Prions: from neurografts to neuroinvasion

  • M. Glatzel
  • M. A. Klein
  • S. Brandner
  • A. Aguzzi
Part of the Archives of Virology. Supplementa book series (ARCHIVES SUPPL, volume 16)


Spongiform encephalopathies are infectious neurodegenerative diseases caused by pathogens that seem to be devoid of any informational nucleic acids. Histopathologically, these diseases are characterized by spongiform degeneration of the central nervous system. Although the main pathological changes during the course of the disease occur in the brain, the infectious agent accumulates early in lymphoid tissue. The consecutive development of clinical disease depends on the presence of an intact immune system including mature B-cells and follicular dendritic cells. In this article we review the state of knowledge on the routes of neuroinvasion used by the infectious agent in order to gain access to the central nervous system upon entry into extracerebral sites.


Dorsal Root Ganglion Prion Protein Prion Disease Bovine Spongiform Encephalopathy Follicular Dendritic Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Aguzzi A (1998) Grafting mouse brains: from neurocarcinogenesis to neurode-generation. Embo J 17: 6107–6114PubMedCrossRefGoogle Scholar
  2. 2.
    Aguzzi A (1997) Neuro-immune connection in spread of prions in the body? Lancet 349: 742–743PubMedCrossRefGoogle Scholar
  3. 3.
    Baldauf E, Beekes M, Diringer H (1997) Evidence for an alternative direct route of access for the scrapie agent to the brain bypassing the spinal cord. J Gen Virol 78: 1187–1197PubMedGoogle Scholar
  4. 4.
    Beekes M, McBride PA, Baldauf E (1998) Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie. J Gen Virol 79: 601–607PubMedGoogle Scholar
  5. 5.
    Blättler T, Brandner S, Raeber AJ, Klein MA, Voigtländer T, Weissmann C, Aguzzi A (1997) PrP-expressing tissue required for transfer of scrapie infectivity from spleen to brain. Nature 389: 69–73PubMedCrossRefGoogle Scholar
  6. 6.
    Borchelt DR, Koliatsos VE, Guarnieri M, Pardo CA, Sisodia SS, Price DL (1994) Rapid anterograde axonal transport of the cellular prion glycoprotein in the peripheral and central nervous systems. J Biol Chem 269: 14711–14714PubMedGoogle Scholar
  7. 7.
    Brandner S, Isenmann S, Kuhne G, Aguzzi A (1998) Identification of the end stage of scrapie using infected neural grafts. Brain Pathol 8: 19–27PubMedCrossRefGoogle Scholar
  8. 8.
    Brandner S, Isenmann S, Raeber A, Fischer M, Sailer A, Kobayashi Y, Marino S, Weissmann C, Aguzzi A (1996) Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 379: 339–343PubMedCrossRefGoogle Scholar
  9. 9.
    Brandner S, Raeber A, Sailer A, Blattler T, Fischer M, Weissmann C, Aguzzi A (1996) Normal host prion protein (PrPc) is required for scrapie spread within the central nervous system. Proc Natl Acad Sci USA 93: 13148–13151PubMedCrossRefGoogle Scholar
  10. 10.
    Brown KL, Stewart K, Ritchie DL, Mabbott NA, Williams A, Fraser H, Morrison WI, Bruce ME (1999) Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells. Nature Med 5: 1308–1312PubMedCrossRefGoogle Scholar
  11. 11.
    Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, McCardle L, Chree A, Hope J, Birkett C, Cousens S, Fraser H, Bostock CJ (1997). Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 389: 498–501PubMedCrossRefGoogle Scholar
  12. 12.
    Büeler HR, Fischer M, Lang Y, Bluethmann H, Lipp HP, DeArmond SJ, Prusiner SB, Aguet M, Weissmann C (1992) Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356: 577–582PubMedCrossRefGoogle Scholar
  13. 13.
    Cole S, Kimberlin RH (1985) Pathogenesis of mouse scrapie: dynamics of vacuolation in brain and spinal cord after intraperitoneal infection. Neuropathol Appl Neurobiol 11: 213–227PubMedCrossRefGoogle Scholar
  14. 14.
    Collinge J, Whittington MA, Sidle KC, Smith CJ, Palmer MS, Clarke AR, Jefferys JG (1994) Prion protein is necessary for normal synaptic function. Nature 370: 295–297PubMedCrossRefGoogle Scholar
  15. 15.
    Eklund CM, Kennedy RC, Hadlow WJ (1967) Pathogenesis of scrapie virus infection in the mouse. J Infect Dis 117: 15–22PubMedCrossRefGoogle Scholar
  16. 16.
    Fischer M, Rülicke T, Raeber A, Sailer A, Moser M, Oesch B, Brandner S, Aguzzi A, Weissmann C (1996) Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J 15: 1255–1264PubMedGoogle Scholar
  17. 17.
    Forloni G, Angeretti N, Chiesa R, Monzani E, Salmona M, Bugiani O, Tagliavini F (1993) Neurotoxicity of a prion protein fragment. Nature 362: 543–546PubMedCrossRefGoogle Scholar
  18. 18.
    Fraser H, Dickinson AG (1985) Targeting of scrapie lesions and spread of agent via the retino-tectal projection. Brain Res 346: 32–41PubMedCrossRefGoogle Scholar
  19. 19.
    Fraser H, Farquhar CF (1987) Ionising radiation has no influence on scrapie incubation period in mice. Vet Microbiol 13: 211–223PubMedCrossRefGoogle Scholar
  20. 20.
    Frigg R, Klein MA, Hegyi I, Zinkernagel RM, Aguzzi A (1999) Scrapie pathogenesis in subclinically infected B-cell-deficient mice [In Process Citation]. J Virol 73: 9584–9588PubMedGoogle Scholar
  21. 21.
    Glatzel M, Flechsig E, Navarro B, Klein MA, Paterna JC, Bueler H, Aguzzi A (2000) Adenoviral and adeno-associated viral transfer of genes to the peripheral nervous system. Proc Natl Acad Sci USA 97: 442–447PubMedCrossRefGoogle Scholar
  22. 22.
    Groschup MH, Beekes M, McBride PA, Hardt M, Hainfellner JA, Budka H (1999) Deposition of disease-associated prion protein involves the peripheral nervous system in experimental scrapie. Acta Neuropathol (Berl) 98: 453–457CrossRefGoogle Scholar
  23. 23.
    Hill AF, Desbruslais M, Joiner S, Sidle KC, Gowland I, Collinge J, Doey LJ, Lantos P (1997) The same prion strain causes vCJD and BSE. Nature 389: 448–504PubMedCrossRefGoogle Scholar
  24. 24.
    Hill AF, Zeidler M, Ironside J, Collinge J (1997) Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet 349: 99PubMedCrossRefGoogle Scholar
  25. 25.
    Isenmann S, Brandner S, Aguzzi A (1996) Neuroectodermal grafting: a new tool for the study of neurodegenerative diseases. Histol Histopathol 11: 1063–1073PubMedGoogle Scholar
  26. 26.
    Isenmann S, Brandner S, Kuhne G, Boner J, Aguzzi A (1996) Comparative in vivo and pathological analysis of the blood-brain barrier in mouse telencephalic transplants. Neuropathol Appl Neurobiol 22: 118–128PubMedCrossRefGoogle Scholar
  27. 27.
    Isenmann S, Brandner S, Sure U, Aguzzi A (1996) Telencephalic transplants in mice: characterization of growth and differentiation patterns. Neuropathol Appl Neurobiol 21: 108–117CrossRefGoogle Scholar
  28. 28.
    Kimberlin RH, Hall SM, Walker CA (1983) Pathogenesis of mouse scrapie. Evidence for direct neural spread of infection to the CNS after injection of sciatic nerve. J Neurol Sci 61: 315–325PubMedCrossRefGoogle Scholar
  29. 29.
    Kimberlin RH, Walker CA (1980) Pathogenesis of mouse scrapie: evidence for neural spread of infection to the CNS. J Gen Virol 51: 183–187PubMedCrossRefGoogle Scholar
  30. 30.
    Kimberlin RH, Walker CA (1982) Pathogenesis of mouse scrapie: patterns of agent replication in different parts of the CNS following intraperitoneal infection. J R Soc Med 75: 618–624PubMedGoogle Scholar
  31. 31.
    Kimberlin RH, Walker CA (1989) Pathogenesis of scrapie in mice after intragastric infection. Virus Res 12: 213–220PubMedCrossRefGoogle Scholar
  32. 32.
    Kimberlin RH, Walker CA (1989) The role of the spleen in the neuroinvasion of scrapie in mice. Virus Res 12: 201–211PubMedCrossRefGoogle Scholar
  33. 33.
    Kitamoto T, Muramoto T, Mohri S, Dohura K, Tateishi J (1991) Abnormal isoform of prion protein accumulates in follicular dendritic cells in mice with Creutzfeldt-Jakob disease. J Virol 65: 6292–6295PubMedGoogle Scholar
  34. 34.
    Klein MA, Frigg R, Flechsig E, Raeber AJ, Kalinke U, Bluethmann H, Bootz F, Suter M, Zinkernagel RM, Aguzzi A (1997) A crucial role for B cells in neuroinvasive scrapie. Nature 390: 687–690PubMedGoogle Scholar
  35. 35.
    Lasmezas CI, Cesbron JY, Deslys JP, Demaimay R, Adjou KT, Rioux R, Lemaire C, Locht C, Dormont D (1996) Immune system-dependent and -independent replication of the scrapie agent. J Virol 70: 1292–1295PubMedGoogle Scholar
  36. 36.
    Manson JC, Clarke AR, Hooper ML, Aitchison L, McConnell I, Hope J (1994) l29/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal. Mol Neurobiol 8: 121–127PubMedCrossRefGoogle Scholar
  37. 37.
    McBride PA, Beekes M (1999) Pathological PrP is abundant in sympathetic and sensory ganglia of hamsters fed with scrapie. Neurosci Lett 265: 135–138PubMedCrossRefGoogle Scholar
  38. 38.
    Muramoto T, Kitamoto T, Hoque MZ, Tateishi J, Goto I (1993) Species barrier prevents an abnormal isoform of prion protein from accumulating in follicular dendritic cells of mice with Creutzfeldt-Jakob disease. J Virol 67: 6808–6810PubMedGoogle Scholar
  39. 39.
    Race R, Oldstone M, Chesebro B (2000) Entry versus blockade of brain infection following oral or intraperitoneal scrapie administration: role of prion protein expression in peripheral nerves and spleen. J Virol 74: 828–833PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2000

Authors and Affiliations

  • M. Glatzel
    • 1
  • M. A. Klein
    • 1
  • S. Brandner
    • 1
  • A. Aguzzi
    • 1
  1. 1.Institute of NeuropathologyUniversity Hospital ZurichZurichSwitzerland

Personalised recommendations