scholarly journals Sleep Deprivation Induces Cognitive Impairment by Increasing Blood-Brain Barrier Permeability via CD44

2020 ◽  
Vol 11 ◽  
Author(s):  
Jing Sun ◽  
Jusheng Wu ◽  
Fuzhou Hua ◽  
Yong Chen ◽  
Fenfang Zhan ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Sleep Deprivation ◽  
Rna Sequencing ◽  
Blood Brain Barrier ◽  
Nervous System Development ◽  
Brain Barrier ◽  
Receptor Interaction ◽  
Blood Brain ◽  
Bbb Permeability

Sleep deprivation occurs frequently in older adults, which can result in delirium and cognitive impairment. CD44 is a key molecular in blood-brain barrier (BBB) regulation. However, whether CD44 participates in the role of sleep deprivation in cognitive impairment remains unclear. In this study, the effect of sleep deprivation on cognitive ability, tissue inflammation, BBB permeability, and astrocyte activity were evaluated in vivo. The differentially expressed genes (DEGs) were identified by RNA sequencing. A CD44 overexpression in the BBB model was performed in vitro to assess the effect and mechanisms of CD44. Sleep deprivation impaired the learning and memory ability and increased the levels of inflammatory cytokines, along with increased BBB permeability and activated astrocytes in hippocampus tissue. RNA sequencing of the hippocampus tissue revealed that 329 genes were upregulated in sleep deprivation-induced mice compared to control mice, and 147 genes were downregulated. GO and pathways showed that DEGs were mainly involved in BBB permeability and astrocyte activation, including nervous system development, neuron development, and brain development, and neuroactive ligand-receptor interaction. Moreover, the PCR analysis revealed that CD44 was dramatically increased in mice with sleep deprivation induction. The overexpression of CD44 in astrocytes promoted BBB permeability in vitro and induced the expression of the downstream gene NANOG. Our results indicate that sleep deprivation upregulated CD44 expression in hippocampus tissue, and increased BBB permeability, resulting in cognitive impairment.

scholarly journals Pseudogene ACTBP2 increases blood–brain barrier permeability by promoting KHDRBS2 transcription through recruitment of KMT2D/WDR5 in Aβ1–42 microenvironment

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qianshuo Liu ◽  
Xiaobai Liu ◽  
Defeng Zhao ◽  
Xuelei Ruan ◽  
Rui Su ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Vital Role ◽  
Brain Barrier ◽  
Blood Brain ◽  
Bbb Permeability ◽  
Novel Target ◽  
And Function

AbstractThe blood–brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer’s disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. We elucidated the function and possible molecular mechanisms of the effect of pseudogene ACTBP2 on the permeability of BBB in Aβ1–42 microenvironment. BBB model treated with Aβ1–42 for 48 h were used to simulate Aβ-mediated BBB dysfunction in AD. We proved that pseudogene ACTBP2, RNA-binding protein KHDRBS2, and transcription factor HEY2 are highly expressed in ECs that were obtained in a BBB model in vitro in Aβ1–42 microenvironment. In Aβ1–42-incubated ECs, ACTBP2 recruits methyltransferases KMT2D and WDR5, binds to KHDRBS2 promoter, and promotes KHDRBS2 transcription. The interaction of KHDRBS2 with the 3′UTR of HEY2 mRNA increases the stability of HEY2 and promotes its expression. HEY2 increases BBB permeability in Aβ1–42 microenvironment by transcriptionally inhibiting the expression of ZO-1, occludin, and claudin-5. We confirmed that knocking down of Khdrbs2 or Hey2 increased the expression levels of ZO-1, occludin, and claudin-5 in APP/PS1 mice brain microvessels. ACTBP2/KHDRBS2/HEY2 axis has a crucial role in the regulation of BBB permeability in Aβ1–42 microenvironment, which may provide a novel target for the therapy of AD.

scholarly journals BMSCs Regulate Astrocytes through TSG-6 to Protect the Blood-Brain Barrier after Subarachnoid Hemorrhage

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Yilv Wan ◽  
Min Song ◽  
Xun Xie ◽  
Zhen Chen ◽  
Ziyun Gao ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Blood Brain Barrier ◽  
Mapk Signaling ◽  
Brain Barrier ◽  
Inflammatory Factors ◽  
Blue Staining ◽  
Nissl Staining ◽  
Blood Brain ◽  
Bbb Permeability

Background. In patients with subarachnoid hemorrhage (SAH), the damage of the blood-brain barrier (BBB) can be life-threatening. Mesenchymal stem cells are widely used in clinical research due to their pleiotropic properties. This study is aimed at exploring the effect of BMSCs regulating astrocytes on the BBB after SAH. Methods. The SAH model was established by perforating the blood vessels. BMSCs were transfected with TSG-6 inhibitor plasmid and cocultured with astrocytes. Intravenous transplantation of BMSCs was utilized to treat SAH rats. We performed ELISA, neurological scoring, Evans blue staining, NO measurement, immunofluorescence, BBB permeability, Western blot, HE staining, Nissl staining, and immunohistochemistry to evaluate the effect of BMSCs on astrocytes and BBB. Results. SAH rats showed BBB injury, increased BBB permeability, and brain histological damage. BMSCs will secrete TSG-6 after being activated by TNF-α. Under the influence of TSG-6, the NF-κB and MAPK signaling pathways of astrocytes were inhibited. The expression of iNOS was reduced, while occludin, claudin 3, and ZO-1 expression was increased. The production of harmful substances NO and ONOO- decreased. The level of inflammatory factors decreased. The apoptosis of astrocytes was weakened. TSG-6 secreted by BMSCs can relieve inflammation caused by SAH injury. The increase in BBB permeability of SAH rats was further reduced and the risk of rebleeding was reduced. Conclusion. BMSCs can regulate the activation of astrocytes through secreting TSG-6 in vivo and in vitro to protect BBB.

scholarly journals TRA2A-induced upregulation of LINC00662 regulates blood-brain barrier permeability by affecting ELK4 mRNA stability in Alzheimer's microenvironment

2019 ◽  
Author(s):  
Qianshuo Liu ◽  
Lu Zhu ◽  
Xiaobai Liu ◽  
Jian Zheng ◽  
Yunhui Liu ◽  
...  
Keyword(s):  
Tight Junction ◽  
Blood Brain Barrier ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Brain Barrier ◽  
Blood Brain ◽  
Bbb Permeability ◽  
Novel Target ◽  
Related Proteins

Abstract The blood-brain barrier (BBB) plays a pivotal role in maintenance and regulation of the neural microenvironment. The occurrence of BBB disruption is the pathological change of early Alzheimer’s disease (AD). RNA-binding proteins and long non-coding RNAs are involved in the regulation of BBB permeability. Our study was performed to demonstrate TRA2A/LINC00662/ELK4 axis in regulating BBB permeability in AD microenvironment. In Aβ1-42-incubated microvascular endothelial cells (ECs) of BBB model in vitro, TRA2A and LINC00662 were enriched. TRA2A increased the stability of LINC00662 by binding with it. The knockdown of either TRA2A or LINC00662 decreased the BBB permeability via upregulating the expressions of tight junction-related proteins. ELK4 was lower expressed in BBB model in vitro in AD microenvironment. LINC00662 mediated the degradation of ELK4 mRNA by SMD pathway. The downregulated ELK4 increased the permeability of BTB by increasing the tight junction-related proteins expressions. TRA2A/LINC00662/ELK4 axis plays a crucial role in the regulation of BBB permeability in AD microenvironment, which may provide a novel target for the therapy of AD.

scholarly journals Yuzu and Hesperidin Ameliorate Blood-Brain Barrier Disruption during Hypoxia via Antioxidant Activity

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 843
Author(s):  
Bo Kyung Lee ◽  
Soo-Wang Hyun ◽  
Yi-Sook Jung
Keyword(s):  
Endothelial Cell ◽  
Blood Brain Barrier ◽  
Cell Model ◽  
Antioxidant Properties ◽  
Brain Barrier ◽  
Blood Brain ◽  
In Vivo Animal Model ◽  
Bbb Permeability

Yuzu and its main component, hesperidin (HSP), have several health benefits owing to their anti-inflammatory and antioxidant properties. We examined the effects of yuzu and HSP on blood–brain barrier (BBB) dysfunction during ischemia/hypoxia in an in vivo animal model and an in vitro BBB endothelial cell model, and also investigated the underlying mechanisms. In an in vitro BBB endothelial cell model, BBB permeability was determined by measurement of Evans blue extravasation in vivo and in vitro. The expression of tight junction proteins, such as claudin-5 and zonula occludens-1 (ZO-1), was detected by immunochemistry and western blotting, and the reactive oxygen species (ROS) level was measured by 2′7′-dichlorofluorescein diacetate intensity. Yuzu and HSP significantly ameliorated the increase in BBB permeability and the disruption of claudin-5 and ZO-1 in both in vivo and in vitro models. In bEnd.3 cells, yuzu and HSP were shown to inhibit the disruption of claudin-5 and ZO-1 during hypoxia, and the protective effects of yuzu and HSP on claudin-5 degradation seemed to be mediated by Forkhead box O 3a (FoxO3a) and matrix metalloproteinase (MMP)-3/9. In addition, well-known antioxidants, trolox and N-acetyl cysteine, significantly attenuated the BBB permeability increase, disruption of claudin-5 and ZO-1, and FoxO3a activation during hypoxia, suggesting that ROS are important mediators of BBB dysfunction during hypoxia. Collectively, these results indicate that yuzu and HSP protect the BBB against dysfunction via maintaining integrity of claudin-5 and ZO-1, and these effects of yuzu and HSP appear to be a facet of their antioxidant properties. Our findings may contribute to therapeutic strategies for BBB-associated neurodegenerative diseases.

Assessing the roles of inflammation and blood brain barrier permeability in cognitive impairment: A nationwide longitudinal study of patients receiving chemotherapy and non-cancer controls.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 12070-12070
Author(s):  
Elizabeth Belcher ◽  
Nikesha Gilmore ◽  
Amber Kleckner ◽  
Ian Kleckner ◽  
Eva Culakova ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Blood Brain Barrier ◽  
Inflammatory Cytokine ◽  
Brain Barrier ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Bbb Permeability ◽  
Over Time

12070 Background: Cognitive impairment is a prevalent side effect of chemotherapy. We have previously shown that chemotherapy treatment is associated with worse performance on the Rapid Visual Processing test (RVP), an objective measure of sustained attention, over time compared to non-cancer controls. Better understanding of the biologic mechanisms underlying cognitive impairment in cancer patients is needed. The pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) has been implicated in increasing blood brain barrier (BBB) permeability, which in turn is associated with cognitive impairment. This study assessed the relationships of TNFα and S100β, a biomarker of BBB permeability, to each other and to RVP performance over time. Methods: We analyzed a subset of participants (n = 89 patients, n = 52 controls, mean age = 60) from a prospective longitudinal study of women with breast cancer receiving chemotherapy and non-cancer controls. TNFα and S100β were measured in serum pre-chemotherapy (T1, ≤7 days before first treatment) and post-chemotherapy (T2, ≤1 month after last treatment) and at corresponding times for controls. Sustained attention was assessed by total correct rejections on the RVP test at T1 and T2. Separate linear regression models including all participants were used to relate 1) baseline TNFα and S100β levels to change in RVP performance over time, 2) change in TNFα and S100β to change in RVP performance over time, and 3) change in TNFα to change in S100β. Models were adjusted for age. 4) T-tests were used to compare the TNFα and S100β change scores (T1 to T2) of patients vs controls. Results: Greater increase (T1 to T2) in the pro-inflammatory cytokine TNFα was associated with worse cognition, measured by performance on RVP over time (p = 0.02). Higher baseline S100β, a biomarker of BBB permeability, was associated with worse performance on RVP over time (p = 0.09). Increase in TNFα was associated with increase in S100β (p = 0.11). S100β increased from T1 to T2 in patients relative to controls (p = 0.09). Conclusions: These results suggest that higher TNFα may be related to increases in blood brain barrier permeability and worse cognition. Future studies will further define the link between inflammation, blood brain barrier permeability and chemotherapy-related cognitive decline, with the goal of informing the development of new interventions. Funding: R01CA231014, T32CA102618, DP2CA195765, UG1CA189961.

Abstract 44: Enlarged Perivascular Spaces Correlate With CSF Biomarkers for Abnormal Blood-brain Barrier Permeability and Neuroinflammation in Patients With Vascular Cognitive Impairment

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Laith Maali ◽  
Branko Huisa ◽  
Jillian Prestopnik ◽  
Clifford Qualls ◽  
Jeffrey Thompson ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Blood Brain Barrier ◽  
Vascular Cognitive Impairment ◽  
Brain Barrier ◽  
Csf Biomarkers ◽  
Perivascular Spaces ◽  
Albumin Ratio ◽  
Blood Brain ◽  
Bbb Permeability

Background: Enlarged perivascular spaces (PVS) in the brain are common but their etiology and specificity are unclear. Multiple studies have shown a correlation between enlarged PVS and white matter hyperintensities (WMHs), but the relationship with vascular disease is uncertain. We used albumin CSF to blood ratio as a method to measure permeability of the blood-brain barrier (BBB) in patients with vascular cognitive impairment (VCI). It is possible that the enlarged PVS are associated with an increase in BBB permeability, which could interfere with perivascular fluid flow. Therefore, we hypothesized that enlarged PVS correlate with CSF markers of increased BBB permeability and neuroinflammation. Methods: We prospectively recruited 107 VCI patients with white matter disease. At entry, they had brain MRIs with standardized ranking for enlarged PVS. Sixty-one had lumbar puncture to obtain CSF for analysis of albumin ratio, matrix metalloproteinases-2 (MMP-2) index, and amyloid-beta1-42 (Abeta42). The data was analyzed statistically with nonparametric correlation methods. Results: Enlarged PVS had a positive correlation with CSF albumin ratio, which is a biomarker for increased BBB permeability ( p <0.01), and a negative correlation with the neuroinflammatory biomarker, MMP2 index ( p <0.02), and with Abeta42 ( p <0.02), which is cleared by the PVS. Conclusion: Our results suggest an association between PVS, MMP-mediated increased BBB permeability, and clearance of Abeta42. The role of perivascular fluid movement and its relationship with CSF biomarkers will require further investigation.

scholarly journals A host-gut microbial co-metabolite of aromatic amino acids, p-cresol glucuronide, promotes blood-brain barrier integrity in vivo

2022 ◽  
Author(s):  
Andrew V Stachulski ◽  
Tobias B-A Knausenberger ◽  
Sita N Shah ◽  
Lesley Hoyles ◽  
Simon McArthur
Keyword(s):  
Amino Acids ◽  
Blood Brain Barrier ◽  
Aromatic Amino Acids ◽  
Biologically Active ◽  
Brain Barrier ◽  
Whole Brain ◽  
Blood Brain ◽  
Bbb Permeability

Purpose: The sequential activity of gut microbial and host processes can exert a powerful modulatory influence on dietary components, as exemplified by the metabolism of the amino acids tyrosine and phenylalanine to p-cresol by gut microbes, and then to p-cresol glucuronide (pCG) by host enzymes. Although such glucuronide conjugates are classically thought to be biologically inert, there is accumulating evidence that this may not always be the case. We investigated the activity of pCG, studying its interactions with the cerebral vasculature and the brain in vitro and in vivo. Methods: Male C57Bl/6J mice were used to assess blood-brain barrier (BBB) permeability and whole brain transcriptomic changes in response to pCG treatment. Effects were then further explored using the human cerebromicrovascular endothelial cell line hCMEC/D3, assessing paracellular permeability, transendothelial electrical resistance and barrier protein expression. Results: Mice exposed to pCG showed reduced BBB permeability and significant changes in whole brain transcriptome expression. Surprisingly, treatment of hCMEC/D3 cells with pCG had no notable effects until co-administered with bacterial lipopolysaccharide, at which point it was able to prevent the permeabilising effects of endotoxin. Further analysis suggested that pCG acts as an antagonist at the principal lipopolysaccharide receptor TLR4. Conclusion: The amino acid phase II metabolic product pCG is biologically active at the BBB, highlighting the complexity of gut microbe to host communication and the gut-brain axis.

DDRE-49. TRANSIENT OPENING OF THE BLOOD-BRAIN BARRIER BY VASOACTIVE PEPTIDES TO INCREASE CNS DRUG DELIVERY: REALITY VERSUS WISHFUL THINKING?

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi85-vi85
Author(s):  
Matthew Smith-Cohn ◽  
Nicholas Burley ◽  
Stuart Grossman
Keyword(s):  
Drug Delivery ◽  
Blood Vessels ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Specific Information ◽  
Vasoactive Peptides ◽  
Cns Drug Delivery ◽  
Blood Brain ◽  
Bbb Permeability

Abstract BACKGROUND Drug delivery to treat neurologic disease and cancers of the central nervous system (CNS) is severely limited by the blood-brain barrier (BBB). Vasoactive peptides (VAPs) such as regadenoson, adenosine, and labradimil have been shown in animal studies to transiently open the BBB, and regadenoson is currently under investigation in humans to determine if it might improve CNS drug delivery. There is currently limited information regarding the potential for other VAPs to open the BBB transiently. METHODS We performed a review of the literature evaluating the physiologic effects of vasoactive peptides on the vasculature of the brain and systemic organs. To assess the likelihood that a vasoactive peptide might transiently disrupt the BBB, we devised a four-tier classification system to organize data available in the literature which factors in alterations in BBB integrity and effects on normal brain vasculature and systemic blood vessels. This data was further sorted based on whether it comes from humans, animals, or in vitro systems. RESULTS We identified 38 VAPs with potential BBB permeability-altering properties. To date, none of these has been shown to open the BBB in humans. Thirteen VAPs increased BBB permeability in rodents. The remaining 25 had favorable physiologic effects on blood vessels but lack specific information on permeability changes to the BBB. We ranked VAPs in a four-tier ranking system related to their known physiologic actions. CONCLUSION Rodent studies document that analogs of bradykinin and adenosine transiently disrupt the BBB leading to higher chemotherapy concentrations in the CNS. VAPs remain an understudied class of drugs with the potential to increase drug delivery to the CNS. Dozens of VAPs have yet to be formally evaluated for this important clinical effect. This retrospective review summarizes the available data on VAPs highlighting agents that deserve further in vitro and in vivo investigations.

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