Skip to main content

Advertisement

Log in

Blood–brain Barrier: Structural Components and Function Under Physiologic and Pathologic Conditions

  • Invited Review
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

The blood–brain barrier (BBB) is the specialized system of brain microvascular endothelial cells (BMVEC) that shields the brain from toxic substances in the blood, supplies brain tissues with nutrients, and filters harmful compounds from the brain back to the bloodstream. The close interaction between BMVEC and other components of the neurovascular unit (astrocytes, pericytes, neurons, and basement membrane) ensures proper function of the central nervous system (CNS). Transport across the BBB is strictly limited through both physical (tight junctions) and metabolic barriers (enzymes, diverse transport systems). A functional polarity exists between the luminal and abluminal membrane surfaces of the BMVEC. As a result of restricted permeability, the BBB is a limiting factor for the delivery of therapeutic agents into the CNS. BBB breakdown or alterations in transport systems play an important role in the pathogenesis of many CNS diseases (HIV-1 encephalitis, Alzheimer's disease, ischemia, tumors, multiple sclerosis, and Parkinson's disease). Proinflammatory substances and specific disease-associated proteins often mediate such BBB dysfunction. Despite seemingly diverse underlying causes of BBB dysfunction, common intracellular pathways emerge for the regulation of the BBB structural and functional integrity. Better understanding of tight junction regulation and factors affecting transport systems will allow the development of therapeutics to improve the BBB function in health and disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abbott NJ (2000) Inflammatory mediators and modulation of blood–brain barrier permeability. Cell Mol Neurobiol 20:131–147

    PubMed  CAS  Google Scholar 

  • Abbott NJ (2002) Astrocyte–endothelial interactions and blood–brain barrier permeability. J Anat 200:629–638

    PubMed  CAS  Google Scholar 

  • Abbott NJ (2005) Dynamics of CNS barriers: evolution, differentiation, and modulation. Cell Mol Neurobiol 25:5–23

    PubMed  Google Scholar 

  • Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte–endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7:41–53

    PubMed  CAS  Google Scholar 

  • Adamson P, Etienne S, Couraud PO, Calder V, Greenwood J (1999) Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a rho-dependent pathway. J Immunol 162:2964–2973

    PubMed  CAS  Google Scholar 

  • Alexander JS, Jackson SA, Chaney E, Kevil CG, Haselton FR (1998) The role of cadherin endocytosis in endothelial barrier regulation: involvement of protein kinase C and actin–cadherin interactions. Inflammation 22:419–433

    PubMed  CAS  Google Scholar 

  • Allport JR, Muller WA, Luscinskas FW (2000) Monocytes induce reversible focal changes in vascular endothelial cadherin complex during transendothelial migration under flow [In Process Citation]. J Cell Biol 148:203–216

    PubMed  CAS  Google Scholar 

  • Andras IE, Pu H, Tian J, Deli MA, Nath A, Hennig B, Toborek M (2005) Signaling mechanisms of HIV-1 Tat-induced alterations of claudin-5 expression in brain endothelial cells. J Cereb Blood Flow Metab 25:1159–1170

    PubMed  CAS  Google Scholar 

  • Andreeva AY, Krause E, Muller EC, Blasig IE, Utepbergenov DI (2001) Protein kinase C regulates the phosphorylation and cellular localization of occludin. J Biol Chem 276:38480–38486

    PubMed  CAS  Google Scholar 

  • Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, Gardner TW (1999) Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem 274:23463–23467

    PubMed  CAS  Google Scholar 

  • Antonetti DA, Wolpert EB, DeMaio L, Harhaj NS, Scaduto RC, Jr. (2002) Hydrocortisone decreases retinal endothelial cell water and solute flux coincident with increased content and decreased phosphorylation of occludin. J Neurochem 80:667–677

    PubMed  CAS  Google Scholar 

  • Aurrand-Lions M, Johnson-Leger C, Imhof BA (2002) Role of interendothelial adhesion molecules in the control of vascular functions. Vasc Pharmacol 39:239–246

    CAS  Google Scholar 

  • Avison MJ, Nath A, Greene-Avison R, Schmitt FA, Greenberg RN, Berger JR (2004) Neuroimaging correlates of HIV-associated BBB compromise. J Neuroimmunol 157:140–146

    PubMed  CAS  Google Scholar 

  • Balda MS, Gonzalez-Mariscal L, Contreras RG, Macias-Silva M, Torres-Marquez ME, Garcia-Sainz JA, Cereijido M (1991) Assembly and sealing of tight junctions: possible participation of G-proteins, phospholipase C, protein kinase C and calmodulin. J Membr Biol 122:193–202

    PubMed  CAS  Google Scholar 

  • Balda MS, Gonzalez-Mariscal L, Matter K, Cereijido M, Anderson JM (1993) Assembly of the tight junction: the role of diacylglycerol. J Cell Biol 123:293–302

    PubMed  CAS  Google Scholar 

  • Banks WA (2005) Blood–brain barrier transport of cytokines: a mechanism for neuropathology. Curr Pharm Des 11:973–984

    PubMed  CAS  Google Scholar 

  • Banks WA, Lebel CR (2002) Strategies for the delivery of leptin to the CNS. J Drug Target 10:297–308

    PubMed  CAS  Google Scholar 

  • Barreiro O, Yanez-Mo M, Serrador JM, Montoya MC, Vicente-Manzanares M, Tejedor R, Furthmayr H, Sanchez-Madrid F (2002) Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J Cell Biol 157:1233–1245

    PubMed  CAS  Google Scholar 

  • Ben-Menachem E, Johansson BB, Svensson TH (1982) Increased vulnerability of the blood–brain barrier to acute hypertension following depletion of brain noradrenaline. J Neural Transm 53:159–167

    PubMed  CAS  Google Scholar 

  • Betanzos A, Huerta M, Lopez-Bayghen E, Azuara E, Amerena J, Gonzalez-Mariscal L (2004) The tight junction protein ZO-2 associates with Jun, Fos and C/EBP transcription factors in epithelial cells. Exp Cell Res 292:51–66

    PubMed  CAS  Google Scholar 

  • Beyenbach KW (2003) Regulation of tight junction permeability with switch-like speed. Curr Opin Nephrol Hypertens 12:543–550

    PubMed  Google Scholar 

  • Blouin E, Halbwachs-Mecarelli L, Rieu P (1999) Redox regulation of β2-integrin CD11b/CD18 activation. Eur J Immunol 29:3419–3431

    PubMed  CAS  Google Scholar 

  • Bolton S, Anthony D, Perry V (1998) Loss of tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neurophil induced blood–brain barrier breakdown in vivo. Neuroscience 86:1245–1257

    PubMed  CAS  Google Scholar 

  • Brown RC, Davis TP (2002) Calcium modulation of adherens and tight junction function: a potential mechanism for blood–brain barrier disruption after stroke. Stroke 33:1706–1711

    PubMed  CAS  Google Scholar 

  • Burridge K, Wennerberg K (2004) Rho and Rac take center stage. Cell 116:167–179

    PubMed  CAS  Google Scholar 

  • Carman CV, Jun CD, Salas A, Springer TA (2003) Endothelial cells proactively form microvilli-like membrane projections upon intercellular adhesion molecule 1 engagement of leukocyte LFA-1. J Immunol 171:6135–6144

    PubMed  CAS  Google Scholar 

  • Chen ML, Pothoulakis C, LaMont JT (2002) Protein kinase C signaling regulates ZO-1 translocation and increased paracellular flux of T84 colonocytes exposed to Clostridium difficile toxin A. J Biol Chem 277:4247–4254

    PubMed  CAS  Google Scholar 

  • Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, Jiang H, Prior JL, Sagare A, Bales KR, Paul SM, Zlokovic BV, Piwnica-Worms D, Holtzman DM (2005) P-glycoprotein deficiency at the blood–brain barrier increases amyloid-β deposition in an Alzheimer disease mouse model. J Clin Invest 115:3285–3290

    PubMed  CAS  Google Scholar 

  • Cisternino S, Mercier C, Bourasset F, Roux F, Scherrmann JM (2004) Expression, up-regulation, and transport activity of the multidrug-resistance protein Abcg2 at the mouse blood–brain barrier. Cancer Res 64:3296–3301

    PubMed  CAS  Google Scholar 

  • Clarke H, Soler AP, Mullin JM (2000) Protein kinase C activation leads to dephosphorylation of occludin and tight junction permeability increase in LLC-PK1 epithelial cell sheets. J Cell Sci 113(Pt 18):3187–3196

    PubMed  CAS  Google Scholar 

  • Cohen RM, Andreason PJ, Doudet DJ, Carson RE, Sunderland T (1997a) Opiate receptor avidity and cerebral blood flow in Alzheimer's disease. J Neurol Sci 148:171–180

    PubMed  CAS  Google Scholar 

  • Cohen Z, Molinatti G, Hamel E (1997b) Astroglial and vascular interactions of noradrenaline terminals in the rat cerebral cortex. J Cereb Blood Flow Metab 17:894–904

    PubMed  CAS  Google Scholar 

  • Cook-Mills JM (2002) VCAM-1 signals during lymphocyte migration: role of reactive oxygen species. Mol Immunol 39:499–508

    PubMed  CAS  Google Scholar 

  • Cullere X, Shaw SK, Andersson L, Hirahashi J, Luscinskas FW, Mayadas TN (2005) Regulation of vascular endothelial barrier function by Epac, a cAMP-activated exchange factor for Rap GTPase. Blood 105:1950–1955

    PubMed  CAS  Google Scholar 

  • Dallasta LM, Pisarov LA, Esplen JE, Werley JV, Moses AV, Nelson JA, Achim CL (1999) Blood–brain barrier tight junction disruption in human immunodeficiency virus-1 encephalitis. Am J Pathol 155:1915–1927

    PubMed  CAS  Google Scholar 

  • Del Maschio A, Zanetti A, Corada M, Rival Y, Ruco L, Lampugnani MG, Dejana E (1996) Polymorphonuclear leukocyte adhesion triggers the disorganization of endothelial cell-to-cell adherens junctions. J Cell Biol 135:497–510

    PubMed  Google Scholar 

  • Del Maschio A, De Luigi A, Martin-Padura I, Brockhaus M, Bartfai T, Fruscella P, Adorini L, Martino G, Furlan R, De Simoni MG, Dejana E (1999) Leukocyte recruitment in the cerebrospinal fluid of mice with experimental meningitis is inhibited by an antibody to junctional adhesion molecule (JAM). J Exp Med 190:1351–1356

    PubMed  Google Scholar 

  • del Zoppo GJ, Hallenbeck JM (2000) Advances in the vascular pathophysiology of ischemic stroke. Thromb Res 98:73–81

    PubMed  Google Scholar 

  • Denker BM, Nigam SK (1998) Molecular structure and assembly of the tight junction. Am J Physiol 274:F1–F9

    PubMed  CAS  Google Scholar 

  • Doolittle ND, Abrey LE, Bleyer WA, Brem S, Davis TP, Dore-Duffy P, Drewes LR, Hall WA, Hoffman JM, Korfel A, Martuza R, Muldoon LL, Peereboom D, Peterson DR, Rabkin SD, Smith Q, Stevens GH, Neuwelt EA (2005) New frontiers in translational research in neuro-oncology and the blood–brain barrier: report of the tenth annual Blood–Brain Barrier Disruption Consortium Meeting. Clin Cancer Res 11:421–428

    PubMed  Google Scholar 

  • Dore-Duffy P, Owen C, Balabanov R, Murphy S, Beaumont T, Rafols JA (2000) Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc Res 60:55–69

    PubMed  CAS  Google Scholar 

  • Etienne S, Adamson P, Greenwood J, Strosberg AD, Cazaubon S, Couraud PO (1998) ICAM-1 signaling pathways associated with Rho activation in microvascular brain endothelial cells. J Immunol 161:5755–5761

    PubMed  CAS  Google Scholar 

  • Etienne-Manneville S, Manneville JB, Adamson P, Wilbourn B, Greenwood J, Couraud PO (2000) ICAM-1-coupled cytoskeletal rearrangements and transendothelial lymphocyte migration involve intracellular calcium signaling in brain endothelial cell lines. J Immunol 165:3375–3383

    PubMed  CAS  Google Scholar 

  • Fanning AS, Jameson BJ, Jesaitis LA, Anderson JM (1998) The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J Biol Chem 273:29745–29753

    PubMed  CAS  Google Scholar 

  • Feldman GJ, Mullin JM, Ryan MP (2005) Occludin: structure, function and regulation. Adv Drug Deliv Rev 57:883–917

    PubMed  CAS  Google Scholar 

  • Fricker G, Miller DS (2004) Modulation of drug transporters at the blood–brain barrier. Pharmacology 70:169–176

    PubMed  CAS  Google Scholar 

  • Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S (1993) Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 123:1777–1788

    PubMed  CAS  Google Scholar 

  • Furuse M, Hata M, Furuse K, Yoshida Y, Haratake A, Sugitani Y, Noda T, Kubo A, Tsukita S (2002) Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice. J Cell Biol 156:1099–1111

    PubMed  CAS  Google Scholar 

  • Gonul E, Duz B, Kahraman S, Kayali H, Kubar A, Timurkaynak E (2002) Early pericyte response to brain hypoxia in cats: an ultrastructural study. Microvasc Res 64:116–119

    PubMed  Google Scholar 

  • Gonzalez-Mariscal L, Chavez de Ramirez B, Cereijido M (1985) Tight junction formation in cultured epithelial cells (MDCK). J Membr Biol 86:113–125

    PubMed  CAS  Google Scholar 

  • Gonzalez-Mariscal L, Betanzos A, Avila-Flores A (2000) MAGUK proteins: structure and role in the tight junction. Semin Cell Dev Biol 11:315–324

    PubMed  CAS  Google Scholar 

  • Graff CL, Pollack GM (2004) Drug transport at the blood–brain barrier and the choroid plexus. Curr Drug Metab 5:95–108

    PubMed  CAS  Google Scholar 

  • Grigoriadis N, Grigoriadis S, Polyzoidou E, Milonas I, Karussis D (2006) Neuroinflammation in multiple sclerosis: evidence for autoimmune dysregulation, not simple autoimmune reaction. Clin Neurol Neurosurg 108:241–244

    PubMed  Google Scholar 

  • Groothuis DR, Vriesendorp FJ, Kupfer B, Warnke PC, Lapin GD, Kuruvilla A, Vick NA, Mikhael MA, Patlak CS (1991) Quantitative measurements of capillary transport in human brain tumors by computed tomography. Ann Neurol 30:581–588

    PubMed  CAS  Google Scholar 

  • Guo X, Geng M, Du G (2005) Glucose transporter 1, distribution in the brain and in neural disorders: its relationship with transport of neuroactive drugs through the blood–brain barrier. Biochem Genet 43:175–187

    PubMed  CAS  Google Scholar 

  • Haorah J, Knipe B, Leibhart J, Ghorpade A, Persidsky Y (2005a) Alcohol-induced oxidative stress in brain endothelial cells causes blood–brain barrier dysfunction. J Leukoc Biol 78:1223–1232

    PubMed  CAS  Google Scholar 

  • Haorah J, Heilman D, Knipe B, Chrastil J, Leibhart J, Ghorpade A, Miller DW, Persidsky Y (2005b) Ethanol-induced activation of myosin light chain kinase leads to dysfunction of tight junctions and blood–brain barrier compromise. Alcohol Clin Exp Res 29:999–1009

    PubMed  CAS  Google Scholar 

  • Hawkins BT, Davis TP (2005) The blood–brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57:173–185

    PubMed  CAS  Google Scholar 

  • Hayashi K, Pu H, Tian J, Andras IE, Lee YW, Hennig B, Toborek M (2005a) HIV-Tat protein induces P-glycoprotein expression in brain microvascular endothelial cells. J Neurochem 93:1231–1241

    PubMed  CAS  Google Scholar 

  • Hayashi K, Pu H, Andras IE, Eum SY, Yamauchi A, Hennig B, Toborek M (2005b) HIV-TAT protein upregulates expression of multidrug resistance protein 1 in the blood–brain barrier. J Cereb Blood Flow Metab

  • Hirase T, Staddon JM, Saitou M, Ando-Akatsuka Y, Itoh M, Furuse M, Fujimoto K, Tsukita S, Rubin LL (1997) Occludin as a possible determinant of tight junction permeability in endothelial cells. J Cell Sci 110 (Pt 14):1603–1613

    PubMed  CAS  Google Scholar 

  • Hirase T, Kawashima S, Wong E, Uemada T, Rikitake Y, Tsukita S, Yokoyama M, Staddon J (2001) Regulation of tight junction permeability and occludin phosphorylation byRhoA-p160ROCK-dependent and independent mechanism. J Biol Chem 276:10423–10431

    PubMed  CAS  Google Scholar 

  • Holash JA, Noden DM, Stewart PA (1993) Re-evaluating the role of astrocytes in blood–brain barrier induction. Dev Dyn 197:14–25

    PubMed  CAS  Google Scholar 

  • Hopkins AM, Li D, Mrsny RJ, Walsh SV, Nusrat A (2000) Modulation of tight junction function by G protein-coupled events. Adv Drug Deliv Rev 41:329–340

    PubMed  CAS  Google Scholar 

  • Howarth AG, Hughes MR, Stevenson BR (1992) Detection of the tight junction-associated protein ZO-1 in astrocytes and other nonepithelial cell types. Am J Physiol 262:C461–C469

    PubMed  CAS  Google Scholar 

  • Huber JD, Egleton RD, Davis TP (2001) Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier. Trends Neurosci 24:719–725

    PubMed  CAS  Google Scholar 

  • Inoko A, Itoh M, Tamura A, Matsuda M, Furuse M, Tsukita S (2003) Expression and distribution of ZO-3, a tight junction MAGUK protein, in mouse tissues. Genes Cells 8:837–845

    PubMed  CAS  Google Scholar 

  • Islas S, Vega J, Ponce L, Gonzalez-Mariscal L (2002) Nuclear localization of the tight junction protein ZO-2 in epithelial cells. Exp Cell Res 274:138–148

    PubMed  CAS  Google Scholar 

  • Itoh M, Morita K, Tsukita S (1999) Characterization of ZO-2 as a MAGUK family member associated with tight as well as adherens junctions with a binding affinity to occludin and α catenin. J Biol Chem 274:5981–5986

    PubMed  CAS  Google Scholar 

  • Jian Liu K, Rosenberg GA (2005) Matrix metalloproteinases and free radicals in cerebral ischemia. Free Radic Biol Med 39:71–80

    PubMed  CAS  Google Scholar 

  • Kanmogne GD, Primeaux C, Grammas P (2005) HIV-1 gp120 proteins alter tight junction protein expression and brain endothelial cell permeability: implications for the pathogenesis of HIV-associated dementia. J Neuropathol Exp Neurol 64:498–505

    PubMed  CAS  Google Scholar 

  • Kanmogne GD, Schall K, Leibhart J, Knipe B, Gendelman HE, Persidsky Y (2006) HIV-1 gp120 compromises blood–brain barrier integrity and enhance monocyte migration across blood–brain barrier: implication for viral neuropathogenesis. J Cereb Blood Flow Metab. (in press)

  • Khanday FA, Yamamori T, Mattagajasingh I, Zhang Z, Bugayenko A, Naqvi A, Santhanam L, Nabi N, Kasuno K, Day BW, Irani K (2006) Rac1 leads to phosphorylation-dependent increase in stability of the p66shc adaptor protein: role in Rac1-induced oxidative stress. Mol Biol Cell 17:122–129

    PubMed  CAS  Google Scholar 

  • Klingler C, Kniesel U, Bamforth SD, Wolburg H, Engelhardt B, Risau W (2000) Disruption of epithelial tight junctions is prevented by cyclic nucleotide-dependent protein kinase inhibitors. Histochem Cell Biol 113:349–361

    PubMed  CAS  Google Scholar 

  • Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J, Willemsen AT, Hendrikse NH (2005) Blood–brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol 57:176–179

    PubMed  CAS  Google Scholar 

  • Kubota K, Furuse M, Sasaki H, Sonoda N, Fujita K, Nagafuchi A, Tsukita S (1999) Ca(2+)-independent cell-adhesion activity of claudins, a family of integral membrane proteins localized at tight junctions. Curr Biol 9:1035–1038

    PubMed  CAS  Google Scholar 

  • Kunsch C, Luchoomun J, Grey JY, Olliff LK, Saint LB, Arrendale RF, Wasserman MA, Saxena U, Medford RM (2004) Selective inhibition of endothelial and monocyte redox-sensitive genes by AGI-1067: a novel antioxidant and anti-inflammatory agent. J Pharmacol Exp Ther 308:820–829

    PubMed  CAS  Google Scholar 

  • Lai CH, Kuo KH (2005) The critical component to establish in vitro BBB model: pericyte. Brain Res Rev 50:258–265

    PubMed  CAS  Google Scholar 

  • Lamszus K, Laterra J, Westphal M, Rosen EM (1999) Scatter factor/hepatocyte growth factor (SF/HGF) content and function in human gliomas. Int J Dev Neurosci 17:517–530

    PubMed  CAS  Google Scholar 

  • Langford D, Grigorian A, Hurford R, Adame A, Ellis RJ, Hansen L, Masliah E (2004) Altered P-glycoprotein expression in AIDS patients with HIV encephalitis. J Neuropathol Exp Neurol 63:1038–1047

    PubMed  CAS  Google Scholar 

  • Lassmann H (2004) Recent neuropathological findings in MS—implications for diagnosis and therapy. J Neurol 251(Suppl 4):IV2–IV5

    PubMed  Google Scholar 

  • Le Moellic C, Boulkroun S, Gonzalez-Nunez D, Dublineau I, Cluzeaud F, Fay M, Blot-Chabaud M, Farman N (2005) Aldosterone and tight junctions: modulation of claudin-4 phosphorylation in renal collecting duct cells. Am J Physiol Cell Physiol 289:C1513–C1521

    PubMed  Google Scholar 

  • Lee G, Bendayan R (2004) Functional expression and localization of P-glycoprotein in the central nervous system: relevance to the pathogenesis and treatment of neurological disorders. Pharm Res 21:1313–1330

    PubMed  CAS  Google Scholar 

  • Lee EJ, Hung YC, Lee MY (1999) Early alterations in cerebral hemodynamics, brain metabolism, and blood–brain barrier permeability in experimental intracerebral hemorrhage. J Neurosurg 91:1013–1019

    Article  PubMed  CAS  Google Scholar 

  • Lee G, Dallas S, Hong M, Bendayan R (2001) Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacol Rev 53:569–596

    PubMed  CAS  Google Scholar 

  • Leslie EM, Deeley RG, Cole SP (2005) Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol 204:216–237

    PubMed  CAS  Google Scholar 

  • Liebner S, Fischmann A, Rascher G, Duffner F, Grote EH, Kalbacher H, Wolburg H (2000) Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Acta Neuropathol (Berl) 100:323–331

    CAS  Google Scholar 

  • Loscher W, Potschka H (2005a) Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci 6:591–602

    PubMed  Google Scholar 

  • Loscher W, Potschka H (2005b) Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol 76:22–76

    PubMed  Google Scholar 

  • Ma TY, Tran D, Hoa N, Nguyen D, Merryfield M, Tarnawski A (2000) Mechanism of extracellular calcium regulation of intestinal epithelial tight junction permeability: role of cytoskeletal involvement. Microsc Res Tech 51:156–168

    PubMed  CAS  Google Scholar 

  • Mankowski JL, Queen SE, Kirstein LM, Spelman JP, Laterra J, Simpson IA, Adams RJ, Clements JE, Zink MC (1999) Alterations in blood–brain barrier glucose transport in SIV-infected macaques. J Neurovirology 5:695–702

    CAS  Google Scholar 

  • Mark KS, Davis TP (2002) Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation. Am J Physiol Heart Circ Physiol 282:H1485–H1494

    PubMed  CAS  Google Scholar 

  • Marroni M, Marchi N, Cucullo L, Abbott NJ, Signorelli K, Janigro D (2003) Vascular and parenchymal mechanisms in multiple drug resistance: a lesson from human epilepsy. Curr Drug Targets 4:297–304

    PubMed  CAS  Google Scholar 

  • Martin-Padura I, Lostaglio S, Schneemann M, Williams L, Romano M, Fruscella P, Panzeri C, Stoppacciaro A, Ruco L, Villa A, Simmons D, Dejana E (1998) Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol 142:117–127

    PubMed  CAS  Google Scholar 

  • Matheny HE, Deem TL, Cook-Mills JM (2000) Lymphocyte migration through monolayers of endothelial cell lines involves VCAM-1 signaling via endothelial cell NADPH oxidase. J Immunol 164:6550–6559

    PubMed  CAS  Google Scholar 

  • McCarthy KM, Skare IB, Stankewich MC, Furuse M, Tsukita S, Rogers RA, Lynch RD, Schneeberger EE (1996) Occludin is a functional component of the tight junction. J Cell Sci 109(Pt 9):2287–2298

    PubMed  CAS  Google Scholar 

  • McGeer EG, Klegeris A, McGeer PL (2005) Inflammation, the complement system and the diseases of aging. Neurobiol Aging 26(Suppl 1):94–97

    PubMed  Google Scholar 

  • Minagar A, Alexander JS (2003) Blood–brain barrier disruption in multiple sclerosis. Mult Scler 9:540–549

    PubMed  CAS  Google Scholar 

  • Mitic LL, Anderson JM (1998) Molecular architecture of tight junctions. Annu Rev Physiol 60:121–142

    PubMed  CAS  Google Scholar 

  • Morita K, Sasaki H, Furuse M, Tsukita S (1999) Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells. J Cell Biol 147:185–194

    PubMed  CAS  Google Scholar 

  • Morita K, Sasaki H, Furuse K, Furuse M, Tsukita S, Miyachi Y (2003) Expression of claudin-5 in dermal vascular endothelia. Exp Dermatol 12:289–295

    PubMed  CAS  Google Scholar 

  • Muller WA (2003) Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol 24:327–334

    PubMed  CAS  Google Scholar 

  • Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, Furuse M, Tsukita S (2003) Size-selective loosening of the blood–brain barrier in claudin-5-deficient mice. J Cell Biol 161:653–660

    PubMed  CAS  Google Scholar 

  • Nottet HS, Persidsky Y, Sasseville VG, Nukuna AN, Bock P, Zhai QH, Sharer LR, McComb RD, Swindells S, Soderland C, Gendelman HE (1996) Mechanisms for the transendothelial migration of HIV-1-infected monocytes into brain. J Immunol 156:1284–1295

    PubMed  CAS  Google Scholar 

  • Nunbhakdi-Craig V, Machleidt T, Ogris E, Bellotto D, White CL, 3rd, Sontag E (2002) Protein phosphatase 2A associates with and regulates atypical PKC and the epithelial tight junction complex. J Cell Biol 158:967–978

    PubMed  CAS  Google Scholar 

  • Oldendorf WH, Cornford ME, Brown WJ (1977) The large apparent work capability of the blood–brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann Neurol 1:409–417

    PubMed  CAS  Google Scholar 

  • Paemeleire K (2002) The cellular basis of neurovascular metabolic coupling. Acta Neurol Belg 102:153–157

    PubMed  CAS  Google Scholar 

  • Palant CE, Duffey ME, Mookerjee BK, Ho S, Bentzel CJ (1983) Ca2+ regulation of tight-junction permeability and structure in Necturus gallbladder. Am J Physiol 245:C203–C212

    PubMed  CAS  Google Scholar 

  • Papadopoulos MC, Saadoun S, Davies DC, Bell BA (2001) Emerging molecular mechanisms of brain tumour oedema. Br J Neurosurg 15:101–108

    PubMed  CAS  Google Scholar 

  • Pardridge WM (2005) Molecular biology of the blood–brain barrier. Mol Biotechnol 30:57–70

    PubMed  CAS  Google Scholar 

  • Pedram A, Razandi M, Levin ER (2002) Deciphering vascular endothelial cell growth factor/vascular permeability factor signaling to vascular permeability. Inhibition by atrial natriuretic peptide. J Biol Chem 277:44385–44398

    PubMed  CAS  Google Scholar 

  • Persidsky Y, Gendelman HE (2003) Mononuclear phagocyte immunity and the neuropathogenesis of HIV-1 infection. J Leukoc Biol 74:691–701

    PubMed  CAS  Google Scholar 

  • Persidsky Y, Stins M, Way D, Witte MH, Weinand M, Kim KS, Bock P, Gendelman HE, Fiala M (1997) A model for monocyte migration through the blood–brain barrier during HIV-1 encephalitis. J Immunol 158:3499–3510

    PubMed  CAS  Google Scholar 

  • Persidsky g, Ghorpade A, Rasmussen J, Limoges J, Liu X, Stins M, Fiala M, Way D, Kim K, Witte M, Weinand M, Carchart L, Gendelman H (1999) Microglial and astrocyte chemokines regulate monocyte migration through blood–brain barrier in human immunodeficiency virus-1 encephalitis. Am J Pathol 155:1599–1611

    PubMed  Google Scholar 

  • Persidsky Y, Zheng J, Miller D, Gendelman HE (2000) Mononuclear phagocytes mediate blood–brain barrier compromise and neuronal injury during HIV-1-associated dementia. J Leukoc Biol 68:413–422

    PubMed  CAS  Google Scholar 

  • Pesidsky Y, Heilman D, Haorah J, Zelivyanskay M, Persidsky R, Weber G, Shimokawa H, Kaibuchi K, Ikezu T (2006) Rho-mediated regulation of tight junctions during monocyte migration across blood–brain barrier in HIV-1 encephalitis (HIVE). Blood 107:4720–4730

    Google Scholar 

  • Petty MA, Wettstein JG (2001) Elements of cerebral microvascular ischaemia. Brain Res Rev 36:23–34

    PubMed  CAS  Google Scholar 

  • Pratico D (2005) Antioxidants and endothelium protection. Atherosclerosis 181:215–224

    PubMed  CAS  Google Scholar 

  • Price LS, Langeslag M, ten Klooster JP, Hordijk PL, Jalink K, Collard JG (2003) Calcium signaling regulates translocation and activation of Rac. J Biol Chem 278:39413–39421

    PubMed  CAS  Google Scholar 

  • Raivich G, Banati R (2004) Brain microglia and blood-derived macrophages: molecular profiles and functional roles in multiple sclerosis and animal models of autoimmune demyelinating disease. Brain Res Rev 46:261–281

    PubMed  CAS  Google Scholar 

  • Rascher G, Fischmann A, Kroger S, Duffner F, Grote EH, Wolburg H (2002) Extracellular matrix and the blood–brain barrier in glioblastoma multiforme: spatial segregation of tenascin and agrin. Acta Neuropathol (Berl) 104:85–91

    CAS  Google Scholar 

  • Said HM, Ma TY (1994) Mechanism of riboflavine uptake by Caco-2 human intestinal epithelial cells. Am J Physiol 266:G15–G21

    PubMed  CAS  Google Scholar 

  • Sakakibara A, Furuse M, Saitou M, Ando-Akatsuka Y, Tsukita S (1997) Possible involvement of phosphorylation of occludin in tight junction formation. J Cell Biol 137:1393–1401

    PubMed  CAS  Google Scholar 

  • Savettieri G, Di Liegro I, Catania C, Licata L, Pitarresi GL, D'Agostino S, Schiera G, De Caro V, Giandalia G, Giannola LI, Cestelli A (2000) Neurons and ECM regulate occludin localization in brain endothelial cells. NeuroReport 11:1081–1084

    PubMed  CAS  Google Scholar 

  • Schenkel AR, Mamdouh Z, Muller WA (2004) Locomotion of monocytes on endothelium is a critical step during extravasation. Nat Immunol 5:393–400

    PubMed  CAS  Google Scholar 

  • Schinkel AH, Jonker JW (2003) Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev 55:3–29

    PubMed  CAS  Google Scholar 

  • Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, Mol CA, van der Valk MA, Robanus-Maandag EC, te Riele HP, et al. (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs. Cell 77:491–502

    PubMed  CAS  Google Scholar 

  • Schmeck B, Brunsch M, Seybold J, Krull M, Eichel-Streiber C, Suttorp N, Hippenstiel S (2003) Rho protein inhibition blocks cyclooxygenase-2 expression by proinflammatory mediators in endothelial cells. Inflammation 27:89–95

    PubMed  CAS  Google Scholar 

  • Schulze C, Smales C, Rubin LL, Staddon JM (1997) Lysophosphatidic acid increases tight junction permeability in cultured brain endothelial cells. J Neurochem 68:991–1000

    Article  PubMed  CAS  Google Scholar 

  • Shasby DM, Shasby SS (1986) Effects of calcium on transendothelial albumin transfer and electrical resistance. J Appl Physiol 60:71–79

    PubMed  CAS  Google Scholar 

  • Shaw SK, Bamba PS, Perkins BN, Luscinskas FW (2001) Real-time imaging of vascular endothelial–cadherin during leukocyte transmigration across endothelium. J Immunol 167:2323–2330

    PubMed  CAS  Google Scholar 

  • Soma T, Chiba H, Kato-Mori Y, Wada T, Yamashita T, Kojima T, Sawada N (2004) Thr(207) of claudin-5 is involved in size-selective loosening of the endothelial barrier by cyclic AMP. Exp Cell Res 300:202–212

    PubMed  CAS  Google Scholar 

  • Spudich A, Kilic E, Xing H, Kilic U, Rentsch KM, Wunderli-Allenspach H, Bassetti CL, Hermann DM (2006) Inhibition of multidrug resistance transporter-1 facilitates neuroprotective therapies after focal cerebral ischemia. Nat Neurosci 9:487–488

    PubMed  CAS  Google Scholar 

  • Stamatovic SM, Keep RF, Kunkel SL, Andjelkovic AV (2003) Potential role of MCP-1 in endothelial cell tight junction “opening”: signaling via Rho and Rho kinase. J Cell Sci 116:4615–4628

    PubMed  CAS  Google Scholar 

  • Stamatovic SM, Shakui P, Keep RF, Moore BB, Kunkel SL, Van Rooijen N, Andjelkovic AV (2005) Monocyte chemoattractant protein-1 regulation of blood–brain barrier permeability. J Cereb Blood Flow Metab 25:593–606

    PubMed  CAS  Google Scholar 

  • Stamatovic SM, Dimitrijevic OB, Keep RF, Andjelkovic AV (2006) Protein kinase C-α: Rhoa cross talk in CCL2-induced alterations in brain endothelial permeability. J Biol Chem

  • Stevenson BR (1999) Understanding tight junction clinical physiology at the molecular level [comment]. J Clin Invest 104:3–4

    Article  PubMed  CAS  Google Scholar 

  • Strey A, Janning A, Barth H, Gerke V (2002) Endothelial Rho signaling is required for monocyte transendothelial migration. FEBS Lett 517:261–266

    PubMed  CAS  Google Scholar 

  • Sun ZY, Wei J, Xie L, Shen Y, Liu SZ, Ju GZ, Shi JP, Yu YQ, Zhang X, Xu Q, Hemmings GP (2004) The CLDN5 locus may be involved in the vulnerability to schizophrenia. Eur Psychiatr 19:354–357

    Google Scholar 

  • Tao-Cheng JH, Brightman MW (1988) Development of membrane interactions between brain endothelial cells and astrocytes in vitro. Int J Dev Neurosci 6:25–37

    PubMed  CAS  Google Scholar 

  • Tao-Cheng JH, Nagy Z, Brightman MW (1987) Tight junctions of brain endothelium in vitro are enhanced by astroglia. J Neurosci 7:3293–3299

    PubMed  CAS  Google Scholar 

  • Tilling T, Engelbertz C, Decker S, Korte D, Huwel S, Galla HJ (2002) Expression and adhesive properties of basement membrane proteins in cerebral capillary endothelial cell cultures. Cell Tissue Res 310:19–29

    PubMed  CAS  Google Scholar 

  • Toneatto S, Finco O, van der Putten H, Abrignani S, Annunziata P (1999) Evidence of blood–brain barrier alteration and activation in HIV-1 gp120 transgenic mice. AIDS 13:2343–2348

    PubMed  CAS  Google Scholar 

  • Tong XK, Hamel E (1999) Regional cholinergic denervation of cortical microvessels and nitric oxide synthase-containing neurons in Alzheimer's disease. Neuroscience 92:163–175

    PubMed  CAS  Google Scholar 

  • Tontsch U, Bauer H (1991) Glial cells and neurons induce blood–brain barrier enzymes in cerebral endothelial cells. Brain Res 539:247–253

    PubMed  CAS  Google Scholar 

  • Traweger A, Fuchs R, Krizbai IA, Weiger TM, Bauer HC, Bauer H (2003) The tight junction protein ZO-2 localizes to the nucleus and interacts with the heterogeneous nuclear ribonucleoprotein scaffold attachment factor-B. J Biol Chem 278:2692–2700

    PubMed  CAS  Google Scholar 

  • Tsukamoto T, Nigam SK (1999) Role of tyrosine phosphorylation in the reassembly of occludin and other tight junction proteins. Am J Physiol 276:F737–F750

    PubMed  CAS  Google Scholar 

  • Umeda K, Matsui T, Nakayama M, Furuse K, Sasaki H, Furuse M, Tsukita S (2004) Establishment and characterization of cultured epithelial cells lacking expression of ZO-1. J Biol Chem 279:44785–44794

    PubMed  CAS  Google Scholar 

  • van Bruggen N, Thibodeaux H, Palmer JT, Lee WP, Fu L, Cairns B, Tumas D, Gerlai R, Williams SP, van Lookeren Campagne M, Ferrara N (1999) VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest 104:1613–1620

    PubMed  Google Scholar 

  • van Buul JD, Hordijk PL (2004) Signaling in leukocyte transendothelial migration. Arterioscler Thromb Vasc Biol 24:824–833

    PubMed  Google Scholar 

  • van Wetering S, van Buul JD, Quik S, Mul FP, Anthony EC, ten Klooster JP, Collard JG, Hordijk PL (2002) Reactive oxygen species mediate Rac-induced loss of cell–cell adhesion in primary human endothelial cells. J Cell Sci 115:1837–1846

    PubMed  Google Scholar 

  • Vaucher E, Tong XK, Cholet N, Lantin S, Hamel E (2000) GABA neurons provide a rich input to microvessels but not nitric oxide neurons in the rat cerebral cortex: a means for direct regulation of local cerebral blood flow. J Comp Neurol 421:161–171

    PubMed  CAS  Google Scholar 

  • Volk H, Potschka H, Loscher W (2005) Immunohistochemical localization of P-glycoprotein in rat brain and detection of its increased expression by seizures are sensitive to fixation and staining variables. J Histochem Cytochem 53:517–531

    PubMed  CAS  Google Scholar 

  • Vorbrodt AW, Dobrogowska DH (2003) Molecular anatomy of intercellular junctions in brain endothelial and epithelial barriers: electron microscopist's view. Brain Res Rev 42:221–242

    PubMed  CAS  Google Scholar 

  • Wachtel M, Frei K, Ehler E, Fontana A, Winterhalter K, Gloor SM (1999) Occludin proteolysis and increased permeability in endothelial cells through tyrosine phosphatase inhibition. J Cell Sci 112:4347–4356

    PubMed  CAS  Google Scholar 

  • Williams KC, Corey S, Westmoreland SV, Pauley D, Knight H, deBakker C, Alvarez X, Lackner AA (2001) Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS. J Exp Med 193:905–915

    PubMed  CAS  Google Scholar 

  • Willis CL, Leach L, Clarke GJ, Nolan CC, Ray DE (2004a) Reversible disruption of tight junction complexes in the rat blood–brain barrier, following transitory focal astrocyte loss. Glia 48:1–13

    PubMed  Google Scholar 

  • Willis CL, Nolan CC, Reith SN, Lister T, Prior MJ, Guerin CJ, Mavroudis G, Ray DE (2004b) Focal astrocyte loss is followed by microvascular damage, with subsequent repair of the blood–brain barrier in the apparent absence of direct astrocytic contact. Glia 45:325–337

    PubMed  Google Scholar 

  • Witt KA, Mark KS, Huber J, Davis TP (2005) Hypoxia-inducible factor and nuclear factor kappa-B activation in blood–brain barrier endothelium under hypoxic/reoxygenation stress. J Neurochem 92:203–214

    PubMed  CAS  Google Scholar 

  • Wittchen ES, van Buul JD, Burridge K, Worthylake RA (2005a) Trading spaces: Rap, Rac, and Rho as architects of transendothelial migration. Curr Opin Hematol 12:14–21

    PubMed  CAS  Google Scholar 

  • Wittchen ES, Worthylake RA, Kelly P, Casey PJ, Quilliam LA, Burridge K (2005b) Rap1 GTPase inhibits leukocyte transmigration by promoting endothelial barrier function. J Biol Chem 280:11675–11682

    PubMed  CAS  Google Scholar 

  • Wojciak-Stothard B, Williams L, Ridley AJ (1999) Monocyte adhesion and spreading on human endothelial cells is dependent on Rho-regulated receptor clustering. J Cell Biol 145:1293–1307

    PubMed  CAS  Google Scholar 

  • Wolburg H, Lippoldt A (2002) Tight junctions of the blood–brain barrier: development, composition and regulation. Vascul Pharmacol 38:323–337

    PubMed  CAS  Google Scholar 

  • Wong V (1997) Phosphorylation of occludin correlates with occludin localization and function at the tight junction. Am J Physiol 273:C1859–C1867

    PubMed  CAS  Google Scholar 

  • Wong V, Gumbiner BM (1997) A synthetic peptide corresponding to the extracellular domain of occludin perturbs the tight junction permeability barrier. J Cell Biol 136:399–409

    PubMed  CAS  Google Scholar 

  • Xu H, Dawson R, Crane IJ, Liversidge J (2005) Leukocyte diapedesis in vivo induces transient loss of tight junction protein at the blood–retina barrier. Invest Ophthalmol Vis Sci 46:2487–2494

    PubMed  Google Scholar 

  • Yamamoto T, Harada N, Kawano Y, Taya S, Kaibuchi K (1999) In vivo interaction of AF-6 with activated Ras and ZO-1. Biochem Biophys Res Commun 259:103–107

    PubMed  CAS  Google Scholar 

  • Yang L, Froio RM, Sciuto TE, Dvorak AM, Alon R, Luscinskas FW (2005) ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-α-activated vascular endothelium under flow. Blood 106:584–592

    PubMed  CAS  Google Scholar 

  • Ye J, Tsukamoto T, Sun A, Nigam SK (1999) A role for intracellular calcium in tight junction reassembly after ATP depletion–repletion. Am J Physiol 277:F524–F532

    PubMed  CAS  Google Scholar 

  • Zhang W, Mojsilovic-Petrovic J, Andrade MF, Zhang H, Ball M, Stanimirovic DB (2003) The expression and functional characterization of ABCG2 in brain endothelial cells and vessels. FASEB J 17:2085–2087

    PubMed  Google Scholar 

  • Zlokovic BV (2002) Vascular disorder in Alzheimer's disease: role in pathogenesis of dementia and therapeutic targets. Adv Drug Deliv Rev 54:1553–1559

    PubMed  CAS  Google Scholar 

  • Zlokovic BV (2005) Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci 28:202–208

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Ms. Robin Taylor and Ms. Debra Baer for excellent administrative support. The NIH National NeuroAIDS Consortium and the CNND brain bank are acknowledged for brain tissue specimens used in this study. This work was supported in part by research grants by the National Institutes of Health: PO1 NS043985, RO1 AA015913, and RO1 MH65151 (Y.P.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yuri Persidsky.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Persidsky, Y., Ramirez, S.H., Haorah, J. et al. Blood–brain Barrier: Structural Components and Function Under Physiologic and Pathologic Conditions. Jrnl Neuroimmune Pharm 1, 223–236 (2006). https://doi.org/10.1007/s11481-006-9025-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-006-9025-3

Key words

Navigation