Functional morphology of the blood–brain barrier in health and disease
Liebner, Stefan; Dijkhuizen, Rick M.; Reiss, Yvonne; Plate, Karl H.; Agalliu, Dritan; Constantin, Gabriela
(2018) Acta Neuropathologica, volume 135, issue 3, pp. 311 - 336
(Article)
Abstract
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
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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.
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Keywords: Alzheimer’s disease, Blood–brain barrier, Brain tumour, Neuroinflammation, Steady state, Stroke, Animals, Humans, Blood-Brain Barrier/cytology, Blood-brain barrier, Alzheimer's disease, Clinical Neurology, Cellular and Molecular Neuroscience, Pathology and Forensic Medicine, Review, Research Support, Non-U.S. Gov't, Journal Article, Research Support, N.I.H., Extramural
ISSN: 0001-6322
Publisher: Springer
Note: Funding Information: Acknowledgements S.L. is supported by the Deutsche Forschungsge- Funding Information: D.A. is supported by the NIH (#R01 HL116995, #R56 MH109987 and #R01 MH112849), the National Multiple Sclerosis Society (NMSS #RG4673A1/1), the Leducq Foundation (D.A.) and an unrestricted gift from John Castle to the Department of Neurology, Stroke Division at CUMC. The authors declare no competing financial interests. Dritan Agalliu thanks Sarah Lutz in the Department of Anatomy and Cell Biology at University of Illinois, Chicago for scientific discussions, illustrations and help with the preparation of the section on neuroinflammation. Funding Information: Y.R and K.P. are supported by the German Research Council (Collaborative Research Center/Transregio23 “Vascular differentiation and remodeling”, the Cluster of Excellence 147 “Cardiopulmonary system”), the German Center for Cardiovascular Research (DZHK) and the German Cancer Consortium (DKTK) (Partnersites Frankfurt/ Mainz). Special thanks to Mariangela Di Tacchio and Jadranka Macas for their contribution to Fig. 3. Funding Information: R.M.D. This work is supported by the Netherlands Organization for Scientific Research (016.130.662; VICI), the EU Joint Programme-Neurodegenerative Disease Research through the Netherlands Organisation for Health Research and Development (733051067; SNOWBALL), and the Netherlands Cardiovascular Research Initiative through the Dutch Heart Foundation (CVON2015-01; CONTRAST) and the Brain Foundation Netherlands (HA2015.01.06). Funding Information: S.L. is supported by the Deutsche Forschungsgemeinschaft SFB/TR23 ?Vascular Differentiation and Remodeling?, the research group FOR2325 ?The Neurovascular Interface?, the Excellence Cluster Cardio-Pulmonary System, the European Union HORIZON 2020 ITN ?BtRAIN?, the German Centre for Heart and Circulation Research (DZHK, Column B: Shared Expertise). Special thanks go to Hartwig Wolburg for providing freeze fracture images, to Jadranka Macas for transmission electron microscopy, to Elif Fidan for immunofluorescence images and Sylvaine Gu?rti for proof reading and scientific discussion. R.M.D. This work is supported by the Netherlands Organization for Scientific Research (016.130.662; VICI), the EU Joint Programme-Neurodegenerative Disease Research through the Netherlands Organisation for Health Research and Development (733051067; SNOWBALL), and the Netherlands Cardiovascular Research Initiative through the Dutch Heart Foundation (CVON2015-01; CONTRAST) and the Brain Foundation Netherlands (HA2015.01.06). Y.R and K.P. are supported by the German Research Council (Collaborative Research Center/Transregio23 ?Vascular differentiation and remodeling?, the Cluster of Excellence 147 ?Cardiopulmonary system?), the German Center for Cardiovascular Research (DZHK) and the German Cancer Consortium (DKTK) (Partnersites Frankfurt/Mainz). Special thanks to Mariangela Di Tacchio and Jadranka Macas for their contribution to Fig.?3. D.A. is supported by the NIH (#R01 HL116995, #R56 MH109987 and #R01 MH112849), the National Multiple Sclerosis Society (NMSS #RG4673A1/1), the Leducq Foundation (D.A.) and an unrestricted gift from John Castle to the Department of Neurology, Stroke Division at CUMC. The authors declare no competing financial interests. Dritan Agalliu thanks Sarah Lutz in the Department of Anatomy and Cell Biology at University of Illinois, Chicago for scientific discussions, illustrations and help with the preparation of the section on neuroinflammation. G.C. is supported by the European Research Council (ERC) grants IMMUNOALZHEIMER (nr. 695714, ERC advanced grant) and IMPEDE (nr. 693606, ERC Proof of Concept grant) (G.C.), the American Drug Discovery Foundation (ADDF), USA, and the National Multiple Sclerosis Society (NMSS), New York, NY, USA. The authors declare that they have no conflict of interest. Funding Information: G.C. is supported by the European Research Council (ERC) grants IMMUNOALZHEIMER (nr. 695714, ERC advanced grant) and IMPEDE (nr. 693606, ERC Proof of Concept grant) (G.C.), the American Drug Discovery Foundation (ADDF), USA, and the National Multiple Sclerosis Society (NMSS), New York, NY, USA. Publisher Copyright: © 2018, The Author(s).
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