Transport of Proteins Across the Blood-Brain Barrier via the Transferrin Receptor

  • Phillip M. Friden
  • Lee R. Walus
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 331)

Abstract

Unlike most other organs in the body, the brain is separated from the blood by a protective cellular barrier known as the blood-brain barrier (BBB). The BBB, although essential in maintaining a defined biochemical environment within the brain, represents a formidable obstacle to the effective delivery of neuropharmaceutical agents from the bloodstream. The capillaries that supply blood to the tissues of the brain constitute this barrier (1,2). Brain capillary endothelial cells are joined together by tight intercellular junctions that form a continuous wall against the passive movement of substances from the blood to the brain. Also characteristic of these cells is a paucity of pinocytic vesicles, which limits the amount of non-selective fluid-phase transport across the capillary wall. Together, these features limit the penetration of blood-borne hydrophilic molecules into brain tissue.

Keywords

Dementia Methotrexate Neurol Thiol Choline 

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References

  1. 1.
    Brightman, M.W., Morphology of blood-brain interfaces, Exp. Eye Res. 25: 1–25, 1977.PubMedCrossRefGoogle Scholar
  2. 2.
    Reese, T.S., and Karnovsky, M.J., Fine structural localization of a blood-brain barrier to exogenous peroxidase, J. Cell Biol 34: 207–217, 1967.PubMedCrossRefGoogle Scholar
  3. 3.
    Pardridge, W.M., Receptor-mediated peptide transport through the blood-brain barrier, Endocrine Rev. 7: 314–330, 1986.CrossRefGoogle Scholar
  4. 4.
    Fishman, J.B., Rubin, J.B., Handrahan, J.V., Connor, J.R., and Fine, R.E., Receptor-mediated transcytosis of transferrin across the blood-brain barrier, J. Neurosci. Res. 18: 299–304, 1987.PubMedCrossRefGoogle Scholar
  5. 5.
    Pardridge, W.M., Eisenberg, J., and Yang, J., Human blood-brain barrier insulin receptor, J. Neurochem. 44, 1771–1778 (1985).Google Scholar
  6. 6.
    Pardridge, W.M., Eisenberg, J., and Yang, J., Human blood-brain barrier transferrin receptor, Metabolism 36: 892–895, 1987.PubMedCrossRefGoogle Scholar
  7. 7.
    Aisen, P., and Listowsky, I., Iron transport and storage proteins, Ann. Rev. Biochem. 49: 357–393, 1980.PubMedCrossRefGoogle Scholar
  8. 8.
    MacGillivray, R.T.A., Mendez, E., Shewale, J.G., Sinha, S.K., Lineback-Zins, J., and Brew, K., The primary structure of human serum transferrin, J. Biol. Chem. 258: 3543–3553, 1981.Google Scholar
  9. 9.
    McClelland, A., Kuhn, L.C., and Ruddle, F.H., The human transferrin receptor gene: Genomic organization, and the complete primary structure of the receptor deduced from a cDNA sequence, Cell 39: 267–274, 1984.PubMedCrossRefGoogle Scholar
  10. 10.
    Omary, M.B., and Trowbridge, I.S., Covalent binding of fatty acid to the transferrin receptor in human cells in vitro, J. Biol. Chem. 256: 12888–12895, 1981.PubMedGoogle Scholar
  11. 11.
    Dautry-Varsat, A., Ciechanover, A., and Lodish, H.F., pH and recycling of transferrin during receptor-mediated endocytosis, Proc. Natl. Acad. Sci. USA 80: 2258–2262, 1983.PubMedCrossRefGoogle Scholar
  12. 12.
    Jefferies, W.A., Brandon, M.R., Hunt, S.V., Williams, A.F., Gatter, K.C., and Mason, D.Y., Transferrin receptor on endothelium of brain capillaries, Nature 312: 162–163, 1984.PubMedCrossRefGoogle Scholar
  13. 13.
    Friden, P.M., Walus, L.R., Musso, G.F., Taylor, M.A., Malfroy, B., and Starzyk, R.M., Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier, Proc. Nail. Acad. Sci. USA 88: 4771–4775, 1991.CrossRefGoogle Scholar
  14. 14.
    Greene, L.A., and Shooter, E.M., The nerve growth factor receptor: biochemistry, synthesis and mechanism of action, Annu. Rev. Neurosci. 3: 353–402, 1980.PubMedCrossRefGoogle Scholar
  15. 15.
    Hartikka, J., and Hefti, F., Development of septal cholinergic neurons in culture: Plating density and glial cells modulate effects of NGF on survival, fiber growth and expression of transmitter-specific enzymes, J. Neurosci. 8: 2967–2985, 1988.PubMedGoogle Scholar
  16. 16.
    Hagg, T., Manthorpe, M., Vahlsing, H.L., and Varon, S., Delayed treatment with nerve growth factor reverses the apparent loss of cholinergic neurons after acute brain damage, Exp. Neurol. 101: 303–312, 1988.PubMedCrossRefGoogle Scholar
  17. 17.
    Kromer, L.F., Nerve growth factor treatment after brain injury prevents neuronal death, Science 235: 214–216, 1987.PubMedCrossRefGoogle Scholar
  18. 18.
    Whittemore, S.R., and Seiger, A., The expression, localization and functional significance of beta-nerve growth factor in the central nervous system, Brain Res. Rev. 12: 439–464, 1987.CrossRefGoogle Scholar
  19. 19.
    Coyle, J.T., Price, D.L., and Delong, M.R., Alzheimer’s disease: a disorder of cortical cholinergic innervation, Science 219: 1184–1190, 1983.PubMedCrossRefGoogle Scholar
  20. 20.
    Hefti, F., Hartikka, J., and Knusel, B., Function of neurotrophic factors in the adult and aging brain and their possible use in treatment of neurodegenerative diseases, Neurobiol. Aging 10: 515–533, 1989.PubMedCrossRefGoogle Scholar
  21. 21.
    Junard, E.O., Montera, C.N., and Hefti, F., Long-term administration of mouse nerve growth factor to adult rats with partial lesions of the cholinergic septohippocampal pathway, Exp. Neurol. 110: 25–38, 1990.PubMedCrossRefGoogle Scholar
  22. 22.
    Hagg, T., Vahlsing, H.L., Manthorpe, M., and Varon, S., Nerve growth factor infusion into the denervated adult rat hippocampal formation promotes its cholinergic reinnervation, J. Neurosci. 10: 3087–3092, 1990.PubMedGoogle Scholar
  23. 23.
    Hoffman, D., Wahlberg, L., and Aebischer, P., NGF released from a polymer matrix prevents loss of ChAT expression in basal forebrain neurons following a fimbria fomix lesion, Exp. Neurol. 110: 39–44, 1990.PubMedCrossRefGoogle Scholar
  24. 24.
    Price, D. L., New perspectives on Alzheimer’s disease, Annu. Rev. Neurosci. 9: 489–512, 1986.PubMedCrossRefGoogle Scholar
  25. 25.
    Whitehouse, P.J., Price, D.L., Stuble, R.G., Clar, A.W., Coyle, J.T., and Delong, M.R., Alzheimer’s disease and senile dementia: Loss of neurons in the basal forebrain, Science 215: 1237–1239, 1982.PubMedCrossRefGoogle Scholar
  26. 26.
    Fischer, W., Wictorin, K., Bjorklund, A., Williams, L.R., Varon, S., and Gage, F.H., Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor, Nature 329: 65–68, 1987.PubMedCrossRefGoogle Scholar
  27. 27.
    Friden, P.M., Walus, L.R., Watson, P., Doctrow, S.R., Kozarich, J.W., Backman, C., Bergman, H., Hoffer, B., Bloom, F., and Granholm, A.-C., NGF-anti-transferrin receptor antibody conjugate crosses the blood-brain barrier and enhances survival of medial septal nucleus neurons, submitted, 1992.Google Scholar
  28. 28.
    Carlsson, J., Drevin, H., and Axen, R., Protein thiolation and reversible protein-protein conjugation, Biochem.J. 173: 723–737, 1978.PubMedGoogle Scholar
  29. 29.
    Greene, L.A., and Tischler, A.S., Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor, Proc. Natl. Acad. Sci. USA 73: 2424–2428, 1976.PubMedCrossRefGoogle Scholar
  30. 30.
    Buxser, S., et al., Single-step purification and biological activity of human nerve growth factor produced from insect cells, J. Neurochem. 56: 1012–1018, 1991.PubMedCrossRefGoogle Scholar
  31. 31.
    Triguero, D., Buciak, J., and Pardridge, W.M., Capillary depletion method for quantification of blood-brain barrier transport of circulating peptides and plasma proteins, J. Neurochem. 54: 1882–1888, 1990.PubMedCrossRefGoogle Scholar
  32. 32.
    Giacobini, M.M.J., Olson, L., Hoffer, B., and Sara, V.R., Truncated IGF-I exerts trophic effects on fetal brain tissue grafts, Exp. Neurol. 108: 33–37, 1990.PubMedCrossRefGoogle Scholar
  33. 33.
    Olson, L., and Seiger, A., Brain tissue transplanted to the anterior chamber of the eye. I. Fluorescence histochemistry of immature catecholamine and 5-hydroxytryptamine neurons reinnervating the rat iris, Z. Zellforsch. Mikrosk. Anat. 135: 175–194, 1972.CrossRefGoogle Scholar
  34. 34.
    Olson, L., Seiger, A., and Stomberg, I., Intraocular transplantation in rodents: a detailed account of the procedure and examples of its use in neurobiology with special reference to brain tissue grafting, in: “Advances in Cellular Neurobiology,” S. Federoff, L. Hertz, eds., Academic Press, New York, vol. 4, pp. 401–442, 1983.Google Scholar
  35. 35.
    Eriksdotter-Nilsson, M., Skirbol, S., Ebendal, T., Hersh, L., Grassi, J., Massoulie, J., and Olson, L., NGF treatment promotes development of basal forebrain tissue grafts in the anterior chamber of the eye, Exp. Brain Res. 74: 89–98, 1989.PubMedCrossRefGoogle Scholar
  36. 36.
    Eriksdotter-Nilsson, M., Skirboll, S., Ebendal, T., and Olson, L., Nerve growth factor can influence growth of cortex cerebri and hippocampus: evidence from intraocular grafts, Neurosci. 30: 755–766, 1989.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Phillip M. Friden
    • 1
  • Lee R. Walus
    • 1
  1. 1.Alkermes, Inc.CambridgeUSA

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