Senescence and associated blood–brain barrier alterations in vitro

AbstractProgressive deterioration of the central nervous system (CNS) is commonly associated with aging. An important component of the neurovasculature is the blood–brain barrier (BBB), majorly made up of endothelial cells joined together by intercellular junctions. The relationship between senescence and changes in the BBB has not yet been thoroughly explored. Moreover, the lack of in vitro models for the study of the mechanisms involved in those changes impede further and more in-depth investigations in the field. For this reason, we herein present an in vitro model of the senescent BBB and an initial attempt to identify senescence-associated alterations within.

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Photostimulation of Extravasation of Beta-Amyloid through the Model of Blood-Brain Barrier

Electronics ◽

10.3390/electronics9061056 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1056

Author(s):

Ekaterina Zinchenko ◽

Maria Klimova ◽

Aysel Mamedova ◽

Ilana Agranovich ◽

Inna Blokhina ◽

...

Keyword(s):

Blood Brain Barrier ◽

Beta Amyloid ◽

Brain Barrier ◽

Therapeutic Effects ◽

Cervical Lymph Nodes ◽

Blood Brain ◽

The Central Nervous System ◽

Vitro Model ◽

The Brain

Alzheimer’s disease (AD) is an incurable pathology associated with progressive decline in memory and cognition. Phototherapy might be a new promising and alternative strategy for the effective treatment of AD, and has been actively discussed over two decades. However, the mechanisms of therapeutic photostimulation (PS) effects on subjects with AD remain poorly understood. The goal of this study was to determine the mechanisms of therapeutic PS effects in beta-amyloid (Aβ)-injected mice. The neurological severity score and the new object recognition tests demonstrate that PS 9 J/cm2 attenuates the memory and neurological deficit in mice with AD. The immunohistochemical assay revealed a decrease in the level of Aβ in the brain and an increase of Aβ in the deep cervical lymph nodes obtained from mice with AD after PS. Using the in vitro model of the blood-brain barrier (BBB), we show a PS-mediated decrease in transendothelial resistance and in the expression of tight junction proteins as well an increase in the BBB permeability to Aβ. These findings suggest that a PS-mediated BBB opening and the activation of the lymphatic clearance of Aβ from the brain might be a crucial mechanism underlying therapeutic effects of PS in mice with AD. These pioneering data open new strategies in the development of non-pharmacological methods for therapy of AD and contribute to a better understanding of the PS effects on the central nervous system.

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Comparative analysis of neuroinvasion by Japanese encephalitis virulent and vaccine viral strains in an in vitro model of human blood-brain barrier

PLoS ONE ◽

10.1371/journal.pone.0252595 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0252595

Author(s):

Cécile Khou ◽

Marco Aurelio Díaz-Salinas ◽

Anaelle da Costa ◽

Christophe Préhaud ◽

Patricia Jeannin ◽

...

Keyword(s):

Blood Brain Barrier ◽

Japanese Encephalitis ◽

In Vitro Model ◽

Molecular Mechanisms ◽

Brain Barrier ◽

Blood Brain ◽

The Central Nervous System ◽

Vitro Model ◽

Viral Determinants

Japanese encephalitis virus (JEV) is the major cause of viral encephalitis in South East Asia. It has been suggested that, as a consequence of the inflammatory process during JEV infection, there is disruption of the blood-brain barrier (BBB) tight junctions that in turn allows the virus access to the central nervous system (CNS). However, what happens at early times of JEV contact with the BBB is poorly understood. In the present work, we evaluated the ability of both a virulent and a vaccine strain of JEV (JEV RP9 and SA14-14-2, respectively) to cross an in vitro human BBB model. Using this system, we demonstrated that both JEV RP9 and SA14-14-2 are able to cross the BBB without disrupting it at early times post viral addition. Furthermore, we find that almost 10 times more RP9 infectious particles than SA14-14 cross the model BBB, indicating this BBB model discriminates between the virulent RP9 and the vaccine SA14-14-2 strains of JEV. Beyond contributing to the understanding of early events in JEV neuroinvasion, we demonstrate this in vitro BBB model can be used as a system to study the viral determinants of JEV neuroinvasiveness and the molecular mechanisms by which this flavivirus crosses the BBB during early times of neuroinvasion.

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Propofol-induced damage to the blood-brain barrier endothelium evinces a vascular endothelial growth factor (VEGF) -dependent mechanism.

Proceedings of IMPRS ◽

10.18060/24725 ◽

2020 ◽

Vol 3 ◽

Author(s):

Dustin Parsons ◽

Jason Hughes ◽

Scott Canfield

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Vegf Receptor ◽

Blood Brain ◽

The Central Nervous System ◽

Vitro Model ◽

Induced Pluripotent ◽

Endothelial Growth Factor ◽

Dependent Mechanism

Background and Hypothesis: Propofol is an anesthetic commonly used to induce general anesthesia for a myriad of medical procedures. However, a growing corpus of evidence suggests that propofol-induced increases in VEGF may contribute to blood-brain barrier (BBB) leakiness in varying animal models. The BBB is a neurovascular structure which protects the central nervous system from pathogens, toxins, and other deleterious metabolites; therefore, considerations regarding BBB integrity in humans are indispensable to the practice of anesthesia. We hypothesize that propofol-induced BBB dysfunction in human models is partially mediated by an increase in VEGF expression. Methods: We utilized human induced pluripotent stem cells (hiPSC) to derive brain microvascular endothelial cells (BMECs)—the barrier forming cell type of the BBB. BMECs were then subjected to clinically relevant doses of propofol for 3 hours, and barrier integrity was monitored via transendothelial electrical resistance (TEER) and para-cellular permeability for up to 72 hours. Propofol-induced VEGF levels were determined with an ELISA assay. Axitinib, a VEGF receptor blocker, was further utilized to assess the role of VEGF in propofol-induced BBB breakdown. Results: Prior works, including this study, have shown that propofol induces BBB damage, as demonstrated by decreases in TEER; here, preliminary work with ELISA assays further suggest that BMECs treated with propofol demonstrate an upregulation of VEGF. Pretreatment of BMECs with Axitinib before the addition of propofol partially rescues TEER and thus attenuates the propofol-mediated diminution of TEER. These observations thereby implicate VEGF as a damage mediator after propofol treatment. Conclusion and Potential Impact: This study utilized an in vitro model to demonstrate that propofol may mediate, in part, damage to blood- brain barrier endothelium via a VEGF dependent mechanism; thus, this work may guide future investigations to facilitate the development of safer anesthetic alternatives, or towards additional pharmacologic interventions that counteract propofol-mediated damage during anesthetic induction.

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Biochemical‐ and Biophysical‐Induced Barriergenesis in the Blood–Brain Barrier: A Review of Barriergenic Factors for Use in In Vitro Models

Advanced NanoBiomed Research ◽

10.1002/anbr.202170051 ◽

2021 ◽

Vol 1 (5) ◽

pp. 2170051

Author(s):

Christina L. Schofield ◽

Aleixandre Rodrigo-Navarro ◽

Matthew J. Dalby ◽

Tom Van Agtmael ◽

Manuel Salmeron-Sanchez

Keyword(s):

Blood Brain Barrier ◽

In Vitro Models ◽

Brain Barrier ◽

Blood Brain

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Understanding the Physiology of the Blood-Brain Barrier: In Vitro Models

Physiology ◽

10.1152/physiologyonline.1998.13.6.287 ◽

1998 ◽

Vol 13 (6) ◽

pp. 287-293 ◽

Cited By ~ 3

Author(s):

Gerald A. Grant ◽

N. Joan Abbott ◽

Damir Janigro

Keyword(s):

Central Nervous System ◽

Tissue Culture ◽

Nervous System ◽

Blood Brain Barrier ◽

In Vitro Models ◽

Brain Barrier ◽

Blood Brain ◽

Brain Tissue Culture ◽

The Brain

Endothelial cells exposed to inductive central nervous system factors differentiate into a blood-brain barrier phenotype. The blood-brain barrier frequently obstructs the passage of chemotherapeutics into the brain. Tissue culture systems have been developed to reproduce key properties of the intact blood-brain barrier and to allow for testing of mechanisms of transendothelial drug permeation.

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