Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Development, maintenance and disruption of the blood-brain barrier

Nature Medicine volume 19, pages 1584–1596 (2013)Cite this article

Subjects

Abstract

The interface between the blood circulation and the neural tissue features unique characteristics that are encompassed by the term 'blood-brain barrier' (BBB). The main functions of this barrier, namely maintenance of brain homeostasis, regulation of influx and efflux transport, and protection from harm, are determined by its specialized multicellular structure. Every constituent cell type makes an indispensable contribution to the BBB's integrity. But if one member of the BBB fails, and as a result the barrier breaks down, there can be dramatic consequences and neuroinflammation and neurodegeneration can occur. In this Review, we highlight recently gained mechanistic insights into the development and maintenance of the BBB. We then discuss how BBB disruption can cause or contribute to neurological disease. Finally, we examine how this knowledge can be used to explore new possibilities for BBB repair.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cellular interplay at the neurovascular unit (capillary level).
Figure 2: Major signaling pathways in BBB development.
Figure 3: Central role of pericytes in the neurovascular unit.
Figure 4: Causes, characteristics and consequences of BBB breakdown.
Figure 5: Pathogenic mechanisms of epilepsy and neuromyelitis optica.

Similar content being viewed by others

References

  1. Abbott, N.J., Rönnbäck, L. & Hansson, E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 7, 41–53 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Ransohoff, R.M. & Engelhardt, B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 12, 623–635 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Daneman, R. The blood-brain barrier in health and disease. Ann. Neurol. 72, 648–672 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Aird, W.C. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ. Res. 100, 158–173 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Aird, W.C. Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ. Res. 100, 174–190 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Neuwelt, E.A. et al. Engaging neuroscience to advance translational research in brain barrier biology. Nat. Rev. Neurosci. 12, 169–182 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hallmann, R. et al. Expression and function of laminins in the embryonic and mature vasculature. Physiol. Rev. 85, 979–1000 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Williams, K., Alvarez, X. & Lackner, A.A. Central nervous system perivascular cells are immunoregulatory cells that connect the CNS with the peripheral immune system. Glia 36, 156–164 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Daneman, R. et al. The mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS ONE 5, e13741 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Shawahna, R. et al. Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. Mol. Pharm. 8, 1332–1341 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Lyck, R. et al. Culture-induced changes in blood-brain barrier transcriptome: implications for amino-acid transporters in vivo. J. Cereb. Blood Flow Metab. 29, 1491–1502 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Urich, E., Lazic, S.E., Molnos, J., Wells, I. & Freskgard, P.O. Transcriptional profiling of human brain endothelial cells reveals key properties crucial for predictive in vitro blood-brain barrier models. PLoS ONE 7, e38149 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1–deficient mice. Nature 376, 62–66 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Raab, S. et al. Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor. Thromb. Haemost. 91, 595–605 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Haigh, J.J. et al. Cortical and retinal defects caused by dosage-dependent reductions in VEGF-A paracrine signaling. Dev. Biol. 262, 225–241 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Olsson, A.K., Dimberg, A., Kreuger, J. & Claesson-Welsh, L. VEGF receptor signalling—in control of vascular function. Nat. Rev. Mol. Cell Biol. 7, 359–371 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Daneman, R. et al. Wnt/β-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc. Natl. Acad. Sci. USA 106, 641–646 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Logan, C.Y. & Nusse, R. The Wnt signaling pathway in development and disease. Annu. Rev. Cell Dev. Biol. 20, 781–810 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Stenman, J.M. et al. Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Science 322, 1247–1250 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Tam, S.J. et al. Death receptors DR6 and TROY regulate brain vascular development. Dev. Cell 22, 403–417 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Liebner, S. et al. Wnt/β-catenin signaling controls development of the blood-brain barrier. J. Cell Biol. 183, 409–417 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kuhnert, F. et al. Essential regulation of CNS angiogenesis by the orphan G protein–coupled receptor GPR124. Science 330, 985–989 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Anderson, K.D. et al. Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein–coupled receptor. Proc. Natl. Acad. Sci. USA 108, 2807–2812 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cullen, M. et al. GPR124, an orphan G protein–coupled receptor, is required for CNS-specific vascularization and establishment of the blood-brain barrier. Proc. Natl. Acad. Sci. USA 108, 5759–5764 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Alvarez, J.I. et al. The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science 334, 1727–1731 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Nagase, T., Nagase, M., Machida, M. & Fujita, T. Hedgehog signalling in vascular development. Angiogenesis 11, 71–77 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Pola, R. et al. The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat. Med. 7, 706–711 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Allt, G. & Lawrenson, J.G. Pericytes: cell biology and pathology. Cells Tissues Organs 169, 1–11 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Armulik, A., Genove, G. & Betsholtz, C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193–215 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Winkler, E.A., Bell, R.D. & Zlokovic, B.V. Central nervous system pericytes in health and disease. Nat. Neurosci. 14, 1398–1405 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dore-Duffy, P. Pericytes: pluripotent cells of the blood brain barrier. Curr. Pharm. Des. 14, 1581–1593 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Sá-Pereira, I., Brites, D. & Brito, M.A. Neurovascular unit: a focus on pericytes. Mol. Neurobiol. 45, 327–347 (2012).

    Article  PubMed  CAS  Google Scholar 

  34. Armulik, A. et al. Pericytes regulate the blood-brain barrier. Nature 468, 557–561 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Bell, R.D. et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409–427 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Daneman, R., Zhou, L., Kebede, A.A. & Barres, B.A. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468, 562–566 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lindahl, P., Johansson, B.R., Leveen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B–deficient mice. Science 277, 242–245 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Hellström, M. et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153, 543–553 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Hellström, M., Kalen, M., Lindahl, P., Abramsson, A. & Betsholtz, C. Role of PDGF-B and PDGFR-β in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126, 3047–3055 (1999).

    Article  PubMed  Google Scholar 

  40. Li, F. et al. Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with Notch. Dev. Cell 20, 291–302 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Tallquist, M.D., French, W.J. & Soriano, P. Additive effects of PDGF receptor β signaling pathways in vascular smooth muscle cell development. PLoS Biol. 1, E52 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Lindblom, P. et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 17, 1835–1840 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gee, J.R. & Keller, J.N. Astrocytes: regulation of brain homeostasis via apolipoprotein E. Int. J. Biochem. Cell Biol. 37, 1145–1150 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Neuhaus, J. Orthogonal arrays of particles in astroglial cells: quantitative analysis of their density, size, and correlation with intramembranous particles. Glia 3, 241–251 (1990).

    Article  CAS  PubMed  Google Scholar 

  45. Stewart, P.A. & Wiley, M.J. Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: a study using quail–chick transplantation chimeras. Dev. Biol. 84, 183–192 (1981).

    Article  CAS  PubMed  Google Scholar 

  46. Hayashi, Y. et al. Induction of various blood-brain barrier properties in non-neural endothelial cells by close apposition to co-cultured astrocytes. Glia 19, 13–26 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. Sun, D., Lytle, C. & O'Donnell, M.E. IL-6 secreted by astroglial cells regulates Na-K-Cl cotransport in brain microvessel endothelial cells. Am. J. Physiol. 272, C1829–C1835 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. Igarashi, Y. et al. Glial cell line-derived neurotrophic factor induces barrier function of endothelial cells forming the blood-brain barrier. Biochem. Biophys. Res. Commun. 261, 108–112 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Sobue, K. et al. Induction of blood-brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. Neurosci. Res. 35, 155–164 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Lee, S.W. et al. SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nat. Med. 9, 900–906 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Milsted, A., Barna, B.P., Ransohoff, R.M., Brosnihan, K.B. & Ferrario, C.M. Astrocyte cultures derived from human brain tissue express angiotensinogen mRNA. Proc. Natl. Acad. Sci. USA 87, 5720–5723 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wosik, K. et al. Angiotensin II controls occludin function and is required for blood brain barrier maintenance: relevance to multiple sclerosis. J. Neurosci. 27, 9032–9042 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hafezi-Moghadam, A., Thomas, K.L. & Wagner, D.D. ApoE deficiency leads to a progressive age-dependent blood-brain barrier leakage. Am. J. Physiol. Cell Physiol. 292, C1256–C1262 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Nishitsuji, K., Hosono, T., Nakamura, T., Bu, G. & Michikawa, M. Apolipoprotein E regulates the integrity of tight junctions in an isoform-dependent manner in an in vitro blood-brain barrier model. J. Biol. Chem. 286, 17536–17542 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bell, R.D. et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512–516 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Deane, R. et al. apoE isoform-specific disruption of amyloid β peptide clearance from mouse brain. J. Clin. Invest. 118, 4002–4013 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Carvey, P.M., Hendey, B. & Monahan, A.J. The blood-brain barrier in neurodegenerative disease: a rhetorical perspective. J. Neurochem. 111, 291–314 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Baeten, K.M. & Akassoglou, K. Extracellular matrix and matrix receptors in blood-brain barrier formation and stroke. Dev. Neurobiol. 71, 1018–1039 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Milner, R. & Campbell, I.L. Developmental regulation of β1 integrins during angiogenesis in the central nervous system. Mol. Cell. Neurosci. 20, 616–626 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Wang, J. & Milner, R. Fibronectin promotes brain capillary endothelial cell survival and proliferation through α5β1 and αvβ3 integrins via MAP kinase signalling. J. Neurochem. 96, 148–159 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Osada, T. et al. Interendothelial claudin-5 expression depends on cerebral endothelial cell-matrix adhesion by β1-integrins. J. Cereb. Blood Flow Metab. 31, 1972–1985 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhu, J. et al. β8 integrins are required for vascular morphogenesis in mouse embryos. Development 129, 2891–2903 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. McCarty, J.H. et al. Defective associations between blood vessels and brain parenchyma lead to cerebral hemorrhage in mice lacking αv integrins. Mol. Cell. Biol. 22, 7667–7677 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cambier, S. et al. Integrin αvβ8-mediated activation of transforming growth factor-β by perivascular astrocytes: an angiogenic control switch. Am. J. Pathol. 166, 1883–1894 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kostka, G. et al. Perinatal lethality and endothelial cell abnormalities in several vessel compartments of fibulin-1–deficient mice. Mol. Cell. Biol. 21, 7025–7034 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dong, L. et al. Neurologic defects and selective disruption of basement membranes in mice lacking entactin-1/nidogen-1. Lab. Invest. 82, 1617–1630 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Pöschl, E. et al. Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 131, 1619–1628 (2004).

    Article  PubMed  CAS  Google Scholar 

  68. Smolich, B.D., McMahon, J.A., McMahon, A.P. & Papkoff, J. Wnt family proteins are secreted and associated with the cell surface. Mol. Biol. Cell 4, 1267–1275 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Willert, K. et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423, 448–452 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Liebner, S. & Plate, K.H. Differentiation of the brain vasculature: the answer came blowing by the Wnt. J. Angiogenes. Res. 2, 1 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Akhmetshina, A. et al. Activation of canonical Wnt signalling is required for TGF-β–mediated fibrosis. Nat. Commun. 3, 735 (2012).

    Article  PubMed  CAS  Google Scholar 

  72. Handel, T.M., Johnson, Z., Crown, S.E., Lau, E.K. & Proudfoot, A.E. Regulation of protein function by glycosaminoglycans—as exemplified by chemokines. Annu. Rev. Biochem. 74, 385–410 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Proudfoot, A.E. The biological relevance of chemokine-proteoglycan interactions. Biochem. Soc. Trans. 34, 422–426 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Shechter, R. & Schwartz, M. Harnessing monocyte-derived macrophages to control central nervous system pathologies: no longer 'if' but 'how'. J. Pathol. 229, 332–346 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. Robberecht, W. Oxidative stress in amyotrophic lateral sclerosis. J. Neurol. 247, I1–I6 (2000).

    Article  PubMed  Google Scholar 

  76. van Horssen, J., Witte, M.E., Schreibelt, G. & de Vries, H.E. Radical changes in multiple sclerosis pathogenesis. Biochim. Biophys. Acta 1812, 141–150 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Olmez, I. & Ozyurt, H. Reactive oxygen species and ischemic cerebrovascular disease. Neurochem. Int. 60, 208–212 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Davis, S.M. & Donnan, G.A. Secondary prevention after ischemic stroke or transient ischemic attack. N. Engl. J. Med. 366, 1914–1922 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. Suzuki, R., Yamaguchi, T., Kirino, T., Orzi, F. & Klatzo, I. The effects of 5-minute ischemia in Mongolian gerbils: I. Blood-brain barrier, cerebral blood flow, and local cerebral glucose utilization changes. Acta Neuropathol. 60, 207–216 (1983).

    Article  CAS  PubMed  Google Scholar 

  80. Pillai, D.R. et al. Cerebral ischemia-reperfusion injury in rats—A 3 T MRI study on biphasic blood-brain barrier opening and the dynamics of edema formation. J. Cereb. Blood Flow Metab. 29, 1846–1855 (2009).

    Article  PubMed  Google Scholar 

  81. Pun, P.B., Lu, J. & Moochhala, S. Involvement of ROS in BBB dysfunction. Free Radic. Res. 43, 348–364 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Montaner, J. et al. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 107, 598–603 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Gu, Y. et al. Caveolin-1 regulates nitric oxide–mediated matrix metalloproteinases activity and blood-brain barrier permeability in focal cerebral ischemia and reperfusion injury. J. Neurochem. 120, 147–156 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Jiao, H., Wang, Z., Liu, Y., Wang, P. & Xue, Y. Specific role of tight junction proteins claudin-5, occludin, and ZO-1 of the blood–brain barrier in a focal cerebral ischemic insult. J. Mol. Neurosci. 44, 130–139 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Bright, R. et al. Protein kinase C δ mediates cerebral reperfusion injury in vivo. J. Neurosci. 24, 6880–6888 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Chou, W.H. et al. Neutrophil protein kinase Cδ as a mediator of stroke-reperfusion injury. J. Clin. Invest. 114, 49–56 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kunsch, C. & Medford, R.M. Oxidative stress as a regulator of gene expression in the vasculature. Circ. Res. 85, 753–766 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Enzmann, G. et al. The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury. Acta Neuropathol. 125, 395–412 (2013).

    Article  PubMed  Google Scholar 

  89. Madden, J.A. Role of the vascular endothelium and plaque in acute ischemic stroke. Neurology 79, S58–S62 (2012).

    Article  CAS  PubMed  Google Scholar 

  90. French, J.A. & Pedley, T.A. Clinical practice. Initial management of epilepsy. N. Engl. J. Med. 359, 166–176 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Fieschi, C., Lenzi, G.L., Zanette, E., Orzi, F. & Passero, S. Effects on EEG of the osmotic opening of the blood-brain barrier in rats. Life Sci. 27, 239–243 (1980).

    Article  CAS  PubMed  Google Scholar 

  92. Marchi, N. et al. Seizure-promoting effect of blood-brain barrier disruption. Epilepsia 48, 732–742 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Rapoport, S.I. Osmotic opening of the blood-brain barrier: principles, mechanism, and therapeutic applications. Cell. Mol. Neurobiol. 20, 217–230 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Kofuji, P. & Newman, E.A. Potassium buffering in the central nervous system. Neuroscience 129, 1045–1056 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Coulter, D.A. & Eid, T. Astrocytic regulation of glutamate homeostasis in epilepsy. Glia 60, 1215–1226 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Cacheaux, L.P. et al. Transcriptome profiling reveals TGF-β signaling involvement in epileptogenesis. J. Neurosci. 29, 8927–8935 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ivens, S. et al. TGF-β receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 130, 535–547 (2007).

    Article  PubMed  Google Scholar 

  98. Heinemann, U., Kaufer, D. & Friedman, A. Blood-brain barrier dysfunction, TGFβ signaling, and astrocyte dysfunction in epilepsy. Glia 60, 1251–1257 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Ravizza, T. et al. Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol. Dis. 29, 142–160 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Morin-Brureau, M. et al. Epileptiform activity induces vascular remodeling and zonula occludens 1 downregulation in organotypic hippocampal cultures: role of VEGF signaling pathways. J. Neurosci. 31, 10677–10688 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Librizzi, L., Noe, F., Vezzani, A., de Curtis, M. & Ravizza, T. Seizure-induced brain-borne inflammation sustains seizure recurrence and blood-brain barrier damage. Ann. Neurol. 72, 82–90 (2012).

    Article  PubMed  Google Scholar 

  102. Fabene, P.F. et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat. Med. 14, 1377–1383 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Palmer, A.M. The role of the blood-CNS barrier in CNS disorders and their treatment. Neurobiol. Dis. 37, 3–12 (2010).

    Article  CAS  PubMed  Google Scholar 

  104. Rowland, L.P. & Shneider, N.A. Amyotrophic lateral sclerosis. N. Engl. J. Med. 344, 1688–1700 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Rosen, D.R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993).

    Article  CAS  PubMed  Google Scholar 

  106. Evans, M.C., Couch, Y., Sibson, N. & Turner, M.R. Inflammation and neurovascular changes in amyotrophic lateral sclerosis. Mol. Cell. Neurosci. 53, 34–41 (2013).

    Article  CAS  PubMed  Google Scholar 

  107. Zlokovic, B.V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Garbuzova-Davis, S. et al. Evidence of compromised blood-spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS. PLoS ONE 2, e1205 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Nicaise, C. et al. Impaired blood–brain and blood–spinal cord barriers in mutant SOD1-linked ALS rat. Brain Res. 1301, 152–162 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Zhong, Z. et al. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat. Neurosci. 11, 420–422 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Miyazaki, K. et al. Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis. J. Neurosci. Res. 89, 718–728 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Wingerchuk, D.M., Lennon, V.A., Lucchinetti, C.F., Pittock, S.J. & Weinshenker, B.G. The spectrum of neuromyelitis optica. Lancet Neurol. 6, 805–815 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Cree, B.A., Goodin, D.S. & Hauser, S.L. Neuromyelitis optica. Semin. Neurol. 22, 105–122 (2002).

    Article  PubMed  Google Scholar 

  114. Lennon, V.A. et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364, 2106–2112 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Lennon, V.A., Kryzer, T.J., Pittock, S.J., Verkman, A.S. & Hinson, S.R. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J. Exp. Med. 202, 473–477 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lucchinetti, C.F. et al. A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica. Brain 125, 1450–1461 (2002).

    Article  PubMed  Google Scholar 

  117. Misu, T. et al. Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis. Brain 130, 1224–1234 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Roemer, S.F. et al. Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain 130, 1194–1205 (2007).

    Article  PubMed  Google Scholar 

  119. Takahashi, T. et al. Anti–aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain 130, 1235–1243 (2007).

    Article  PubMed  Google Scholar 

  120. Kim, S.H. et al. Clinical efficacy of plasmapheresis in patients with neuromyelitis optica spectrum disorder and effects on circulating anti–aquaporin-4 antibody levels. J. Clin. Neurol. 9, 36–42 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Cree, B.A. et al. An open label study of the effects of rituximab in neuromyelitis optica. Neurology 64, 1270–1272 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Hinson, S.R. et al. Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica. Neurology 69, 2221–2231 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Haj-Yasein, N.N. et al. Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood-brain water uptake and confers barrier function on perivascular astrocyte endfeet. Proc. Natl. Acad. Sci. USA 108, 17815–17820 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Hosokawa, T. et al. Increased serum matrix metalloproteinase-9 in neuromyelitis optica: implication of disruption of blood-brain barrier. J. Neuroimmunol. 236, 81–86 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Tomizawa, Y. et al. Blood-brain barrier disruption is more severe in neuromyelitis optica than in multiple sclerosis and correlates with clinical disability. J. Int. Med. Res. 40, 1483–1491 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Cayrol, R., Saikali, P. & Vincent, T. Effector functions of antiaquaporin-4 autoantibodies in neuromyelitis optica. Ann. NY Acad. Sci. 1173, 478–486 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Phuan, P.W., Ratelade, J., Rossi, A., Tradtrantip, L. & Verkman, A.S. Complement-dependent cytotoxicity in neuromyelitis optica requires aquaporin-4 protein assembly in orthogonal arrays. J. Biol. Chem. 287, 13829–13839 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Saadoun, S. et al. Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice. Brain 133, 349–361 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Vincent, T. et al. Functional consequences of neuromyelitis optica-IgG astrocyte interactions on blood-brain barrier permeability and granulocyte recruitment. J. Immunol. 181, 5730–5737 (2008).

    Article  CAS  PubMed  Google Scholar 

  130. Kinoshita, M. et al. Neuromyelitis optica: Passive transfer to rats by human immunoglobulin. Biochem. Biophys. Res. Commun. 386, 623–627 (2009).

    Article  CAS  PubMed  Google Scholar 

  131. Bradl, M. et al. Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo. Ann. Neurol. 66, 630–643 (2009).

    Article  CAS  PubMed  Google Scholar 

  132. Shimizu, F. et al. Sera from neuromyelitis optica patients disrupt the blood-brain barrier. J. Neurol. Neurosurg. Psychiatry 83, 288–297 (2012).

    Article  PubMed  Google Scholar 

  133. Rhen, T. & Cidlowski, J.A. Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N. Engl. J. Med. 353, 1711–1723 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Miller, D.H. et al. High dose steroids in acute relapses of multiple sclerosis: MRI evidence for a possible mechanism of therapeutic effect. J. Neurol. Neurosurg. Psychiatry 55, 450–453 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Blecharz, K.G. et al. Glucocorticoid effects on endothelial barrier function in the murine brain endothelial cell line cEND incubated with sera from patients with multiple sclerosis. Mult. Scler. 16, 293–302 (2010).

    Article  CAS  PubMed  Google Scholar 

  136. Förster, C., Kahles, T., Kietz, S. & Drenckhahn, D. Dexamethasone induces the expression of metalloproteinase inhibitor TIMP-1 in the murine cerebral vascular endothelial cell line cEND. J. Physiol. (Lond.) 580, 937–949 (2007).

    Article  CAS  Google Scholar 

  137. Förster, C. et al. Differential effects of hydrocortisone and TNFα on tight junction proteins in an in vitro model of the human blood-brain barrier. J. Physiol. (Lond.) 586, 1937–1949 (2008).

    Article  CAS  Google Scholar 

  138. Go, K.G. et al. Effect of steroids on brain lipocortin immunoreactivity. Acta Neurochir. Suppl. (Wien) 60, 101–103 (1994).

    CAS  Google Scholar 

  139. Cristante, E. et al. Identification of an essential endogenous regulator of blood-brain barrier integrity, and its pathological and therapeutic implications. Proc. Natl. Acad. Sci. USA 110, 832–841 (2013).

    Article  CAS  PubMed  Google Scholar 

  140. Argaw, A.T. et al. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. J. Clin. Invest. 122, 2454–2468 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. da Silva Meirelles, L., Caplan, A.I. & Nardi, N.B. In search of the in vivo identity of mesenchymal stem cells. Stem Cells 26, 2287–2299 (2008).

    Article  PubMed  Google Scholar 

  142. Auletta, J.J. et al. The potential of mesenchymal stromal cells as a novel cellular therapy for multiple sclerosis. Immunotherapy 4, 529–547 (2012).

    Article  CAS  PubMed  Google Scholar 

  143. Zacharek, A. et al. Angiopoietin1/Tie2 and VEGF/Flk1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke. J. Cereb. Blood Flow Metab. 27, 1684–1691 (2007).

    Article  CAS  PubMed  Google Scholar 

  144. Pfeiffer, F. et al. Claudin-1 induced sealing of blood-brain barrier tight junctions ameliorates chronic experimental autoimmune encephalomyelitis. Acta Neuropathol. 122, 601–614 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Sohet, F. & Daneman, R. Genetic mouse models to study blood-brain barrier development and function. Fluids Barriers CNS 10, 3 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Geldenhuys, W.J., Allen, D.D. & Bloomquist, J.R. Novel models for assessing blood-brain barrier drug permeation. Expert Opin. Drug Metab. Toxicol. 8, 647–653 (2012).

    Article  CAS  PubMed  Google Scholar 

  147. Dolghih, E. & Jacobson, M.P. Predicting efflux ratios and blood-brain barrier penetration from chemical structure: combining passive permeability with active efflux by P-glycoprotein. ACS Chem. Neurosci. 4, 361–367 (2013).

    Article  CAS  PubMed  Google Scholar 

  148. Lippmann, E.S. et al. Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells. Nat. Biotechnol. 30, 783–791 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Thanabalasundaram, G., El-Gindi, J., Lischper, M. & Galla, H.-J. Methods to assess pericyte-endothelial cell interactions in a coculture model. Methods Mol. Biol. 686, 379–399 (2011).

    Article  CAS  PubMed  Google Scholar 

  150. Abbott, N.J., Dolman, D.E., Drndarski, S. & Fredriksson, S.M. An improved in vitro blood-brain barrier model: rat brain endothelial cells co-cultured with astrocytes. Methods Mol. Biol. 814, 415–430 (2012).

    Article  CAS  PubMed  Google Scholar 

  151. Vandenhaute, E. et al. Modelling the neurovascular unit and the blood-brain barrier with the unique function of pericytes. Curr. Neurovasc. Res. 8, 258–269 (2011).

    Article  CAS  PubMed  Google Scholar 

  152. Hatherell, K., Couraud, P.O., Romero, I.A., Weksler, B. & Pilkington, G.J. Development of a three-dimensional, all-human in vitro model of the blood-brain barrier using mono-, co-, and tri-cultivation Transwell models. J. Neurosci. Methods 199, 223–229 (2011).

    Article  PubMed  Google Scholar 

  153. Sumi, N. et al. Lipopolysaccharide-activated microglia induce dysfunction of the blood-brain barrier in rat microvascular endothelial cells co-cultured with microglia. Cell. Mol. Neurobiol. 30, 247–253 (2010).

    Article  CAS  PubMed  Google Scholar 

  154. Xue, Q. et al. A novel brain neurovascular unit model with neurons, astrocytes and microvascular endothelial cells of rat. Int. J. Biol. Sci. 9, 174–189 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Man, S. et al. CXCL12-induced monocyte-endothelial interactions promote lymphocyte transmigration across an in vitro blood-brain barrier. Sci. Transl. Med. 4, 119ra114 (2012).

    Article  CAS  Google Scholar 

  156. Cucullo, L., Hossain, M., Tierney, W. & Janigro, D. A new dynamic in vitro modular capillaries-venules modular system: cerebrovascular physiology in a box. BMC Neurosci. 14, 18 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Dohgu, S. et al. Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-β production. Brain Res. 1038, 208–215 (2005).

    Article  CAS  PubMed  Google Scholar 

  158. Liebner, S., Czupalla, C.J. & Wolburg, H. Current concepts of blood-brain barrier development. Int. J. Dev. Biol. 55, 467–476 (2011).

    Article  CAS  PubMed  Google Scholar 

  159. Cucullo, L., Hossain, M., Puvenna, V., Marchi, N. & Janigro, D. The role of shear stress in Blood-Brain Barrier endothelial physiology. BMC Neurosci. 12, 40 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Gursoy-Ozdemir, Y., Yemisci, M. & Dalkara, T. Microvascular protection is essential for successful neuroprotection in stroke. J. Neurochem. 123 (suppl. 2), 2–11 (2012).

    Article  CAS  PubMed  Google Scholar 

  161. Janigro, D. Are you in or out? Leukocyte, ion, and neurotransmitter permeability across the epileptic blood-brain barrier. Epilepsia 53 (suppl. 1), 26–34 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Fabene, P.F., Laudanna, C. & Constantin, G. Leukocyte trafficking mechanisms in epilepsy. Mol. Immunol. 55, 100–104 (2013).

    Article  CAS  PubMed  Google Scholar 

  163. Sagare, A.P., Bell, R.D. & Zlokovic, B.V. Neurovascular dysfunction and faulty amyloid β-peptide clearance in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a011452 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Zlokovic, B.V. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat. Rev. Neurosci. 12, 723–738 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Garbuzova-Davis, S. et al. Amyotrophic lateral sclerosis: a neurovascular disease. Brain Res. 1398, 113–125 (2011).

    Article  CAS  PubMed  Google Scholar 

  166. Lu, M. & Hu, G. Targeting metabolic inflammation in Parkinson's disease: implications for prospective therapeutic strategies. Clin. Exp. Pharmacol. Physiol. 39, 577–585 (2012).

    Article  CAS  PubMed  Google Scholar 

  167. Bartels, A.L. et al. Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson's disease, PSP and MSA. J. Neural Transm. 115, 1001–1009 (2008).

    Article  CAS  PubMed  Google Scholar 

  168. Engelhardt, B. & Ransohoff, R.M. Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol. 33, 579–589 (2012).

    Article  CAS  PubMed  Google Scholar 

  169. Kleinschmidt-DeMasters, B.K., Miravalle, A., Schowinsky, J., Corboy, J. & Vollmer, T. Update on PML and PML-IRIS occurring in multiple sclerosis patients treated with natalizumab. J. Neuropathol. Exp. Neurol. 71, 604–617 (2012).

    Article  CAS  PubMed  Google Scholar 

  170. Hinson, S.R., McKeon, A. & Lennon, V.A. Neurological autoimmunity targeting aquaporin-4. Neuroscience 168, 1009–1018 (2010).

    Article  CAS  PubMed  Google Scholar 

  171. Gowdie, P., Twilt, M. & Benseler, S.M. Primary and secondary central nervous system vasculitis. J. Child Neurol. 27, 1448–1459 (2012).

    Article  PubMed  Google Scholar 

  172. Hajj-Ali, R.A. & Calabrese, L.H. Primary angiitis of the central nervous system. Autoimmun. Rev. 12, 463–466 (2013).

    Article  PubMed  Google Scholar 

  173. Gilden, D., Cohrs, R.J., Mahalingam, R. & Nagel, M.A. Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment. Lancet Neurol. 8, 731–740 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Combes, V., Guillemin, G.J., Chan-Ling, T., Hunt, N.H. & Grau, G.E. The crossroads of neuroinflammation in infectious diseases: endothelial cells and astrocytes. Trends Parasitol. 28, 311–319 (2012).

    Article  CAS  PubMed  Google Scholar 

  175. Takeuchi, H., Matsuda, K., Kitai, R., Sato, K. & Kubota, T. Angiogenesis in primary central nervous system lymphoma (PCNSL). J. Neurooncol. 84, 141–145 (2007).

    Article  PubMed  Google Scholar 

  176. Wolburg, H., Noell, S., Fallier-Becker, P., Mack, A.F. & Wolburg-Buchholz, K. The disturbed blood-brain barrier in human glioblastoma. Mol. Aspects Med. 33, 579–589 (2012).

    Article  CAS  PubMed  Google Scholar 

  177. Bartynski, W.S. Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features. AJNR Am. J. Neuroradiol. 29, 1036–1042 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Chodobski, A., Zink, B.J. & Szmydynger-Chodobska, J. Blood-brain barrier pathophysiology in traumatic brain injury. Transl. Stroke Res. 2, 492–516 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Sánchez-del-Rio, M. & Reuter, U. Migraine aura: new information on underlying mechanisms. Curr. Opin. Neurol. 17, 289–293 (2004).

    Article  PubMed  Google Scholar 

  180. Mogi, M. & Horiuchi, M. Neurovascular coupling in cognitive impairment associated with diabetes mellitus. Circ. J. 75, 1042–1048 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

R.M.R. is supported by US National Insititutes of Health grant R21 NS074820 and the Guthy Jackson Charitable Foundation. R.D. is supported by the Program for Breakthrough Biomedical Sciences and the American Heart Association. B.O. is supported by a two-year Research Fellowship from the Deutsche Forschungsgemeinschaft.

Author information

Authors and Affiliations

  1. Department of Neuroscience, Neuroinflammation Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA

    Birgit Obermeier & Richard M Ransohoff

  2. Department of Anatomy, University of California, San Francisco, California, USA

    Richard Daneman

Authors
  1. Birgit Obermeier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard Daneman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard M Ransohoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard M Ransohoff.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Obermeier, B., Daneman, R. & Ransohoff, R. Development, maintenance and disruption of the blood-brain barrier. Nat Med 19, 1584–1596 (2013). https://doi.org/10.1038/nm.3407

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3407

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing