Molecular Biotechnology

, Volume 30, Issue 1, pp 57–69 | Cite as

Molecular biology of the blood-brain barrier

  • William M. Pardridge


Molecular biological investigations into the brain capillary endothelium and microvasculature, which forms the blood-brain barrier (BBB) in vivo, can provide the platform for the discovery and the molecular cloning of BBB-specific genes. Novel BBB genes can be discovered with either a genomics-based approach such as subtractive suppressive hybridization, or a proteomics approach using subtractive antibody expression cloning. BBB-specific genes are disproportionately transporter genes encoding either for carrier-mediated transporters, active efflux transporters, or receptor-mediated transporters. The discovery of new BBB transporters can lead to the development of new approaches to brain drug delivery using endogenous brain endothelial transporters.

Index Entries

Blood-brain barrier (BBB) endothelium drug delivery genomics proteomics 


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  1. 1.
    Brightman, M. W. (1977) Morphology of blood-brain interfaces. Exp. Eye Res. 25 Suppl., 1–25.PubMedCrossRefGoogle Scholar
  2. 2.
    Oldendorf, W. H. (1971) Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am. J. Physiol. 221, 1629–1639.PubMedGoogle Scholar
  3. 3.
    Pardridge, W. M. (1999) A morphological approach to the analysis of blood-brain barrier transport function, in Brain Barrier Systems (Paulson, O., Knudsen, G. M., and Moos, T., eds.), Munksgaard, Copenhagen, pp. 19–42.Google Scholar
  4. 4.
    Johanson, C. E. (1980) Pereability and vascularity of the developing brain: cerebellum vs. cerebral cortex. Brain Res. 190, 3–16.PubMedCrossRefGoogle Scholar
  5. 5.
    Cohen, Z., Ehret, M., Maitre, M., and Hamel, E. (1995) Ultrastructural analysis of tryptophan hydroxylase immunoreactive nerve terminals in the rat cerebral cortex and hippocampus: their associations with local blood vessels. Neuroscience 66, 555–569.PubMedCrossRefGoogle Scholar
  6. 6.
    Paspalas, C. D. and Papadopoulos, G. C. (1996) Ultrastructural relationships between noradrenergic nerve fibers and non-neuronal elements in the rat cerebral cortex. GLIA 17, 133–146.PubMedCrossRefGoogle Scholar
  7. 7.
    Paulson, O. B. and Newman, E. A. (1987) Does the release of potassium from astrocyte endfeet regulate cerebral blood flow? Science 237, 896–898.PubMedCrossRefGoogle Scholar
  8. 8.
    Solhonne, B., Gros, C., Pollard, H., and Schwartz, J. C. (1987) Major localization of aminopeptidase M in rat brain microvessels. Neuroscience 22, 225–232.PubMedCrossRefGoogle Scholar
  9. 9.
    Kunz, J., Krause, D., Kremer, M., and Dermietzel, R. (1994) The 140-kDa protein of blood-brain barrier-associated pericytes is identical to aminopeptidase M. J. Neurochem. 62, 2375–2386.PubMedCrossRefGoogle Scholar
  10. 10.
    Cordon-Cardo, C., OBrien, J. P., Casals, D., Rittman-Grauer, L., Biedler, J. L., Melamed, M. R., and Bertino, J. R. (1989) Multi-drug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc. Natl. Acad. Sci. USA 86, 695–698.PubMedCrossRefGoogle Scholar
  11. 11.
    Thiebaut, F., Tsuruo, T., Hamada, H., Gottesman, M. M., Pastan, I., and Willingham, M. C. (1989) Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. J. Histochem. Cytochem. 37, 159–164.PubMedGoogle Scholar
  12. 12.
    Raine, C. S., Lee, S. C., Scheinberg L. C., Duijvestin, A. M., and Cross, A. H. (1990) Adhesion molecules on endothelial cells in the central nervous system: an emerging area in the neuroimmunology of multiple sclerosis. Clin. Immunol. Immunopathol. 57, 173–187.PubMedCrossRefGoogle Scholar
  13. 13.
    Wisniewski, H. M., Wegiel, J., Vorbrodt, A. W., Mazur-Kolecka, B., and Frackowiak, J. (2000) Role of perivascular cells and myocytes in vascular amyloidosis. Ann. N. Y. Acad. Sci. 903, 6–18.PubMedCrossRefGoogle Scholar
  14. 14.
    Pardridge, W. M. (2001) Brain Drug Targeting; The Future of Brain Drug Development. Cambridge University Press, Cambridge, United Kingdom.Google Scholar
  15. 15.
    Shi, N., Zhang, Y., Boado, R. J., Zhu, C., and Pardridge, W. M. (2001) Brain-specific expression of an exogenous gene following intravenous administration. Proc. Natl. Acad. Sci. USA 98, 12754–12759.PubMedCrossRefGoogle Scholar
  16. 16.
    Shi, N., Boado, R. J., and Pardridge, W. M. (2000) Antisense imaging of gene expression in the brain in vivo. Proc. Natl. Acad. Sci. USA 97, 14709–14714.PubMedCrossRefGoogle Scholar
  17. 17.
    Li, J. Y., Sugimura, K., Boado, R. J., Lee, H. J., Zhang, C., Dubel, S., and Pardridge, W. M. (1999) Genetically engineered brain drug delivery vectors—cloning, expression, and in vivo application of an anti-transferrin receptor single chain antibody-streptavidin fusion gene and protein. Protein Engineering 12, 787–796.PubMedCrossRefGoogle Scholar
  18. 18.
    Pardridge, W. M., Eisenberg, J., and Yang, J. (1985) Human blood-brain barrier insulin receptor. J. Neurochem. 44, 1771–1778.PubMedCrossRefGoogle Scholar
  19. 19.
    Shusta, E. V., Boado, R. J., Mathern, G. W., and Pardridge, W. M. (2002) Vascular genomics of the human brain. J. Cereb. Blood Flow Metabol. 22, 245–252.CrossRefGoogle Scholar
  20. 20.
    Lasbennes, R. and Gayet, J. (1983) Capacity for energy metabolism in microvessels isolated from rat brain. Neurochem. Res. 9, 1–9.CrossRefGoogle Scholar
  21. 21.
    Boado, R. J. and Pardridge, W. M. (1991) A one-step procedure for isolation of poly A+ mRNA from isolated brain capillaries and endothelial cells in culture. J. Neurochem. 57, 2136–2139.PubMedCrossRefGoogle Scholar
  22. 22.
    Boado, R. J., Li, J. Y., Nagaya, M., Zhang, C., and Pardridge, W. M. (1999) Selective expression of the large neutral amino acid transporter (LAT) at the blood-brain barrier. Proc. Natl. Acad. Sci USA 96, 12079–12084.PubMedCrossRefGoogle Scholar
  23. 23.
    Pardridge, W. M. (1983) Brain metabolism: a perspective from the blood-brain barrier. Physiol. Rev. 63, 1481–1535.PubMedGoogle Scholar
  24. 24.
    Shusta, E. V., Boado, R. J., and Pardridge, W. M. (2002) Vascular proteomics and subtractive antibody expression cloning. Mol. Cell. Proteomics 1, 75–82.PubMedCrossRefGoogle Scholar
  25. 25.
    Yoshida, K., Seto-Ohshima, A., and Sinohara, H. (1997) Sequencing of cDNA encoding serum albumin and its extrahepatic synthesis in the Mongolian gerbil. Meriones unguiculatus. DNA Res. 4, 351–354.CrossRefGoogle Scholar
  26. 26.
    Boado, R. J. and Pardridge, W. M. (1994) Measurement of blood-brain barrier GLUT1 glucose transporter and actin mRNA by a quantitative polymerase chain reaction assay. J. Neurochem. 62, 2085–2090.PubMedCrossRefGoogle Scholar
  27. 27.
    Boado, R. J. and Pardridge, W. M. (1990) Molecular cloning of the bovine blood-brain barrier glucose transporter cDNA and demonstration of phylogenetic conservation of the 5′-untranslated region. Mol. Cell. Neurosci. 1, 224–232.CrossRefPubMedGoogle Scholar
  28. 28.
    Li, J. Y., Boado, R. J., and Pardridge, W. M. (2001) Cloned blood-brain barrier adenosine transporter is identical to the rat concentrative Na+ nucleoside cotransporter CNT2. J. Cereb. Blood Flow Metabol. 21, 929–936.CrossRefGoogle Scholar
  29. 29.
    Gao, B., Stieger, B., Noe, B., Fritschy, J. M., and Meier, P. J. (1999) Localization of the organic anion transporting polypeptide 2 (Oatp2) in capillary endothelium and choroid plexus epithelium of rat brain. J. Histochem. Cytochem. 47, 1255–1264.PubMedGoogle Scholar
  30. 30.
    Li, J. Y., Boado, R. J., and Pardridge, W. M. (2001) Blood-brain barrier genomics. J. Cereb. Blood Flow Metabol. 21, 61–68.CrossRefGoogle Scholar
  31. 31.
    Boado, R. J., Golden, P. L., Levin, N., and Pardridge, W. M. (1998) Upregulation of blood-brain barrier short form leptin receptor gene products in rats fed a high fat diet. J. Neurochem. 71, 1761–1764.PubMedCrossRefGoogle Scholar
  32. 32.
    Choi, T. and Pardridge, W. M. (1986) Phenylalanine transport at the human blood-brain barrier. Studies in isolated human brain capillaries. J. Biol. Chem. 261, 6536–6541.PubMedGoogle Scholar
  33. 33.
    Santoni, V., Molloy, M., and Rabilloud, T. (2000) Membrane proteins and proteomics: un amour possible? Electrophoresis 21, 1054–1070.PubMedCrossRefGoogle Scholar
  34. 34.
    Pardridge, W. M., Yang, J., Eisenberg, J., and Mietus, L. J. (1986) Antibodies to blood-brain barrier bind selectively to brain capillary endothelial lateral membranes and to a 46K protein. J. Cereb. Blood Flow Metab. 6, 203–211.PubMedGoogle Scholar
  35. 35.
    Shusta, E. V., Zhu, C., Boado, R. J., and Pardridge, W. M. (2002) Subtractive expression cloning reveals high expression of CD46 at the blood-brain barrier. J. Neuropathol. Exp. Neurol. 61, 597–604.PubMedGoogle Scholar
  36. 36.
    Pardridge, W. M., Triguero, D., Yang, J., and Cancilla, P. A. (1990) Comparison of in vitro and in vivo models of drug transcytosis through the blood-brain barrier. J. Pharmacol. Exp. Ther. 253, 884–891.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2005

Authors and Affiliations

  1. 1.Department of MedicineUCLALos AngelesUSA

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