Acta Neuropathologica

, Volume 79, Issue 2, pp 117–128 | Cite as

Transcytosis of macromolecules through the blood-brain barrier: a cell biological perspective and critical appraisal

  • R. D. Broadwell
Review

Summary

A critical appraisal is presented of nearly two decades of research publications and review articles advocating the bidirectional transcytosis of fluid-phase molecules, most notably native horseradish peroxidase (HRP), through the normal and experimentally modified blood-brain barrier (BBB). Extracellular routes circumventing the BBB in normal and pathological states and artifact introduced in histological preparation of CNS tissue exposed to blood-borne peroxidase are emphasized. The potential for transcytosis of macromolecules entering the nonfenestrated cerebral endothelium by the processes of nonspecific fluid phase endocytosis (e.g., HRP), adsorptive endocytosis (e.g., lectins) and receptor-mediated endocytosis (e.g., ligands) is analyzed in the context of the cellular secretory process and the complimentary events of endocytosis and exocytosis at the luminal and abluminal plasma membranes. Available data suggest that the cerebral endothelium is polarized with regard to endocytosis and the internalization of cell surface membrane; hence, the transcytosis of specific macromolecules through the BBB may be vectorial. If these data are correct, the blood-brain barrier is not absolute, whereas its counterpart, the brain-blood barrier, may be.

Key words

Transcytosis Endocytosis Horseradish peroxidase Blood-brain barrier Endothelium 

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References

  1. 1.
    Balin BJ, Broadwell RD (1987) Lectin-labeled membrane is transferred to the Golgi complex in mouse pituitary cells in vivo. J Histochem Cytochem 35: 489–498Google Scholar
  2. 2.
    Balin BJ, Broadwell RD (1988) Transcytosis of protein through the mammalian cerebral epithelium and endothelium. I. Choroid plexus and the blood-cerebrospinal fluid barrier. J Neurocytol 17: 809–826Google Scholar
  3. 3.
    Balin BJ, Broadwell RD, Salcman M, El-Kalliny M (1986) Avenues for entry of peripherally administered protein to the CNS in mouse, rat, and monkey. J Comp Neurol 251:260–280Google Scholar
  4. 4.
    Balin BJ, Broadwell RD, Salcman M (1987) Evidence against tubular profiles contributing to the formation of transendothelial channels through the blood-brain barrier. J Neurocytol 16:721–728Google Scholar
  5. 5.
    Brightman MW (1965) The distribution within the brain of ferritin injected into cerebral spinal fluid compartments. I. Ependymal distribution J Cell Biol 26:99–123Google Scholar
  6. 6.
    Brightman MW, Hori M, Rapoport SI, Reese TS, Westergaard E (1973) Osmotic opening of tight junctions in cerebral endothelium. J Comp Neurol 152:317–326Google Scholar
  7. 7.
    Broadwell RD (1988) Addressing the absence of a blood-brain barrier within transplanted brain tissue. Science 24:473Google Scholar
  8. 8.
    Broadwell RD (1989) Movement of macromolecules across the blood-brain barrier. In: Ginsburg M, Dietrich WD (eds) The 16th Princeton Conference on Cerebrovascular Diseases. Raven Press, New York, pp 411–416Google Scholar
  9. 9.
    Broadwell RD, Balin BJ (1985) Endocytic and exocytic pathways of the neuronal secretory process and trans-synaptic transfer of wheatgerm agglutinin-horseradish peroxidase in vivo. J Comp Neurol 242: 632–650Google Scholar
  10. 10a.
    Broadwell RD, Brightman MW (1976) Entry of peroxidase into neurons of the central and peripheral nervous systems from extracerebral and cerebral blood. J Comp Neurol 166:257–284Google Scholar
  11. 10b.
    Broadwell RD, Brightman MW (1979) Cytochemistry of undamaged neurons transporting exogenous protein in vivo. J Comp Neurol 185:31–73Google Scholar
  12. 11.
    Broadwell RD, Brightman MW (1983) Horseradish peroxidase: a tool for study of the neuroendocrine cell and other peptide-secreting cells. Methods Enzymol 103:187–218Google Scholar
  13. 12.
    Broadwell RD, Cataldo AM (1983) The neuronal endoplasmic reticulum: its cytochemistry and contribution to the endomembrane system. I. Cell bodies and dendrites. J Histochem Cytochem 31:1077–1088Google Scholar
  14. 13.
    Broadwell RD, Oliver C (1983) An enzyme cytochemical study of the endocytic pathways in anterior pituitary cells of the mouse in vivo. J Histochem Cytochem 31:325–335Google Scholar
  15. 14.
    Broadwell RD, Salcman M (1981) Expanding the definition of the blood-brain barrier to protein. Proc Natl Acad Sci USA 78:7820–2824Google Scholar
  16. 15.
    Broadwell RD, Balin B, Salcman M, Kaplan RS (1983) A brain-blood barrier? Yes and No. Proc Natl Acad Sci USA 80:7352–7356Google Scholar
  17. 16.
    Broadwell RD, Cataldo AM, Salcman M (1983) Cytochemical localization of glucose-6-phosphatase activity in cerebral endothelial cells. J Histochem Cytochem 31: 818–822Google Scholar
  18. 17.
    Broadwell RD, Cataldo AM, Balin BJ (1984) Further studies of the secretory process in hypothalmo-neurohypophysial neurons. An analysis using immunochemistry, wheatgerm agglutinin-peroxidase and native peroxidase. J Comp Neurol 228:155–167Google Scholar
  19. 18.
    Broadwell RD, Balin BJ, Cataldo AM (1987) Fine structure and cytochemistry of the mammalian median eminence. In: Gross PM (ed) Circumventricular organs and body fluids, vol 2. CRC Press, Boca Raton, pp 61–85Google Scholar
  20. 19.
    Broadwell RD, Balin BJ Salcman M (1987) Polarity of the blood-brain barrier to the endocytosis of exogenous protein. Wiss Z Karl-Marx-Univ 36:170–174Google Scholar
  21. 20.
    Broadwell RD, Charlton HM, Balin B, Salcman M (1987) Angioarchitecture of the CNS, pituitary gland and intracerebral grafts revealed with peroxidase cytochemistry. J Comp Neurol 260:47–62Google Scholar
  22. 21.
    Broadwell RD, Balin BJ, Salcman M (1988) Transcytosis of blood-borne protein through the blood-brain barier. Proc Natl Acad Sci USA 85:632–636Google Scholar
  23. 22.
    Broadwell RD, Charlton HM, Ganong WF, Salcman M, Sofroniew M (1989) Allografts of CNS tissue possess a blood-brain barrier. I. Grafts of medial preoptic area in hypogonadal mice. Exp Neurol 105:135–151Google Scholar
  24. 23.
    Broadwell RD, Moriyama E, Oliver C, Tangoren M, Wolf A (1989) Transcytosis of protein through the mammalian cerebral epithelium and endothelium. II. The blood-brain and brain-blood barriers. Exp Neurol (submitted)Google Scholar
  25. 24.
    Broadwell RD, Wolf A, Tangoren M (1989) Transcytosis of blood-borne ferrotransferrin and insulin through the blood-brain barrier. Soc Neurosci Abstr 15:821Google Scholar
  26. 25.
    Bundgaard M (1983) Vesicular transport in capillary endothelium: does it occur. Fed Proc 42:2425–2430Google Scholar
  27. 26.
    Bundgaard M (1986) pathways across the vertebrate blood-brain barrier: morphological viewpoints. Ann NY Acad Sci 484:7–19Google Scholar
  28. 27.
    Cataldo AM, Broadwell RD (1986) Cytochemical identification of cerebral glycogen and glucose-6-phosphatase activity under normal and experimental conditions. I. Neurons and glia. J Electron Microsc Technol 3:413–437Google Scholar
  29. 28.
    Cataldo AM, Broadwell RD (1986) Cytochemical identification of cerebral glycogen and glucose-6-phosphatase activity under normal and experimental conditions. II. Choroid plexus and ependymal epithelia, endothelia, and pericytes. J Neurocytol 15:511–524Google Scholar
  30. 29.
    Cataldo AM, Broadwell RD (1986) Cytochemical investigations of peptide-secreting cells in the intermediate lobe of the pituitary gland. Histochem Soc (1985) Abstr 34:107Google Scholar
  31. 30.
    Coomber BL, Stewart PA (1986) Three-dimensional reconstruction of vesicles in endothelium of blood-brain barrier versus highly permeable microvessels. Anat Rec 215:256–261Google Scholar
  32. 31.
    Cotran RS, Karnovsky MJ (1967) Vascular leakage induced by horseradish peroxidase in the rat. Proc Soc Exp Biol 126:557–560Google Scholar
  33. 32.
    Dautry-Varsat A, Lodish HF (1984) How receptors bring proteins and particles into cells. Sci Am 250: 52–58Google Scholar
  34. 33.
    Duffy KR, Pardridge WM (1987) Blood-brain barrier transcytosis of insulin in developing rabbits. Brain Res 420:32–38Google Scholar
  35. 34.
    DeBruyn PPH, Michelson S, Becker RP (1975) Endocytosis, transfer tubules, and lysosomal activity in myeloid sinusoidal endothelium. J Ultrastruct Res 53:133–151Google Scholar
  36. 35.
    Dorovini-Ziss K, Sato M, Goping G, Rapoport S, Brightman M (1983) Ionic lanthanum passage across cerebral endothelium exposed to hyperosmotic arabinose. Acta Neuropathol (Berl) 60:49–60Google Scholar
  37. 36.
    Dux E, Doczi T, Joo F, Szerdahely P, Siklos L (1988) Reverse pinocytosis induced in cerebral endothelial cells by injection of histamine into the cerebral ventricle. Acta Neuropathol 76:484–488Google Scholar
  38. 37.
    Ellison MD, Povlishock JT, Merchant RE (1987) Blood-brain barrier dysfunction in cats following recombinant interleukin-2 infusion. Cancer Res 47:5765–5770Google Scholar
  39. 38.
    Fishman JB, Rubin JB, Handrahan JV, Connor JR, Fine RE (1987) Receptor-mediated transcytosis of transferrin across the blood-brain barrier. J Neurosci Res 18: 299–304Google Scholar
  40. 39.
    Helenius A, Mellman I, Wall D, Hubbard A (1983) Endosomes. Trends Biochem Sci 8:245–249Google Scholar
  41. 40.
    Lossinsky AS, Moretz RC, Carp RI, Wisniewski HM (1987) Ultrastructural observations of spinal cord lesions and blood-brain barrier changes in scrapie-infected mice. Acta Neuropathol (Berl) 73:43–52Google Scholar
  42. 41.
    Lossinsky AS, Song MJ, Wisniewski HM (1989) High-volt-age electron microscopic studies of endothelial cell tubular structures in the mouse blood-brain barrier following brain trauma. Acta Neuropathol 77:489–493Google Scholar
  43. 42.
    Mollgard K, Saunders NR (1975) Complex tight junctions of epithelial and endothelial cells in early foetal brain. J Neurocytol 4:453–468Google Scholar
  44. 43.
    Mollgard K, Saunders NR (1977) A possible transepithelial pathway via endoplasmic reticulum in foetal sheep choroid plexus. Proc R Soc Lond [Biol] 199:321–326Google Scholar
  45. 44.
    Nag S, Harik SI (1987) Cerebrovascular permeability to horseradish peroxidase in hypertensive rat: effects of unilateral locus ceruleus lesion. Acta Neuropathol (Berl) 73:247–353Google Scholar
  46. 45a.
    Noble LJ, Wrathall JR (1988) Blood-spinal cord barrier disruption proximal to a spinal cord transection in the rat: time course and pathways associated with protein leakage. Exp Neurol 99:567–578Google Scholar
  47. 45b.
    Noble LJ, Ellison JA (1989) Effect of transection on the blood-spinal cord barrier of the rat after isolation from descending sources. Brain Res 487:299–310Google Scholar
  48. 46.
    Noguchi Y, Yamamoto T, Shibata Y (1986) Distribution of endothelial vesicles in the microvasculature of skeletal muscle and brain cortex of the rat, as demonstrated by tannic acid tracer analysis. Cell Tissue Res 246:487–494Google Scholar
  49. 47.
    Oliver C (1983) Characterization of basal lysosomes in exocrine acinar cells. J Histochem Cytochem 31: 1209–1216Google Scholar
  50. 48.
    Palade G (1975) Intracellular aspects of the process of protein synthesis. Science 189:347–358Google Scholar
  51. 49.
    Petito CK, Levy DE (1980) The importance of cerebral arterioles in alterations of the blood-brain barrier. Lab Invest 43:262–268Google Scholar
  52. 50.
    Rapoport SI (1985) Tight junctional modification as compared to increased pinocytosis as the basis CF osmotically-induced opening of the blood-brain barrier. Further evidence of the tight junctional mechanism and against pinocytosis. Acta Neurol Scand 72:107Google Scholar
  53. 51.
    Rapoport SI (1988) Osmotic opening of the blood-brain barrier. Ann Neurol 24:677–680Google Scholar
  54. 52.
    Rennels ML, Gregory TF, Blaumanis OR, Fujimoto K, Grady PA (1985) Evidence for a “paravascular” fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space. Brain Res 326:47–63Google Scholar
  55. 53.
    Reese TS, Karnovsky MJ (1967) Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 34:207–217Google Scholar
  56. 54.
    Rodewald R (1973) Intestinal transport of antibodies in the newborn rat. J Cell Biol 58:189–211Google Scholar
  57. 55.
    Rodewald R, Abrahamson DR (1982) Receptor-mediated transport of IgG through the intestinal epithelium of the neotatal rat. Ciba Found Symp 92:209–232Google Scholar
  58. 56.
    Rodewald R, Kraehenbuhl J-P (1984) Receptor-mediated transport or IgG. J Cell Biol 99:159s-164sGoogle Scholar
  59. 57.
    Rosenstein JM (1987) Neocortical transplants in the mammalian brain lack a blood-brain barrier to macromolecules. Science 235:772–774Google Scholar
  60. 58.
    Rosenstein JM (1988) Addressing the absence of a blood-brain barrier within transplanted brain tissue. A response. Science 241:473–474Google Scholar
  61. 59.
    Simionescu M, Ghitsecu L, Fixman A, Simionescu N (1987) How plasma macromolecules cross the endothelium. News Physiol Sci. 2:97–100Google Scholar
  62. 60.
    Steinman RM, Mellman IS, Muller WA, Cohn ZA (1983) Endocytosis and the recycling of plasma membrane. J Cell Biol 96:1–27Google Scholar
  63. 61.
    Sternberger N, Sternberger L (1987) Blood-brain barrier protein recognized by monoclonal antibody. Proc Natl Acad Sci USA 84:8169–8173Google Scholar
  64. 62.
    Tangoren M, Broadwell RD, Moriyama E, Oliver C, Wolf A (1988) How significant is the blood-brain barrier? Abstr Soc Neurosci 14:617Google Scholar
  65. 63.
    Van Deurs B (1977) Vesicular transport of horseradish peroxidase from brain to blood in segments of the cerebral microvasculature in adult mice. Brain Res 124:1–8Google Scholar
  66. 64.
    Vorbrodt AW (1986) Changes in the distribution of endothelial surface glycoconjugates associated with altered permeability of brain micro-blood vessels. Acta Neuropathol (Berl) 70:103–111Google Scholar
  67. 65.
    Vorbrodt AW (1988) Ultrastructural cytochemistry of blood-brain barrier endothelia. Prog Histochem Cytochem 18:1–99Google Scholar
  68. 66.
    Vorbrodt AW, Lossinsky AS, Wisniewski HM, Suzaki R, Yamaguchi T, Masaoka H, Klatzo I (1985) Ultrastructural observations on the transvascular route of protein removal in vasogenic brain edema. Acta Neuropathol (Berl) 63:265–273Google Scholar
  69. 67.
    Wagner H-J, Pilgrim CH, Brandl J (1974) Penetration and removal of cerebral horseradish peroxidase injected into the cerebrospinal fluid: role of cerebral perivascular spaces, endothelium and microglia. Acta Neuropathol (Berl) 27:299–315Google Scholar
  70. 68.
    Westergard E (1977) The blood-brain barrier to horseradish peroxidase under normal and experimental conditions. Acta Neuropathol (Berl) 39:181–187Google Scholar
  71. 69.
    Westergard E (1980) Ultrastructural permeability properties of cerebral microvasculature under normal and experimental conditions after application of tracers. Adv Neurol 28:55–74Google Scholar
  72. 70.
    Westergaard E, Brightman MW (1973) Transport of proteins across normal cerebral arterioles. J Comp Neurol 152:17–44Google Scholar
  73. 71.
    Santos TQ, Valdimarsson H (1982) T-dependent antigens are more immunogenic in the subarachnoid space than in other sites. J Neuroimmunol 2:215–222Google Scholar
  74. 72.
    Blasberg RG, Fenstermacher JD, Patlak CS (1983) Transport of 14C-amino isobutyric acid across brain capillary and cellular membranes. J Cereb Blood Flow Metab 3:8–32Google Scholar
  75. 73.
    Ellison MD, Povlishock JT, Hayes RL (1986) Examination of the blood-to-brain transfer of 14C-amino isobutyric acid and horseradish peroxidase. Regional alterations in blood-brain barrier function following acute hypertension. J Cereb Blood Flow Metab 6:471–480Google Scholar
  76. 74.
    Dobbin J, Crockard HA, Ross-Russell R (1989) Transient blood-brain barrier permeability following profound temporary global ischemia: An experimental study using 14C-AIB. J Cereb Blood Flow Metab 9:71–78Google Scholar
  77. 75.
    Triguero D, Buciak JB, Yang J, Pardridge WM (1989) Blood-brain barrier transport of cationized immunoglobulin G: Enhanced delivery compared to native protein. Proc Natl Acad Sci USA 86:4761–4765Google Scholar
  78. 76.
    Smith KB, Borchardt RT (1989) Permeability and mechanism of albumin, cationized albumin, and glycosylated albumin transcellular transport across monolayers of cultured bovine capillary endothelial cells. Pharmaceut Res 6:466–472Google Scholar
  79. 77.
    Risling M, Lindå H, Cullheim S, Franson P (1989) A persistent defect in the blood-brain barrier after ventral furniculus lesion in adult cats: implications for CNS regeneration. Brain Res 494:13–21Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • R. D. Broadwell
    • 1
  1. 1.Division of Neurological Surgery and Neuropathology, 634 MSTF BuildingUniversity of Maryland School of MedicineBaltimoreUSA

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