD34+ stem cells cocultivated with brain pericytes. We demonstrated that TNF-α and IL-1β differentially induced changes in BLECs’ permeability by inducing alterations in the organization of junctional complexes as well as in transcelluar trafficking. Further, TNF-α and IL-1β act directly on BLECs by decreasing LRP1 and BCRP protein expression as well as the specific efflux of Aβ peptide. These results provide mechanisms by which CNS inflammation might modulate BBB permeability and promote Aβ peptide accumulation. A future therapeutic intervention targeting vascular inflammation at the BBB may have the therapeutic potential to slow down the progression of AD. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 2.0)

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14 pages, 903 KiB

Open AccessCommunication

RNA-Seq Profiling of Neutrophil-Derived Microvesicles in Alzheimer’s Disease Patients Identifies a miRNA Signature That May Impact Blood–Brain Barrier Integrity

by Irina Vázquez-Villaseñor, Cynthia I. Smith, Yung J. R. Thang, Paul R. Heath, Stephen B. Wharton, Daniel J. Blackburn, Victoria C. Ridger and Julie E. Simpson

Int. J. Mol. Sci. 2022, 23(11), 5913; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23115913 - 25 May 2022

Cited by 7 | Viewed by 2243

Abstract

(1) Background: Systemic infection is associated with increased neuroinflammation and accelerated cognitive decline in AD patients. Activated neutrophils produce neutrophil-derived microvesicles (NMV), which are internalised by human brain microvascular endothelial cells and increase their permeability in vitro, suggesting that NMV play a role in blood–brain barrier (BBB) integrity during infection. The current study investigated whether microRNA content of NMV from AD patients is significantly different compared to healthy controls and could impact cerebrovascular integrity. (2) Methods: Neutrophils isolated from peripheral blood samples of five AD and five healthy control donors without systemic infection were stimulated to produce NMV. MicroRNAs isolated from NMV were analysed by RNA-Seq, and online bioinformatic tools were used to identify significantly differentially expressed microRNAs in the NMV. Target and pathway analyses were performed to predict the impact of the candidate microRNAs on vascular integrity. (3) Results: There was no significant difference in either the number of neutrophils (p = 0.309) or the number of NMV (p = 0.3434) isolated from AD donors compared to control. However, 158 microRNAs were significantly dysregulated in AD NMV compared to controls, some of which were associated with BBB dysfunction, including miR-210, miR-20b-5p and miR-126-5p. Pathway analysis revealed numerous significantly affected pathways involved in regulating vascular integrity, including the TGFβ and PDGFB pathways, as well as Hippo, IL-2 and DNA damage signalling. (4) Conclusions: NMV from AD patients contain miRNAs that may alter the integrity of the BBB and represent a novel neutrophil-mediated mechanism for BBB dysfunction in AD and the accelerated cognitive decline seen as a result of a systemic infection. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 2.0)

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11 pages, 2337 KiB

Open AccessArticle

Blood–Brain Barrier Disruption Mediated by FFA1 Receptor—Evidence Using Miniscope

by Kristen L. Lindenau, Jeffrey L. Barr, Christopher R. Higgins, Kevin T. Sporici, Eugen Brailoiu and Gabriela C. Brailoiu

Int. J. Mol. Sci. 2022, 23(4), 2258; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042258 - 18 Feb 2022

Cited by 4 | Viewed by 2325

Abstract

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), obtained from diet and dietary supplements, have been tested in clinical trials for the prevention or treatment of several diseases. n-3 PUFAs exert their effects by activation of free fatty acid (FFA) receptors. FFA1 receptor, expressed in the pancreas and brain, is activated by medium- to long-chain fatty acids. Despite some beneficial effects on cognition, the effects of n-3 PUFAs on the blood–brain barrier (BBB) are not clearly understood. We examined the effects of FFA1 activation on BBB permeability in vitro, using rat brain microvascular endothelial cells (RBMVEC), and in vivo, by assessing Evans Blue extravasation and by performing live imaging of brain microcirculation in adult rats. AMG837, a synthetic FFA1 agonist, produced a dose-dependent decrease in RBMVEC monolayer resistance assessed with Electric Cell–Substrate Impedance Sensing (ECIS); the effect was attenuated by the FFA1 antagonist, GW1100. Immunofluorescence studies revealed that AMG837 produced a disruption in tight and adherens junction proteins. AMG837 increased Evans Blue content in the rat brain in a dose-dependent manner. Live imaging studies of rat brain microcirculation with miniaturized fluorescence microscopy (miniscope) showed that AMG837 increased extravasation of sodium fluorescein. Taken together, our results demonstrate that FFA1 receptor activation reduced RBMVEC barrier function and produced a transient increase in BBB permeability. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 2.0)

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Review

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18 pages, 2590 KiB

Open AccessReview

Mechanistic Insights, Treatment Paradigms, and Clinical Progress in Neurological Disorders: Current and Future Prospects

by Saad Alkahtani, Norah S. AL-Johani and Saud Alarifi

Int. J. Mol. Sci. 2023, 24(2), 1340; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021340 - 10 Jan 2023

Cited by 8 | Viewed by 2060

Abstract

Neurodegenerative diseases (NDs) are a major cause of disability and are related to brain development. The neurological signs of brain lesions can vary from mild clinical shortfalls to more delicate and severe neurological/behavioral symptoms and learning disabilities, which are progressive. In this paper, we have tried to summarize a collective view of various NDs and their possible therapeutic outcomes. These diseases often occur as a consequence of the misfolding of proteins post-translation, as well as the dysfunctional trafficking of proteins. In the treatment of neurological disorders, a challenging hurdle to cross regarding drug delivery is the blood–brain barrier (BBB). The BBB plays a unique role in maintaining the homeostasis of the central nervous system (CNS) by exchanging components between the circulations and shielding the brain from neurotoxic pathogens and detrimental compounds. Here, we outline the current knowledge about BBB deterioration in the evolving brain, its origin, and therapeutic interventions. Additionally, we summarize the physiological scenarios of the BBB and its role in various cerebrovascular diseases. Overall, this information provides a detailed account of BBB functioning and the development of relevant treatments for neurological disorders. This paper will definitely help readers working in the field of neurological scientific communities. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 2.0)

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30 pages, 2832 KiB

Open AccessReview

Blood–Brain Barrier Disruption and Its Involvement in Neurodevelopmental and Neurodegenerative Disorders

by Ana Aragón-González, Pamela J. Shaw and Laura Ferraiuolo

Int. J. Mol. Sci. 2022, 23(23), 15271; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315271 - 03 Dec 2022

Cited by 11 | Viewed by 3449

Abstract

The blood–brain barrier (BBB) is a highly specialized and dynamic compartment which regulates the uptake of molecules and solutes from the blood. The relevance of the maintenance of a healthy BBB underpinning disease prevention as well as the main pathomechanisms affecting BBB function will be detailed in this review. Barrier disruption is a common aspect in both neurodegenerative diseases, such as amyotrophic lateral sclerosis, and neurodevelopmental diseases, including autism spectrum disorders. Throughout this review, conditions altering the BBB during the earliest and latest stages of life will be discussed, revealing common factors involved. Due to the barrier’s role in protecting the brain from exogenous components and xenobiotics, drug delivery across the BBB is challenging. Potential therapies based on the BBB properties as molecular Trojan horses, among others, will be reviewed, as well as innovative treatments such as stem cell therapies. Additionally, due to the microbiome influence on the normal function of the brain, microflora modulation strategies will be discussed. Finally, future research directions are highlighted to address the current gaps in the literature, emphasizing the idea that common therapies for both neurodevelopmental and neurodegenerative pathologies exist. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 2.0)

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52 pages, 1994 KiB

Open AccessReview

Laminin as a Biomarker of Blood–Brain Barrier Disruption under Neuroinflammation: A Systematic Review

by Juan F. Zapata-Acevedo, Valentina García-Pérez, Ricardo Cabezas-Pérez, Monica Losada-Barragán, Karina Vargas-Sánchez and Rodrigo E. González-Reyes

Int. J. Mol. Sci. 2022, 23(12), 6788; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126788 - 17 Jun 2022

Cited by 8 | Viewed by 3357

Abstract

Laminin, a non-collagenous glycoprotein present in the brain extracellular matrix, helps to maintain blood–brain barrier (BBB) integrity and regulation. Neuroinflammation can compromise laminin structure and function, increasing BBB permeability. The aim of this paper is to determine if neuroinflammation-induced laminin functional changes may serve as a potential biomarker of alterations in the BBB. The 38 publications included evaluated neuroinflammation, BBB disruption, and laminin, and were assessed for quality and risk of bias (protocol registered in PROSPERO; CRD42020212547). We found that laminin may be a good indicator of BBB overall structural integrity, although changes in expression are dependent on the pathologic or experimental model used. In ischemic stroke, permanent vascular damage correlates with increased laminin expression (β and γ subunits), while transient damage correlates with reduced laminin expression (α subunits). Laminin was reduced in traumatic brain injury and cerebral hemorrhage studies but increased in multiple sclerosis and status epilepticus studies. Despite these observations, there is limited knowledge about the role played by different subunits or isoforms (such as 411 or 511) of laminin in maintaining structural architecture of the BBB under neuroinflammation. Further studies may clarify this aspect and the possibility of using laminin as a biomarker in different pathologies, which have alterations in BBB function in common. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 2.0)

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40 pages, 4659 KiB

Open AccessReview

Form and Function of the Vertebrate and Invertebrate Blood-Brain Barriers

by Alicia D. Dunton, Torben Göpel, Dao H. Ho and Warren Burggren

Int. J. Mol. Sci. 2021, 22(22), 12111; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212111 - 09 Nov 2021

Cited by 16 | Viewed by 3673

Abstract

The need to protect neural tissue from toxins or other substances is as old as neural tissue itself. Early recognition of this need has led to more than a century of investigation of the blood-brain barrier (BBB). Many aspects of this important neuroprotective barrier have now been well established, including its cellular architecture and barrier and transport functions. Unsurprisingly, most research has had a human orientation, using mammalian and other animal models to develop translational research findings. However, cell layers forming a barrier between vascular spaces and neural tissues are found broadly throughout the invertebrates as well as in all vertebrates. Unfortunately, previous scenarios for the evolution of the BBB typically adopt a classic, now discredited ‘scala naturae’ approach, which inaccurately describes a putative evolutionary progression of the mammalian BBB from simple invertebrates to mammals. In fact, BBB-like structures have evolved independently numerous times, complicating simplistic views of the evolution of the BBB as a linear process. Here, we review BBBs in their various forms in both invertebrates and vertebrates, with an emphasis on the function, evolution, and conditional relevance of popular animal models such as the fruit fly and the zebrafish to mammalian BBB research. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 2.0)

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22 pages, 20898 KiB

Open AccessReview

Deficient Leptin Cellular Signaling Plays a Key Role in Brain Ultrastructural Remodeling in Obesity and Type 2 Diabetes Mellitus

by Melvin R. Hayden and William A. Banks

Int. J. Mol. Sci. 2021, 22(11), 5427; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115427 - 21 May 2021

Cited by 22 | Viewed by 4322

Abstract

The triad of obesity, metabolic syndrome (MetS), Type 2 diabetes mellitus (T2DM) and advancing age are currently global societal problems that are expected to grow over the coming decades. This triad is associated with multiple end-organ complications of diabetic vasculopathy (maco-microvessel disease), neuropathy, retinopathy, nephropathy, cardiomyopathy, cognopathy encephalopathy and/or late-onset Alzheimer’s disease. Further, obesity, MetS, T2DM and their complications are associated with economical and individual family burdens. This review with original data focuses on the white adipose tissue-derived adipokine/hormone leptin and how its deficient signaling is associated with brain remodeling in hyperphagic, obese, or hyperglycemic female mice. Specifically, the ultrastructural remodeling of the capillary neurovascular unit, brain endothelial cells (BECs) and their endothelial glycocalyx (ecGCx), the blood-brain barrier (BBB), the ventricular ependymal cells, choroid plexus, blood-cerebrospinal fluid barrier (BCSFB), and tanycytes are examined in female mice with impaired leptin signaling from either dysfunction of the leptin receptor (DIO and db/db models) or the novel leptin deficiency (BTBR ob/ob model). Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 2.0)

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