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Functional morphology of the blood–brain barrier in health and disease
Acta Neuropathologica ( IF 12.7 ) Pub Date : 2018-02-06 , DOI: 10.1007/s00401-018-1815-1
Stefan Liebner , Rick M. Dijkhuizen , Yvonne Reiss , Karl H. Plate , Dritan Agalliu , Gabriela Constantin

The adult quiescent blood–brain barrier (BBB), a structure organised by endothelial cells through interactions with pericytes, astrocytes, neurons and microglia in the neurovascular unit, is highly regulated but fragile at the same time. In the past decade, there has been considerable progress in understanding not only the molecular pathways involved in BBB development, but also BBB breakdown in neurological diseases. Specifically, the Wnt/β-catenin, retinoic acid and sonic hedgehog pathways moved into the focus of BBB research. Moreover, angiopoietin/Tie2 signalling that is linked to angiogenic processes has gained attention in the BBB field. Blood vessels play an essential role in initiation and progression of many diseases, including inflammation outside the central nervous system (CNS). Therefore, the potential influence of CNS blood vessels in neurological diseases associated with BBB alterations or neuroinflammation has become a major focus of current research to understand their contribution to pathogenesis. Moreover, the BBB remains a major obstacle to pharmaceutical intervention in the CNS. The complications may either be expressed by inadequate therapeutic delivery like in brain tumours, or by poor delivery of the drug across the BBB and ineffective bioavailability. In this review, we initially describe the cellular and molecular components that contribute to the steady state of the healthy BBB. We then discuss BBB alterations in ischaemic stroke, primary and metastatic brain tumour, chronic inflammation and Alzheimer’s disease. Throughout the review, we highlight common mechanisms of BBB abnormalities among these diseases, in particular the contribution of neuroinflammation to BBB dysfunction and disease progression, and emphasise unique aspects of BBB alteration in certain diseases such as brain tumours. Moreover, this review highlights novel strategies to monitor BBB function by non-invasive imaging techniques focussing on ischaemic stroke, as well as novel ways to modulate BBB permeability and function to promote treatment of brain tumours, inflammation and Alzheimer’s disease. In conclusion, a deep understanding of signals that maintain the healthy BBB and promote fluctuations in BBB permeability in disease states will be key to elucidate disease mechanisms and to identify potential targets for diagnostics and therapeutic modulation of the BBB.



中文翻译:

血脑屏障在健康和疾病中的功能形态

成人静态血脑屏障(BBB)是一种由内皮细胞通过与神经血管单位中的周细胞,星形胶质细胞,神经元和小胶质细胞相互作用而组织的结构,同时受到高度调控,但同时又很脆弱。在过去的十年中,不仅在了解血脑屏障发展中涉及的分子途径,而且在神经系统疾病中血脑屏障的分解方面取得了长足的进步。具体而言,Wnt /β-catenin,视黄酸和声波刺猬途径已成为BBB研究的重点。此外,与血管生成过程相关的血管生成素/ Tie2信号已经在BBB领域引起关注。血管在许多疾病的发生和发展中起着至关重要的作用,包括中枢神经系统(CNS)外部的炎症。所以,中枢神经系统血管在与BBB改变或神经发炎相关的神经系统疾病中的潜在影响已成为当前研究了解其对发病机理的主要研究重点。此外,血脑屏障仍然是中枢神经系统药物干预的主要障碍。并发症可能是由于治疗传递不足(例如在脑肿瘤中)或药物通过BBB的传递较差以及生物利用度不足而表达的。在这篇综述中,我们最初描述有助于健康BBB稳定状态的细胞和分子成分。然后,我们讨论缺血性中风,原发性和转移性脑瘤,慢性炎症和阿尔茨海默氏病中的血脑屏障变化。在整个审查过程中,我们重点介绍了这些疾病中BBB异常的常见机制,特别是神经炎症对血脑屏障功能障碍和疾病进展的贡献,并强调了血脑屏障在某些疾病(例如脑瘤)中的独特方面。此外,本综述重点介绍了通过针对缺血性中风的非侵入性成像技术监测BBB功能的新策略,以及调节BBB通透性和功能以促进脑瘤,炎症和阿尔茨海默氏病治疗的新颖方法。总之,深入了解维持健康BBB并促进疾病状态下BBB通透性波动的信号,对于阐明疾病机制和确定诊断和治疗BBB的潜在目标至关重要。并强调某些疾病(例如脑瘤)中BBB改变的独特方面。此外,本综述重点介绍了通过针对缺血性中风的非侵入性成像技术监测BBB功能的新策略,以及调节BBB通透性和功能以促进脑瘤,炎症和阿尔茨海默氏病治疗的新颖方法。总之,深入了解维持健康BBB并促进疾病状态下BBB通透性波动的信号,对于阐明疾病机制和确定诊断和治疗BBB的潜在目标至关重要。并强调某些疾病(例如脑瘤)中BBB改变的独特方面。此外,本综述重点介绍了通过针对缺血性中风的非侵入性成像技术监测BBB功能的新策略,以及调节BBB通透性和功能以促进脑瘤,炎症和阿尔茨海默氏病治疗的新颖方法。总之,深入了解维持健康BBB并促进疾病状态下BBB通透性波动的信号,对于阐明疾病机制和确定诊断和治疗BBB的潜在目标至关重要。以及调节BBB渗透性和功能以促进脑肿瘤,炎症和阿尔茨海默氏病治疗的新颖方法。总之,深入了解维持健康BBB并促进疾病状态下BBB通透性波动的信号,对于阐明疾病机制和确定诊断和治疗BBB的潜在目标至关重要。以及调节BBB渗透性和功能以促进脑肿瘤,炎症和阿尔茨海默氏病治疗的新颖方法。总之,深入了解维持健康BBB并促进疾病状态下BBB通透性波动的信号,对于阐明疾病机制和确定诊断和治疗BBB的潜在目标至关重要。

更新日期:2018-02-06
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