Blood–Brain Barrier Breakdown in Stress and Neurodegeneration: Biochemical Mechanisms and New Models for Translational Research

Салмина, А. Б.; KOMLEVA, YULIYA K.; Malinovskaya, N. A.; Моргун, А. В.; Teplyashina, E. A.; Lopatina, Olga; Gorina, Yana V.; Kharitonova, Elena P.; Хилажева, Е. Д.; Shuvaev, Аnton N.

doi:10.1134/s0006297921060122

Cited by 8 publications

(8 citation statements)

References 120 publications

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“…Similarly, we also observed an age-dependent increase in the levels of iron in liver and in serum of old mice indicating a general perturbation of iron metabolism with physiological aging (Supplementary Figure 1S ). Since progressive BBB damage is occurring not only in neurodegeneration 21 but also during aging, we analysed Zonula occludens-1 (ZO-1) protein, whose role is to maintain the compactness of BBB acting as a bridge connecting Claudin and Occludin proteins to the actin cytoskeleton in order to stabilize the tight junction (TJ) structure 22 . ZO-1 levels significantly decrease during aging (Fig.…”

Section: Resultsmentioning

confidence: 99%

Activation of the Hepcidin-Ferroportin1 pathway in the brain and astrocytic–neuronal crosstalk to counteract iron dyshomeostasis during aging

Mezzanotte

Boido

et al. 2022

Sci Rep

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During physiological aging, iron accumulates in the brain with a preferential distribution in regions that are more vulnerable to age-dependent neurodegeneration such as the cerebral cortex and hippocampus. In the brain of aged wild-type mice, alteration of the Brain Blood Barrier integrity, together with a marked inflammatory and oxidative state lead to increased permeability and deregulation of brain-iron homeostasis. In this context, we found that iron accumulation drives Hepcidin upregulation in the brain and the inhibition of the iron exporter Ferroportin1. We also observed the transcription and the increase of NCOA4 levels in the aged brain together with the increase of light-chain enriched ferritin heteropolymers, more efficient as iron chelators. Interestingly, in cerebral cortex and hippocampus, Ferroportin1 is mainly expressed by astrocytes, while the iron storage protein ferritin light-chain by neurons. This differential distribution suggests that astrocytes mediate iron shuttling in the nervous tissue and that neurons are unable to metabolize it. Our findings highlight for the first time that Hepcidin/Ferroportin1 axis and NCOA4 are directly involved in iron metabolism in mice brain during physiological aging as a response to a higher brain iron influx.

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Section: Resultsmentioning

confidence: 99%

Activation of the Hepcidin-Ferroportin1 pathway in the brain and astrocytic–neuronal crosstalk to counteract iron dyshomeostasis during aging

Mezzanotte

Boido

et al. 2022

Sci Rep

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“…The NVU is the fundamental multicellular unit supporting the BBB and consists of ECs, pericytes, astrocytes, microglia, and neurons (Figure 1). 6,7 The capillary lumen is the primary area of contact between the NVU and the periphery, and interfacing factors vary from cytokines and hormones to immune cells that have the potential to extravasate 16,17 . Forming the vessel lumen is specialized CNS ECs, which are semipermeable under homeostatic conditions due to the presence of tight junctions 6,16,18–20 .…”

Section: Structure and Organization Of The Nvumentioning

confidence: 99%

“…Further complexity of the BBB was demonstrated by seminal evidence indicating immune privilege, wherein immune cells are excluded and unable to surveille the CNS, over 100 years ago by Shirai 4 and later confirmed by Murphy and Sturm 5 . However, even now, the permeability, complexity, and dynamics of the BBB are incompletely understood 6,7 …”

Section: Introductionmentioning

confidence: 99%

“…even now, the permeability, complexity, and dynamics of the BBB are incompletely understood. 6,7 The BBB acts as a robust biological gateway, responsible for the flow of nearly all molecules and cells passing into and out of the CNS. 6,8,9 This selective permeability is critical in sparing the CNS from many circulating toxins and pathogens and allowing for availability of necessary nutrients to the CNS.…”

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confidence: 99%

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Targetability of the neurovascular unit in inflammatory diseases of the central nervous system

Smith

Tinkey

Shaw

et al. 2022

Immunological Reviews

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Summary The blood–brain barrier (BBB) is a selectively permeable barrier separating the periphery from the central nervous system (CNS). The BBB restricts the flow of most material into and out of the CNS, including many drugs that could be used as potent therapies. BBB permeability is modulated by several cells that are collectively called the neurovascular unit (NVU). The NVU consists of specialized CNS endothelial cells (ECs), pericytes, astrocytes, microglia, and neurons. CNS ECs maintain a complex “seal” via tight junctions, forming the BBB; breakdown of these tight junctions leads to BBB disruption. Pericytes control the vascular flow within capillaries and help maintain the basal lamina. Astrocytes control much of the flow of material that has moved beyond the CNS EC layer and can form a secondary barrier under inflammatory conditions. Microglia survey the border of the NVU for noxious material. Neuronal activity also plays a role in the maintenance of the BBB. Since astrocytes, pericytes, microglia, and neurons are all able to modulate the permeability of the BBB, understating the complex contributions of each member of the NVU will potentially uncover novel and effective methods for delivery of neurotherapies to the CNS.

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“…Solving this problem will ensure progress in understanding the mechanisms of brain functioning, deciphering the pathogenesis of central nervous system diseases (neurodegeneration, neurodevelopmental disorders, neuroinflammation, etc.) [1][2][3][4]. Methods and Algorithms: Using modern protocols of cell biology, neurobiology, and bioengineering, we have developed several original models of the neurovascular unit, neurogenic niche, and blood-brain barrier in vitro.…”

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confidence: 99%

Modern models of brain diseases for translational studies

2022

The Thirteenth International Multiconference

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Motivation and Aim: Development of new in vivo and in vitro models of brain diseases is one of the objectives of translational studies in Neuroscience. Solving this problem will ensure progress in understanding the mechanisms of brain functioning, deciphering the pathogenesis of central nervous system diseases (neurodegeneration, neurodevelopmental disorders, neuroinflammation, etc.) [1][2][3][4]. Methods and Algorithms: Using modern protocols of cell biology, neurobiology, and bioengineering, we have developed several original models of the neurovascular unit, neurogenic niche, and blood-brain barrier in vitro. These models allow us to reproduce some important aspects of intercellular communication, metabolic control, neurogenesis, angiogenesis/barriergenesis, functional activity and damage of neuronal, glial, and endothelial cells. Results: We will present an analysis of up-to-date methods and approaches to in vitro modeling of brain tissue, application of various multicellular ensembles, scaffolds and structures to reproduce the mechanisms of plasticity, protocols used for monitoring the viability and functional competence of cells and tissues, and key criteria applied for such models, as well as prospects for their further improvement. Conclusion:The choice of an adequate model and biomarkers is a key success factor in translational research in medicine. Modern technological solutions make possible the most reliable reconstruction of mechanisms of brain plasticity in the in vitro systems as well as to promote the development of new pharmacological agents with precise targeting and high efficacy.

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Blood–Brain Barrier Breakdown in Stress and Neurodegeneration: Biochemical Mechanisms and New Models for Translational Research

Cited by 8 publications

References 120 publications

Activation of the Hepcidin-Ferroportin1 pathway in the brain and astrocytic–neuronal crosstalk to counteract iron dyshomeostasis during aging

Activation of the Hepcidin-Ferroportin1 pathway in the brain and astrocytic–neuronal crosstalk to counteract iron dyshomeostasis during aging

Targetability of the neurovascular unit in inflammatory diseases of the central nervous system

Modern models of brain diseases for translational studies

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