The tight junction protein occludin modulates blood–brain barrier integrity and neurological function after ischemic stroke in mice

Sugiyama, Sachio; Sasaki, Tsutomu; Tanaka, Hiroo; Yan, Haomin; Ikegami, Takeshi; Kanki, Hideaki; Nishiyama, Kumiko; Beck, Goichi; Gon, Yasufumi; Okazaki, Shuhei; Todo, Kenichi; Tamura, Atsushi; Tsukita, Sachiko; Mochizuki, Hideki

doi:10.1038/s41598-023-29894-1

Cited by 23 publications

(12 citation statements)

References 52 publications

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“…Tight junctions between brain endothelial cells are crucial for maintaining the integrity and selective permeability of the neurovasculature. [43][44][45] Therefore, we next evaluated whether differences in levels of junctional proteins were associated with the increased cortical extravasation of IgG and fibrinogen in APOE3 Cre+/− mice. At the mRNA level, we did not find any differences between APOE3 Cre−/− and APOE3 Cre+/− mice for tight junction (Ocln and Cldn5) and adherens junction (Cdh5, Ctnnb1, and Ctnnd1) transcripts (Figure 2C; Figure S4).…”

Section: Endothelial Knockdown Of Apoe3 Is Sufficient To Cause Neurov...mentioning

confidence: 99%

Endothelial Cell APOE3 Regulates Neurovascular, Neuronal, and Behavioral Function

Marottoli,

Zhang,

Flores-Barrera

et al. 2023

ATVB

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BACKGROUND: Specialized brain endothelial cells and human APOE3 are independently important for neurovascular function, yet whether APOE3 expression by endothelial cells contributes to brain function is currently unknown. In the present study, we determined whether the loss of endothelial cell APOE3 impacts brain vascular and neural function. METHODS: We developed APOE3 fl/fl /Cdh5(PAC)-CreERT2 +/− ( APOE3 Cre+/− ) and APOE3 fl/fl /Cdh5(PAC)-CreERT2 −/− ( APOE3 Cre −/− , control) mice and induced endothelial cell APOE3 knockdown with tamoxifen at ≈4 to 5 weeks of age. Neurovascular and neuronal function were evaluated by biochemistry, immunohistochemistry, behavioral testing, and electrophysiology at 9 months of age. RESULTS: We found that the loss of endothelial APOE3 expression was sufficient to cause neurovascular dysfunction including higher permeability and lower vessel coverage in tandem with deficits in spatial memory and fear memory extinction and a disruption of cortical excitatory/inhibitory balance. CONCLUSIONS: Our data collectively support the novel concept that endothelial APOE3 plays a critical role in the regulation of the neurovasculature, neural circuit function, and behavior.

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Section: Endothelial Knockdown Of Apoe3 Is Sufficient To Cause Neurov...mentioning

confidence: 99%

Endothelial Cell APOE3 Regulates Neurovascular, Neuronal, and Behavioral Function

Marottoli,

Zhang,

Flores-Barrera

et al. 2023

ATVB

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“…The transmembrane part consists of occludin [11,12], junctional adhesion molecules (JAM) [13] and representatives of the claudin family, while the cytoplasmatic plaque is built of proteins with the PDZ domain-ZO-1, ZO-2 and other proteins, e.g., cingulin [10].…”

Section: Tight Junctionsmentioning

confidence: 99%

Experimental Models to Study the Functions of the Blood–Brain Barrier

2023

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The purpose of this paper was to discuss the achievements of in vitro modeling in terms of the blood–brain barrier [BBB] and to create a clear overview of this research area, which is useful in research planning. The text was divided into three main parts. The first part describes the BBB as a functional structure, its constitution, cellular and noncellular components, mechanisms of functioning and importance for the central nervous system, in terms of both protection and nourishment. The second part is an overview of parameters important in terms of establishing and maintaining a barrier phenotype that allows for formulating criteria of evaluation of the BBB in vitro models. The third and last part discusses certain techniques for developing the BBB in vitro models. It describes subsequent research approaches and models, as they underwent change alongside technological advancement. On the one hand, we discuss possibilities and limitations of different research approaches: primary cultures vs. cell lines and monocultures vs. multicultures. On the other hand, we review advantages and disadvantages of specific models, such as models-on-a-chip, 3D models or microfluidic models. We not only attempt to state the usefulness of specific models in different kinds of research on the BBB but also emphasize the significance of this area of research for advancement of neuroscience and the pharmaceutical industry.

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“…Previous studies have shown that the downregulation of occludin can significantly reduce transcutaneous/transendothelial resistance (TEER) and increase paracellular diffusion ( 70 ). Compared to wild-type mice, the permeability of the BBB significantly increases in occludin-deficient mice after stroke ( 71 ). Many factors, such as matrix metalloproteinase-9 (MMP-9), ubiquitination, phosphorylation, tumor necrosis factor, IL-1β, and IFN-γ, participate in regulating the expression of occludin ( 69 ).…”

Section: Structural Physiological and Pathological Roles Of The Bbbmentioning

confidence: 99%

Anti-NMDAR antibodies, the blood–brain barrier, and anti-NMDAR encephalitis

Gong,

Wang,

Zhu

et al. 2023

Front. Neurol.

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Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an antibody-related autoimmune encephalitis. It is characterized by the existence of antibodies against NMDAR, mainly against the GluN1 subunit, in cerebrospinal fluid (CSF). Recent research suggests that anti-NMDAR antibodies may reduce NMDAR levels in this disorder, compromising synaptic activity in the hippocampus. Although anti-NMDAR antibodies are used as diagnostic indicators, the origin of antibodies in the central nervous system (CNS) is unclear. The blood–brain barrier (BBB), which separates the brain from the peripheral circulatory system, is crucial for antibodies and immune cells to enter or exit the CNS. The findings of cytokines in this disorder support the involvement of the BBB. Here, we aim to review the function of NMDARs and the relationship between anti-NMDAR antibodies and anti-NMDAR encephalitis. We summarize the present knowledge of the composition of the BBB, especially by emphasizing the role of BBB components. Finally, we further provide a discussion on the impact of BBB dysfunction in anti-NMDAR encephalitis.

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The tight junction protein occludin modulates blood–brain barrier integrity and neurological function after ischemic stroke in mice

Cited by 23 publications

References 52 publications

Endothelial Cell APOE3 Regulates Neurovascular, Neuronal, and Behavioral Function

Endothelial Cell APOE3 Regulates Neurovascular, Neuronal, and Behavioral Function

Experimental Models to Study the Functions of the Blood–Brain Barrier

Anti-NMDAR antibodies, the blood–brain barrier, and anti-NMDAR encephalitis

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