scholarly journals A novel epigenetic marker, TET2, is identified in the intractable epileptic brain and regulates ABCB1 in the blood-brain barrier

2021 ◽  
Author(s):  
Fancheng Kong ◽  
Li-Qin Lang ◽  
Xia-Ling Zhang ◽  
Ming-Kang Zhong ◽  
Chun-Lai Ma
Keyword(s):  
Blood Brain Barrier ◽  
Vascular Endothelium ◽  
Hippocampal Sclerosis ◽  
Expression Patterns ◽  
Temporal Cortex ◽  
Brain Barrier ◽  
Brain Vessels ◽  
Blood Brain ◽  
Epigenetic Marker ◽  
Regulatory Effects

Abstract BackgroundDrug-resistant epilepsy (DRE) is a chronic condition derived from spontaneous changes and regulatory effects in the epileptic brain. DNA methylation, an inheritable but reversible epigenetic change, may participate in this complicated regulatory network. As demethylation factors, ten-eleven translocation (TET) family members have become a focus in recent studies of neurological disorders. Thus, we aimed to unravel their role in DRE and their function related to the possible refractory factor ABCB1 in a blood-brain barrier (BBB) model.MethodsWe quantified and localized TET1, TET2 and 5-hydroxymethylcytosine (5-hmC) in the temporal lobe cortex of DRE patients (n = 27) and traumatic brain haemorrhage controls (n = 10) by immunochemical staining. TET2 and ABCB1 expression patterns were determined in the temporal cortex and isolated brain capillaries of DRE patients using immunohistological detection and Western blot analysis, respectively. A BBB model constructed with hCMEC/D3 cells was used to verify the demethylation and regulatory effects of TET2 on ABCB1.ResultsTET2 expression was significantly increased in the temporal cortical tissue of DRE patients with or without hippocampal sclerosis (HS) compared to control patients, while TET1 and 5-hmC showed differences in expression. We also discovered that the vascular endothelium of DRE patients has a strong affinity for TET2. ABCB1 and TET2 have identical densities in the DRE temporal cortex, and they both have evidently higher expression in the vascular endothelium from the neocortex of DRE patients. In the BBB, TET2 depletion can cause attenuated expression and function of ABCB1, as well as a pattern of higher methylation in CpG islands of the ABCB1 promoter.ConclusionsThrough a cohort study performed on the temporal cortex and brain vessels of DRE patients, we identified a novel epigenetic marker, TET2. Data from experiments in a BBB model suggest that TET2 has a specific regulatory effect on ABCB1, which may serve as a potential mechanism and target in DRE and requires further research.

Adverse effects of erenumab on cerebral proliferative angiopathy: A case report

Cephalalgia ◽  
2020 ◽  
pp. 033310242095048
Author(s):  
Laura L Lehman ◽  
Rebecca Bruccoleri ◽  
Amy Danehy ◽  
Julie Swanson ◽  
Christine Mrakotsky ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
White Matter ◽  
Magnetic Resonance ◽  
Blood Brain Barrier ◽  
Vascular Malformations ◽  
Hippocampal Sclerosis ◽  
White Matter Injury ◽  
Brain Barrier ◽  
Resonance Imaging ◽  
Blood Brain

Background Cerebral proliferative angiopathy is a vascular malformation associated with compromised blood-brain barrier and with migraine-like headache. Treating blood-brain barrier-compromised patients with erenumab, an anti-calcitonin gene-related peptide receptor monoclonal antibody, may be risky. Case We describe a case of a 22-year-old chronic migraine patient with cerebral proliferative angiopathy who presented to our hospital in status epilepticus 2 d after his first dose of erenumab. Serial magnetic resonance imaging (MRI) studies demonstrated progressive areas of diffusion restriction including the brain tissue adjacent to the cerebral proliferative angiopathy, bilateral white matter and hippocampi. His 6-month post-presentation magnetic resonance imaging was notable for white matter injury, encephalomalacia surrounding cerebral proliferative angiopathy and bilateral hippocampal sclerosis. He remains clinically affected with residual symptoms, including refractory epilepsy and cognitive deficits. Conclusion The evidence presented in this case supports further investigation into potential deleterious side effects of erenumab in patients with compromised blood-brain barrier, such as individuals with intracranial vascular malformations.

scholarly journals Parallel Regulation of Thyroid Hormone Transporters OATP1c1 and MCT8 During and After Endotoxemia at the Blood-Brain Barrier of Male Rodents

Endocrinology ◽  
2015 ◽  
Vol 156 (4) ◽  
pp. 1552-1564 ◽  
Author(s):  
Gábor Wittmann ◽  
Judit Szabon ◽  
Petra Mohácsik ◽  
Shira S. Nouriel ◽  
Balázs Gereben ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Blood Brain Barrier ◽  
Organic Anion ◽  
Brain Barrier ◽  
Monocarboxylate Transporter ◽  
Mrna Levels ◽  
Brain Vessels ◽  
Altered Expression ◽  
Protein Levels ◽  
Blood Brain

Abstract There is increasing evidence that local thyroid hormone (TH) availability changes profoundly in inflammatory conditions due to altered expression of deiodinases that metabolize TH. It is largely unknown, however, how inflammation affects TH availability via the expression of TH transporters. In this study we examined the effect of bacterial lipopolysaccharide (LPS) administration on two TH transporters that are critically important for brain TH homeostasis, organic anion-transporting polypeptide 1c1 (OATP1c1), and monocarboxylate transporter 8 (MCT8). MRNA levels were studied by in situ hybridization and qPCR as well as protein levels by immunofluorescence in both the rat and mouse forebrain. The mRNA of both transporters decreased robustly in the first 9 hours after LPS injection, specifically in brain blood vessels; OATP1c1 mRNA in astrocytes and MCT8 mRNA in neurons remained unchanged. At 24 and/or 48 hours after LPS administration, OATP1c1 and MCT8 mRNAs increased markedly above control levels in brain vessels. OATP1c1 protein decreased markedly in vessels by 24 hours whereas MCT8 protein levels did not decrease significantly. These changes were highly similar in mice and rats. The data demonstrate that OATP1c1 and MCT8 expression are regulated in a parallel manner during inflammation at the blood-brain barrier of rodents. Given the indispensable role of both transporters in allowing TH access to the brain, the results suggest reduced brain TH uptake during systemic inflammation.

scholarly journals Regulatory effects of simvastatin and apoJ on APP processing and amyloid-β clearance in blood-brain barrier endothelial cells

2018 ◽  
Vol 1863 (1) ◽  
pp. 40-60 ◽  
Author(s):  
Martina Zandl-Lang ◽  
Elham Fanaee-Danesh ◽  
Yidan Sun ◽  
Nicole M. Albrecher ◽  
Chaitanya Chakravarthi Gali ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Amyloid Β ◽  
Brain Barrier ◽  
App Processing ◽  
Blood Brain ◽  
Regulatory Effects

scholarly journals CD146 coordinates brain endothelial cell–pericyte communication for blood–brain barrier development

2017 ◽  
Vol 114 (36) ◽  
pp. E7622-E7631 ◽  
Author(s):  
Jianan Chen ◽  
Yongting Luo ◽  
Hui Hui ◽  
Tanxi Cai ◽  
Hongxin Huang ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Cell Receptor ◽  
Brain Barrier ◽  
Neuronal System ◽  
Pericyte Coverage ◽  
Blood Brain ◽  
Dynamic Expression ◽  
Specific Deletion

The blood–brain barrier (BBB) establishes a protective interface between the central neuronal system and peripheral blood circulation and is crucial for homeostasis of the CNS. BBB formation starts when the endothelial cells (ECs) invade the CNS and pericytes are recruited to the nascent vessels during embryogenesis. Despite the essential function of pericyte–EC interaction during BBB development, the molecular mechanisms coordinating the pericyte–EC behavior and communication remain incompletely understood. Here, we report a single cell receptor, CD146, that presents dynamic expression patterns in the cerebrovasculature at the stages of BBB induction and maturation, coordinates the interplay of ECs and pericytes, and orchestrates BBB development spatiotemporally. In mouse brain, CD146 is first expressed in the cerebrovascular ECs of immature capillaries without pericyte coverage; with increased coverage of pericytes, CD146 could only be detected in pericytes, but not in cerebrovascular ECs. Specific deletion of Cd146 in mice ECs resulted in reduced brain endothelial claudin-5 expression and BBB breakdown. By analyzing mice with specific deletion of Cd146 in pericytes, which have defects in pericyte coverage and BBB integrity, we demonstrate that CD146 functions as a coreceptor of PDGF receptor-β to mediate pericyte recruitment to cerebrovascular ECs. Moreover, we found that the attached pericytes in turn down-regulate endothelial CD146 by secreting TGF-β1 to promote further BBB maturation. These results reveal that the dynamic expression of CD146 controls the behavior of ECs and pericytes, thereby coordinating the formation of a mature and stable BBB.

scholarly journals Platelet Endothelial Cell Adhesion Molecule-1, a Putative Receptor for the Adhesion of Streptococcus pneumoniae to the Vascular Endothelium of the Blood-Brain Barrier

2014 ◽  
Vol 82 (9) ◽  
pp. 3555-3566 ◽  
Author(s):  
Federico Iovino ◽  
Grietje Molema ◽  
Jetta J. E. Bijlsma
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Streptococcus Pneumoniae ◽  
Blood Brain Barrier ◽  
Vascular Endothelium ◽  
Brain Barrier ◽  
Content Type ◽  
Blood Brain ◽  
Endothelial Cell Adhesion

ABSTRACTThe Gram-positive bacteriumStreptococcus pneumoniaeis the main causative agent of bacterial meningitis.S. pneumoniaeis thought to invade the central nervous system via the bloodstream by crossing the vascular endothelium of the blood-brain barrier. The exact mechanism by which pneumococci cross endothelial cell barriers before meningitis develops is unknown. Here, we investigated the role of PECAM-1/CD31, one of the major endothelial cell adhesion molecules, inS. pneumoniaeadhesion to vascular endothelium of the blood-brain barrier. Mice were intravenously infected with pneumococci and sacrificed at various time points to represent stages preceding meningitis. Immunofluorescent analysis of brain tissue of infected mice showed that pneumococci colocalized with PECAM-1. In human brain microvascular endothelial cells (HBMEC) incubated withS. pneumoniae, we observed a clear colocalization between PECAM-1 and pneumococci. Blocking of PECAM-1 reduced the adhesion ofS. pneumoniaeto endothelial cellsin vitro, implying that PECAM-1 is involved in pneumococcal adhesion to the cells. Furthermore, using endothelial cell protein lysates, we demonstrated thatS. pneumoniaephysically binds to PECAM-1. Moreover, bothin vitroandin vivoPECAM-1 colocalizes with theS. pneumoniaeadhesion receptor pIgR. Lastly, immunoprecipitation experiments revealed that PECAM-1 can physically interact with pIgR. In summary, we show for the first time that blood-borneS. pneumoniaecolocalizes with PECAM-1 expressed by brain microvascular endothelium and that, in addition, they colocalize with pIgR. We hypothesize that this interaction plays a role in pneumococcal binding to the blood-brain barrier vasculature prior to invasion into the brain.

scholarly journals The Epithelial Membrane Protein 1 is a Novel Tight Junction Protein of the Blood—Brain Barrier

2008 ◽  
Vol 28 (6) ◽  
pp. 1249-1260 ◽  
Author(s):  
Thorsten Bangsow ◽  
Ewa Baumann ◽  
Carmen Bangsow ◽  
Martina H Jaeger ◽  
Bernhard Pelzer ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cerebral Ischemia ◽  
Membrane Protein ◽  
Rat Brain ◽  
Blood Brain Barrier ◽  
Differentially Expressed ◽  
Brain Barrier ◽  
Brain Vessels ◽  
Blood Brain ◽  
Junction Protein

In the central nervous system, a constant microenvironment required for neuronal cell activity is maintained by the blood—brain barrier (BBB). The BBB is formed by the brain microvascular endothelial cells (BMEC), which are sealed by tight junctions (TJ). To identify genes that are differentially expressed in BMEC compared with peripheral endothelial cells, we constructed a subtractive cDNA library from porcine BMEC (pBMEC) and aortic endothelial cells (AOEC). Screening the library for differentially expressed genes yielded 26 BMEC-specific transcripts, such as solute carrier family 35 member F2 (SLC35F2), ADP-ribosylation factor-like 5B (ARL5B), TSC22 domain family member 1 (TSC22D1), integral membrane protein 2A (ITM2A), and epithelial membrane protein 1 (EMP1). In this study, we show that EMP1 transcript is enriched in pBMEC compared with brain tissue and that EMP1 protein colocalizes with the TJ protein occludin in mouse BMEC by coimmunoprecipitation and in rat brain vessels by immunohistochemistry. Epithelial membrane protein 1 expression was transiently induced in laser-capture microdissected rat brain vessels after a 20-min global cerebral ischemia, in parallel with the loss of occludin immunoreactivity. The study identifies EMP1 as a novel TJ-associated protein of the BBB and suggests its potential role in the regulation of the BBB function in cerebral ischemia.

scholarly journals Posterior Reversible Encephalopathy Syndrome as Presenting Form of Very Early Systemic Sclerosis

2015 ◽  
Vol 2015 ◽  
pp. 1-3
Author(s):  
María Isabel Pedraza ◽  
Julia Barbado ◽  
Marina Ruiz ◽  
Ángel Luis Guerrero
Keyword(s):  
Systemic Sclerosis ◽  
Arterial Hypertension ◽  
Blood Brain Barrier ◽  
Posterior Reversible Encephalopathy Syndrome ◽  
Vascular Endothelium ◽  
Brain Barrier ◽  
Posterior Reversible Encephalopathy ◽  
Blood Brain ◽  
Reversible Encephalopathy ◽  
Early Systemic Sclerosis

Introduction. Posterior Reversible Encephalopathy Syndrome (PRES) is an increasingly recognized clinical and radiological entity with a wide spectrum of symptoms. Its mechanism depends on failure of the blood-brain barrier due to high systemic blood pressure (BP) and loss of integrity of vascular endothelium related with different triggers.Methods. We aim to report a case of PRES induced by arterial hypertension and very early systemic sclerosis (SSc) not previously known.Results. A 64-year-old female was admitted due to 1-week pulsating headache more prominent on frontal scalp, accompanied by phonophobia, photophobia, and facial flushing. Neurological exam revealed brisk deep tendon reflex. Brain magnetic resonance imaging (MRI) showed subcortical lesions mainly located in posterior regions. BP was monitored and episodic arterial hypertension was detected. In laboratory tests positive anti-topoisomerase I antibodies were detected. BP was controlled with angiotensin-converting-enzyme inhibitors and headache improved. In a new MRI a month later improvement of white matter lesions was observed. Capillaroscopy showed “active pattern,” considered typical of SSc.Conclusion. In SSc anti-endothelial cell antibodies impair vascular endothelium and liberation of vasoconstrictors leads to BP increasing and disruption of blood-brain barrier autoregulation mechanisms. PRES can be the first manifestation of very early SSc and this entity should be considered even in absence of skin lesions or Raynaud phenomenon.

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