scholarly journals Age-Associated mRNA and miRNA Expression Changes in the Blood-Brain Barrier

2019 ◽  
Vol 20 (12) ◽  
pp. 3097 ◽  
Author(s):  
Emily F. Goodall ◽  
Vicki Leach ◽  
Chunfang Wang ◽  
Johnathan Cooper-Knock ◽  
Paul R. Heath ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Vascular Dysfunction ◽  
Neurovascular Unit ◽  
Enrichment Analysis ◽  
Brain Barrier ◽  
Pathway Enrichment Analysis ◽  
Altered Expression ◽  
Blood Brain ◽  
Junction Protein ◽  
Laser Capture

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.

scholarly journals Blood-Brain Barrier Damage in Ischemic Stroke and Its Regulation by Endothelial Mechanotransduction

2020 ◽  
Vol 11 ◽  
Author(s):  
Keqing Nian ◽  
Ian C. Harding ◽  
Ira M. Herman ◽  
Eno E. Ebong
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Neurovascular Unit ◽  
The United States ◽  
Brain Barrier ◽  
Endothelial Glycocalyx ◽  
Altered Expression ◽  
Blood Brain

Ischemic stroke, a major cause of mortality in the United States, often contributes to disruption of the blood-brain barrier (BBB). The BBB along with its supportive cells, collectively referred to as the “neurovascular unit,” is the brain’s multicellular microvasculature that bi-directionally regulates the transport of blood, ions, oxygen, and cells from the circulation into the brain. It is thus vital for the maintenance of central nervous system homeostasis. BBB disruption, which is associated with the altered expression of tight junction proteins and BBB transporters, is believed to exacerbate brain injury caused by ischemic stroke and limits the therapeutic potential of current clinical therapies, such as recombinant tissue plasminogen activator. Accumulating evidence suggests that endothelial mechanobiology, the conversion of mechanical forces into biochemical signals, helps regulate function of the peripheral vasculature and may similarly maintain BBB integrity. For example, the endothelial glycocalyx (GCX), a glycoprotein-proteoglycan layer extending into the lumen of bloods vessel, is abundantly expressed on endothelial cells of the BBB and has been shown to regulate BBB permeability. In this review, we will focus on our understanding of the mechanisms underlying BBB damage after ischemic stroke, highlighting current and potential future novel pharmacological strategies for BBB protection and recovery. Finally, we will address the current knowledge of endothelial mechanotransduction in BBB maintenance, specifically focusing on a potential role of the endothelial GCX.

scholarly journals Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

2020 ◽  
Vol 117 (6) ◽  
pp. 3326-3336 ◽  
Author(s):  
Katarzyna A. Dudek ◽  
Laurence Dion-Albert ◽  
Manon Lebel ◽  
Katherine LeClair ◽  
Simon Labrecque ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Social Stress ◽  
Antidepressant Treatment ◽  
Vascular Dysfunction ◽  
Brain Barrier ◽  
Behavioral Strategies ◽  
Stress Resilience ◽  
Molecular Changes ◽  
Blood Brain ◽  
Junction Protein

Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood–brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.

scholarly journals Regulation of blood–brain barrier integrity by microglia in health and disease: A therapeutic opportunity

2020 ◽  
Vol 40 (1_suppl) ◽  
pp. S6-S24 ◽  
Author(s):  
Patrick T Ronaldson ◽  
Thomas P Davis
Keyword(s):  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Neurovascular Unit ◽  
Physiological Role ◽  
Cell Types ◽  
Current Data ◽  
Brain Barrier ◽  
Blood Brain ◽  
Junction Protein ◽  
Anti Inflammatory

The blood–brain barrier (BBB) is a critical regulator of CNS homeostasis. It possesses physical and biochemical characteristics (i.e. tight junction protein complexes, transporters) that are necessary for the BBB to perform this physiological role. Microvascular endothelial cells require support from astrocytes, pericytes, microglia, neurons, and constituents of the extracellular matrix. This intricate relationship implies the existence of a neurovascular unit (NVU). NVU cellular components can be activated in disease and contribute to dynamic remodeling of the BBB. This is especially true of microglia, the resident immune cells of the brain, which polarize into distinct proinflammatory (M1) or anti-inflammatory (M2) phenotypes. Current data indicate that M1 pro-inflammatory microglia contribute to BBB dysfunction and vascular “leak”, while M2 anti-inflammatory microglia play a protective role at the BBB. Understanding biological mechanisms involved in microglia activation provides a unique opportunity to develop novel treatment approaches for neurological diseases. In this review, we highlight characteristics of M1 proinflammatory and M2 anti-inflammatory microglia and describe how these distinct phenotypes modulate BBB physiology. Additionally, we outline the role of other NVU cell types in regulating microglial activation and highlight how microglia can be targeted for treatment of disease with a focus on ischemic stroke and Alzheimer’s disease.

scholarly journals Screening for Interacting Proteins with Peptide Biomarker of Blood–Brain Barrier Alteration under Inflammatory Conditions

2021 ◽  
Vol 22 (9) ◽  
pp. 4725
Author(s):  
Karina Vargas-Sanchez ◽  
Monica Losada-Barragán ◽  
Maria Mogilevskaya ◽  
Susana Novoa-Herrán ◽  
Yehidi Medina ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Specific Interaction ◽  
Brain Barrier ◽  
Mass Spectrometry Analysis ◽  
Peptide Ligand ◽  
Inflammatory Conditions ◽  
Blood Brain ◽  
Potential Biomarker

Neurodegenerative diseases are characterized by increased permeability of the blood–brain barrier (BBB) due to alterations in cellular and structural components of the neurovascular unit, particularly in association with neuroinflammation. A previous screening study of peptide ligands to identify molecular alterations of the BBB in neuroinflammation by phage-display, revealed that phage clone 88 presented specific binding affinity to endothelial cells under inflammatory conditions in vivo and in vitro. Here, we aimed to identify the possible target receptor of the peptide ligand 88 expressed under inflammatory conditions. A cross-link test between phage-peptide-88 with IL-1β-stimulated human hCMEC cells, followed by mass spectrometry analysis, was used to identify the target of peptide-88. We modeled the epitope–receptor molecular interaction between peptide-88 and its target by using docking simulations. Three proteins were selected as potential target candidates and tested in enzyme-linked immunosorbent assays with peptide-88: fibronectin, laminin subunit α5 and laminin subunit β-1. Among them, only laminin subunit β-1 presented measurable interaction with peptide-88. Peptide-88 showed specific interaction with laminin subunit β-1, highlighting its importance as a potential biomarker of the laminin changes that may occur at the BBB endothelial cells under pathological inflammation conditions.

scholarly journals Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions

Blood ◽  
2011 ◽  
Vol 118 (7) ◽  
pp. 2007-2014 ◽  
Author(s):  
Richard S. Beard ◽  
Jason J. Reynolds ◽  
Shawn E. Bearden
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Junction Protein ◽  
Brain Barrier Permeability

Abstract Hyperhomocysteinemia (HHcy) increases permeability of the blood-brain barrier, but the mechanisms are undetermined. Homocysteine (Hcy) is an agonist of the neuronal N-methyl-D-aspartate receptor (NMDAr). We tested the hypothesis that HHcy disrupts the blood-brain barrier by an NMDAr-dependent mechanism in endothelium. In brain microvascular endothelial cells, there was no change in expression of the adherens junction protein VE-cadherin with Hcy treatment, but there was a significant decrease in the amount of β-catenin at the membrane. Moreover, Hcy caused nuclear translocation of β-catenin and attachment to the promoter for the tight junction protein claudin-5, with concomitant reduction in claudin-5 expression. Using a murine model of HHcy (cbs+/−), treatment for 2 weeks with an NMDAr antagonist (memantine) rescued cerebrovascular expression of claudin-5 and blood-brain barrier permeability to both exogenous sodium fluorescein and endogenous IgG. Memantine had no effect on these parameters in wild-type littermates. The same results were obtained using an in vitro model with brain microvascular endothelial cells. These data provide the first evidence that the NMDAr is required for Hcy-mediated increases in blood-brain barrier permeability. Modulating cerebral microvascular NMDAr activity may present a novel therapeutic target in diseases associated with opening of the blood-brain barrier in HHcy, such as stroke and dementia.

Abstract TP256: Mouse Model of Uremic Cerebral Microbleeds

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Wei Ling Lau ◽  
Mary Tarbiat-Boldaji ◽  
Hayley Smalls ◽  
Ane Nunes ◽  
Javad Savoj ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Cerebral Microbleeds ◽  
Brain Barrier ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Increased Risk ◽  
Junction Protein ◽  
Blood Brain Barrier Integrity

Introduction: Cerebral microbleeds are more common in chronic kidney disease (CKD) and dialysis patients compared to the general population. Diminished kidney function alone appears to be a risk factor for microbleeds, independent of age and hypertension. Microbleed burden in CKD patients is associated with increased risk of future hemorrhagic stroke and with cognitive dysfunction. The mechanisms that drive uremic microbleed formation are unclear. Hypothesis: We hypothesized that CKD mice are predisposed to develop cerebral microhemorrhages (the pathologic substrate of microbleeds), and that a standardized inflammatory stimulus (lipopolysaccharide, LPS) will amplify microhemorrhage burden in CKD mice compared to non-CKD controls (CTL). We also hypothesized that uremia induces depletion of tight junction proteins, altering blood-brain barrier integrity and representing a potential mechanism of microbleed formation. Methods: Animal groups included CTL (n=3), CKD (n=3), CTL+LPS (n=5) and CKD+LPS (n=5). CKD induction in male C57BL/6 mice was achieved via nephrotoxic adenine diet x18 days. Two weeks following CKD induction, CKD and control mice were treated with LPS 1 mg/kg i.p. dosed at 0, 6 and 24 hours. Brains were harvested one week after LPS injections and 40-micron sections were stained using Prussian blue to identify microhemorrhages. Immunohistochemistry was performed for the blood-brain barrier tight junction protein claudin-5. Results: CKD mice had significantly elevated blood urea nitrogen, and tubulointerstitial fibrosis was present on kidney histology. Total number of microhemorrhages per brain was 2.3±1.5 (mean ± standard error of the mean) for CTL mice, 8.3±1.5 for CKD mice, 23.2±4.2 for CTL+LPS mice, and 27.6±6.2 for CKD+LPS mice (p<0.05 for CKD+LPS vs. CTL). Immunostaining showed decreased claudin-5 expression in CKD mice compared to CTL. Conclusions: We have generated a mouse model that will facilitate future mechanistic studies in the field of uremic microbleeds. Our initial findings suggest that CKD alters blood-brain barrier integrity and that inflammation amplifies development of microbleeds in CKD.

scholarly journals Time-dependent dual effect of NLRP3 inflammasome in brain ischemia

2020 ◽  
Author(s):  
Alejandra Palomino-Antolin ◽  
Paloma Narros-Fernández ◽  
Víctor Farré-Alins ◽  
Javier Sevilla-Montero ◽  
Celine Decouty-Pérez ◽  
...  
Keyword(s):  
Brain Injury ◽  
Blood Brain Barrier ◽  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Neurovascular Unit ◽  
Time Dependent ◽  
Brain Barrier ◽  
Dependent Manner ◽  
Dual Effect ◽  
Blood Brain

AbstractBackground and purposePost-ischemic inflammation contributes to worsening of ischemic brain injury and in this process, the inflammasomes play a key role. Inflammasomes are cytosolic multiprotein complexes which upon assembly activate the maturation and secretion of the inflammatory cytokines IL-1β and IL-18. However, participation of the NLRP3 inflammasome in ischemic stroke remains controversial. Our aims were to determine the role of NLRP3 in ischemia and to explore the mechanism involved in the potential protective effect of the neurovascular unit.MethodsWT and NLRP3 knock-out mice were subjected to ischemia by middle cerebral artery occlusion (60 minutes) with or without treatment with MCC950 at different time points post-stroke. Brain injury was measured histologically with 2,3,5-triphenyltetrazolium chloride (TTC) staining.ResultsWe identified a time-dependent dual effect of NLRP3. While neither the pre-treatment with MCC950 nor the genetic approach (NLRP3 KO) proved to be neuroprotective, post-reperfusion treatment with MCC950 significantly reduced the infarct volume in a dose-dependent manner. Importantly, MCC950 improved the neuro-motor function and reduced the expression of different pro-inflammatory cytokines (IL-1β, TNF-α), NLRP3 inflammasome components (NLRP3, pro-caspase-1), protease expression (MMP9) and endothelial adhesion molecules (ICAM, VCAM). We observed a marked protection of the blood-brain barrier (BBB), which was also reflected in the recovery of the tight junctions proteins (ZO-1, Claudin-5). Additionally, MCC950 produced a reduction of the CCL2 chemokine in blood serum and in brain tissue, which lead to a reduction in the immune cell infiltration.ConclusionsThese findings suggest that post-reperfusion NLRP3 inhibition may be an effective acute therapy for protecting the blood-brain barrier in cerebral ischemia with potential clinical translation.

scholarly journals Effects of fasudil on blood-brain barrier integrity

2021 ◽  
Author(s):  
Kei Sato ◽  
Shinsuke Nakagawa ◽  
Yoichi Morofuji ◽  
Yuki Matsunaga ◽  
Takashi Fujimoto ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Tight Junction ◽  
Acute Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Tight Junction Protein ◽  
Brain Barrier ◽  
Blood Brain ◽  
Junction Protein ◽  
Culture Models

Abstract Background Cerebral infarction accounts for 85% of all stroke cases. Even in an era of rapid and effective recanalization using an intravascular approach, the majority of patients have poor functional outcomes. Thus, there is an urgent need for the development of therapeutic agents to treat acute ischemic stroke. We evaluated the effect of fasudil, a Rho kinase inhibitor, on blood brain barrier (BBB) functions under normoxia or oxygen-glucose deprivation (OGD) conditions using a primary cell-based in vitro BBB model. Medhods: BBB models from rat primary cultures (brain capillary endothelial cells, astrocytes, and pericytes) were subjected to either normoxia or 6-hour OGD/24-hour reoxygenation. To assess the effects of fasudil on BBB functions, we evaluated real time impedance, transendothelial electrical resistance (TEER), sodium fluorescein permeability, and tight junction protein expression using immunohistochemistry and western blotting. Lastly, to understand the observed protective mechanism on BBB functions by fasudil we examined the role of cyclooxygenase-2 and thromboxane A2 receptor agonist U-46619 in BBB-forming cells. Results We found that treatment with 0.3–30 µM of fasudil increased cellular impedance. Fasudil enhanced barrier properties in a concentration-dependent manner, as measured by an increased (TEER) and decreased permeability. Fasudil also increased the expression of tight junction protein claudin-5. Reductions in TEER and increased permeability were observed after OGD/reoxygenation exposure in mono- and co-culture models. The improvement in BBB integrity by fasudil was confirmed in both of the models, but was significantly higher in the co-culture than in the monoculture model. Treatment with U-46619 did not show significant changes in TEER in the monoculture model, whereas it showed a significant reduction in TEER in the co-culture model. Fasudil significantly improved the U-46619-induced TEER reduction in the co-culture models. Pericytes and astrocytes have opposite effects on endothelial cells and may contribute to endothelial injury in hyperacute ischemic stroke. Overall, fasudil protects the integrity of BBB both by a direct protective effect on endothelial cells and by a pathway mediated via pericytes and astrocytes. Conclusions Our findings suggest that fasudil is a BBB-protective agent against acute ischemic stroke.

scholarly journals Targeting microRNAs to Regulate the Integrity of the Blood–Brain Barrier

2021 ◽  
Vol 9 ◽  
Author(s):  
Juntao Wang ◽  
Fang Xu ◽  
Xiaoming Zhu ◽  
Xianghua Li ◽  
Yankun Li ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Cerebrovascular Diseases ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Blood Brain ◽  
Recent Developments ◽  
Important Regulator

The blood–brain barrier (BBB) is a highly specialized neurovascular unit that protects the brain from potentially harmful substances. In addition, the BBB also engages in the exchange of essential nutrients between the vasculature and brain parenchyma, which is critical for brain homeostasis. Brain diseases, including neurological disorders and cerebrovascular diseases, are often associated with disrupted BBB integrity, evidenced by increased permeability. Therefore, defining the mechanisms underlying the regulation of BBB integrity is crucial for the development of novel therapeutics targeting brain diseases. MicroRNAs (miRNA), a type of small non-coding RNAs, are emerging as an important regulator of BBB integrity. Here we review recent developments related to the role of miRNAs in regulating BBB integrity.

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