BSE, Scrapie, and vCJD: Infectious Neurodegenerative Diseases

  • C. Riemer
  • D. Simon
  • S. Neidhold
  • J. Schultz
  • A. Schwarz
  • M. Baier
Conference paper
Part of the Ernst Schering Research Foundation Workshop book series (SCHERING FOUND, volume 39)


Transmissible spongiform encephalopathies (TSEs) are infectious progressive neurodegenerative disorders. TSEs are usually associated with the appearance of an abnormal insoluble and protease-resistant form of a normal host-encoded protein, the prion protein (PrP). Structurally the disease-associated abnormal form of PrP, termed PrPres or PrPSc, is characterised by a high beta-sheet content in contrast to the predominantly alpha-helical fold of normal PrP (Hope and Manson 1991; Caughey et al. 1998).


Prion Protein Bovine Spongifonn Encephalopathy Fatal Familial Insomnia Sandhoff Disease Scrapie Agent 
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.


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  1. Aguzzi A, Weissmann C (1997) Prion research: the next frontiers. Nature 389: 795–798PubMedCrossRefGoogle Scholar
  2. Alperovitch A, Brown P, Weber T, Pocchiari M, Hofman A, Will RG (1994) The incidence of Creutzfeldt-Jakob disease in Europe. Lancet 334: 918CrossRefGoogle Scholar
  3. Asada-Kubota M, Ueda T, Nakashima T, Kobayashi M, Shimada M, Takeda K, Hamada K, Maekawa S, Sokawa Y (1997) Localization of 2’,5’-oligoadenylate synthetase and the enhancement of its activity with recombinant interferon-alpha A/D in the mouse brain. Anat Embryol 195: 251–257PubMedCrossRefGoogle Scholar
  4. Baker CA, Lu ZY, Zaitsev I, Manuelidis L (1999) Microglial activation varies in different models of Creutzfeldt-Jakob disease. J Virol 73: 5089–5097PubMedGoogle Scholar
  5. Bard F, Cannon C, Barbour R, Burke R-L, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T (2000) Peripherally administered antibodies against amyloid (3-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6: 916–919PubMedCrossRefGoogle Scholar
  6. Beekes M, McBride PA (2000) Early accumulation of pathological PrP in the enteric nervous system and gut-associated lymphoid tissue of hamsters orally infected with scrapie. Neurosci Lett 278: 181–184PubMedCrossRefGoogle Scholar
  7. Beekes M, Otto M, Wiltfang J, Bahn E, Poser S, Baier M (1999) Late increase of serum S 100 beta protein levels in hamsters after oral or intraperitoneal infection with scrapie agent. J Infect Dis 180: 518–520PubMedCrossRefGoogle Scholar
  8. Beringue V, Demoy M, Lasmezas CI, Gouritin B, Weingarten C, Deslys JP, Andreux JP, Couvreur P, Dormont D. (2000) Role of spleen macrophages in the clearance of scrapie agent early in pathogenesis J Pathol 190: 495–502Google Scholar
  9. Bons N, Mestre-Frances N, Belli P, Cathala F, Gajdusek DC, Brown P (1999) Natural and experimental oral infection of nonhuman primates by bovine spongiform encephalopathy agents. Proc Natl Acad Sci USA 96: 4046–4051PubMedCrossRefGoogle Scholar
  10. Brown P, Gajdusek DC (1991) The human spongiform encephalopathies: kuru, Creutzfeldt-Jakob disease, and the Gerstmann-Straussler-Scheinker syndrome. Curr Top Microbiol Immunol 172: 1–20Google Scholar
  11. Brown DR, Kretzschmar HA (1997) Microglia and prion disease: a review. Histol Histopathol 12: 883–892PubMedGoogle Scholar
  12. Brown DR, Schmidt B, Kretzschmar HA (1996) Role of microglia and host prion protein in neurotoxicity of a prion protein fragment. Nature 380: 345–347PubMedCrossRefGoogle Scholar
  13. Brown P, Rohwer RG, Dunstan BC, MacAuley C, Gajdusek DC, Drohan WN (1998) The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy. Transfusion 38: 810–816PubMedCrossRefGoogle Scholar
  14. 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
  15. Büeler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M, Weissmann C (1993) Mice devoid of PrP are resistant to scrapie. Cell 73: 1339–1347PubMedCrossRefGoogle Scholar
  16. Campbell IL, Eddleston M, Kemper P, Oldstone MB, Hobbs MV (1994) Activation of cerebral cytokine gene expression and its correlation with onset of reactive astrocyte and acute-phase response gene expression in scrapie. J Virol 68: 2383–2387PubMedGoogle Scholar
  17. Carp RI, Callahan SM (1981) In vitro interaction of scrapie agent and mouse peritoneal macrophages. Intervirology 16: 8–13PubMedCrossRefGoogle Scholar
  18. Carp RI, Callahan SM (1982) Effect of mouse peritoneal macrophages on scrapie infectivity during extended in vitro incubation. Intervirology 17: 201–207PubMedCrossRefGoogle Scholar
  19. Castelli JC, Hassel BA, Wood KA, Li XL, Amemiya K, Dalakas MC, Torrence PF, Youle RJ (1997) A study of the interferon antiviral mechanism: apoptosis activation by the 2–5A system. J Exp Med 186: 967–972PubMedCrossRefGoogle Scholar
  20. Caughey B, Raymond GJ, Bessen RA (1998) Strain-dependent differences in beta-sheet conformations of abnormal prion protein. J Biol Chem 273: 32230–32235PubMedCrossRefGoogle Scholar
  21. Chesebro B (1997) Human TSE disease—viral or protein only? Nat Med 3: 491–492PubMedCrossRefGoogle Scholar
  22. Combs CK, Johnson DE, Cannady SB, Lehman TM, Landreth GE (1999) Identification of microglial signal transduction pathways mediating a neuro-toxic response to amyloidogenic fragments of beta-amyloid and prion proteins. J. Neurosciences 1: 928–939Google Scholar
  23. Dandoy-Dron F, Guillo F, Benboudjema L, Deslys JP, Lasmezas C, Dormont D, Tovey MG, Dron M (1998) Gene expression in scrapie. Cloning of a new scrapie-responsive gene and the identification of increased levels of seven other mRNA transcripts. J Biol Chem 273: 7691–7697Google Scholar
  24. Diatchenko L, Lau YF, Campbell AP, Chenchik A, Moqadam F, Huang B, Lukyanov S, Lukyanov K, Gurskaya N, Sverdlov ED, Siebert PD (1996) Suppression subtractive hybridization: a method for generating differentially regulated or tissue-specific cDNA probes and libraries. Proc Natl Acad Sci USA 93: 6025–6030PubMedCrossRefGoogle Scholar
  25. Diedrich JF, Minnigan H, Carp RI, Whitaker JN, Race R, Frey W, Haase AT (1991) Neuropathological changes in scrapie and Alzheimer’s disease are associated with increased expression of apolipoprotein E and cathepsin D in astrocytes. J Virol 65: 4759–4768Google Scholar
  26. Diedrich J, Wietgrefe S, Zupancic M, Stash’s K, Retzel E, Haase AT, Race A (1987) The molecular pathogenesis of astrogliosis in scrapie and Alzheimer’s disease. Microb Pathog 2: 435–442PubMedCrossRefGoogle Scholar
  27. Diringer H, Roehmel J, Beekes M (1998) Effect of repeated oral infection of hamsters with scrapie. J Gen Virol 79: 609–612PubMedGoogle Scholar
  28. Doh-ura K, Perryman S, Race R Chesebro B (1995) Identification of differentially expressed genes in scrapie-infected mouse neuroblastoma cells. Microb Pathog 18: 1–9Google Scholar
  29. Duguid JR, Rohwer RG Seed B (1988) Isolation of cDNAs of scrapie-modulated RNAs by subtractive hybridization of a cDNA library. Proc Natl Acad Sci USA 85: 5738–5742PubMedCrossRefGoogle Scholar
  30. Farber JM (1997) Mig and IP-10: CXC chemokines that target lymphocytes. J Leukoc Biol 61: 246–57PubMedGoogle Scholar
  31. Flechsig E, Shmerling D, 2Hegyi I, Raeber AJ, Fischer M, Cozzio A, von Mering C, Aguzzi A,Weissmann C (2000) Prion protein devoid of the octapeptide region restores susceptibility to scrapie in PrP knockout mice. Neuron 27: 399–408Google Scholar
  32. 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
  33. Foster JD, Parnham D, Chong A, Goldmann W, Hunter N (2001) Clinical signs, histopathology and genetics of experimental transmission of BSE and natural scrapie to sheep and goats. Vet Rec 148: 165–171PubMedCrossRefGoogle Scholar
  34. Giese A, Brown DR, Groschup MH, Feldmann C, Haist I, Kretzschmar HA (1998) Role of microglia in neuronal cell death in prion disease. Brain Pathol 8: 449–457PubMedCrossRefGoogle Scholar
  35. Gunn MD, Ngo VN, Ansel KM, Ekland EH, Cyster JG, Williams LT (1998) A B-cell-homing chemokine made in lymphoid follicles activates Burkitt’s lymphoma receptor-1. Nature 391: 799–803PubMedCrossRefGoogle Scholar
  36. Hanan E, Goren O, Eshkenazy M, Solomon B (2001) Immunomodulation of the human prion peptide 106–126 aggregation. Biochem Biophys Res Commun 280: 115–120PubMedCrossRefGoogle Scholar
  37. Hill AF, Desbruslais M, Joiner S, Sidle KC, Gowland I, Collinge J (1997) The same prion strain causes vCJD and BSE. Nature 389: 448–450PubMedCrossRefGoogle Scholar
  38. Hope J, Manson J (1991) The scrapie fibril protein and its cellular isoform. Curr Top Microbiol Immunol 172: 57–74PubMedCrossRefGoogle Scholar
  39. Horuk RA, Martin W, Wang Z, Schweitzer L, Gerassimides A, Guo H, Lu Z, Hesselgesser J, Perez HD, Kim J, Parker J, Hadley TJ, Peiper SC (1997) Expression of chemokine receptors by subsets of neurons in the central nervous system. J Immunol 158: 2882–2890PubMedGoogle Scholar
  40. Husemann J, Loike JD, Kodama T, Silverstein SC (2001) Scavenger receptor class B type I ( SR-BI) mediates adhesion of neonatal murine microglia to fibrillar beta-amyloid. J Neuroimmunol 114: 142–150Google Scholar
  41. Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D (2000) A beta pep tide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 408: 979–982PubMedCrossRefGoogle Scholar
  42. Kenward N, Hope J, Landon M, Mayer RJ (1994) Expression of polyubiquitin and heat-shock protein 70 genes increases in the later stages of disease progression in scrapie-infected mouse brain. J Neurochem 62: 1870–1877PubMedCrossRefGoogle Scholar
  43. Kolb SA, Sporer B, Lahrtz F, Koedel U, Pfister HW, Fontana A (1999) Identification of a T cell chemotactic factor in the cerebrospinal fluid of HIV-1infected individuals as interferon-gamma inducible protein 10. J Neuroimmunol 93: 172–181PubMedCrossRefGoogle Scholar
  44. Kopacek J, Sakaguchi S, Shigematsu K, Nishida N, Atarashi R, Nakaoke R, Moriuchi R, Niwa M, Katamine S (2000) Upregulation of the genes encoding lysosomal hydrolases, a perforin-like protein, and peroxidases in the brains of mice affected with an experimental prion disease. J Virol 74: 411–417PubMedCrossRefGoogle Scholar
  45. Lafarga M, Berciano MT, Saurez I, Andres MA, Berciano J (1993) Reactive astroglia-neuron relationships in the human cerebellar cortex: a quantitative, morphological and immunocytochemical study in Creutzfeldt-Jakob disease. Int J Dev Neurosci 11: 199–213PubMedCrossRefGoogle Scholar
  46. Lasmezas CI, Deslys JP, Robain O, Jaegly A, Beringue V, Peyrin JM, Dormont, D (1997) Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science275: 402–405Google Scholar
  47. Lasmezas CI, Deslys JP, Demalmay R, Adjou KT, Lamoury F, Dormont D, Robain O, Ironside J, Hauw JJ (1996) BSE transmission to macaques. Nature 381: 743–744PubMedCrossRefGoogle Scholar
  48. Le Y, Yazawa H, Gong W, Yu Z, Ferrans VJ, Murphy, PM, Wang JM (2001) The neurotoxic prion peptide fragment PrP106–126 is a chemotactic agonist for the G protein-coupled receptor formyl peptide receptor-like 1. J Immunol 166: 1448–1451PubMedGoogle Scholar
  49. Legler DF, Loetscher M, Roos RS, Clark-Lewis I, Baggiolini M, Moser B (1998) B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J Exp Med 187: 655–660PubMedCrossRefGoogle Scholar
  50. Mabbott NA, Williams A, Farquhar CF, Pasparakis M, Kollias G, Bruce ME (2000) Tumor necrosis factor alpha-deficient, but not interleukin-6-deficient, mice resist peripheral infection with scrapie J Virol 74: 3338–3344PubMedGoogle Scholar
  51. Majumder S, Zhou LZ, Ransohoff RM (1996) Transcriptional regulation of chemokine gene expression in astrocytes. J Neurosci Res 45: 758–769PubMedCrossRefGoogle Scholar
  52. McBride PA, Eikelenboom P, Kraal G, Fraser H, Bruce ME (1992) PrP protein is associated with follicular dendritic cells of spleens and lymph nodes in uninfected and scrapie-infected mice. J Pathol 1992 168: 413–418CrossRefGoogle Scholar
  53. Meda, L, Cassatella MA, Szendrei GI, Otvos L, Baron P, Villalba M, Ferrari D, Rossi F (1995) Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374:647v560Google Scholar
  54. Miele G, Manson J, Clinton M (2001). A novel erythroid-specific marker of transmissible spongiform encephalopathies. Nat Med 7: 361–364PubMedCrossRefGoogle Scholar
  55. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW (2000) A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408: 982–985PubMedCrossRefGoogle Scholar
  56. Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP (1997) Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 17: 171–180PubMedGoogle Scholar
  57. Prusiner SB (1998) Prions Proc Natl Acad Sci USA 95: 13363–13383CrossRefGoogle Scholar
  58. Raeber AJ, Race RE, Brandner S, Priola SA, Sailer A, Bessen RA, Aguzzi, A (1997) Astrocyte-specific expression of hamster prion protein ( PrP) renders PrP knockout mice susceptible to hamster scrapie. EMBO J 16: 6057–6065Google Scholar
  59. Rezaie P, Lantos PL (2001) Microglia and the pathogenesis of spongiform encephalopathies. Brain Res Rev 35: 55–72PubMedCrossRefGoogle Scholar
  60. Riemer C, Queck I, Simon D, Kurth R, Baier M (2000) Identification of upregulated genes in scrapie-infected brain tissue. J Virol 74: 10245–10248PubMedCrossRefGoogle Scholar
  61. Scott MR, Will R, Ironside J, Nguyen HO, Tremblay P, DeArmond SJ, Prusiner SB (1999) Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans. Proc Natl Acad Sci USA 96: 15137–15142PubMedCrossRefGoogle Scholar
  62. Tan J, Town T, Paris D, Mori T, Suo Z, Crawford F, Mattson MP, Flavell RA, Mullan M (1999) Microglial activation resulting from CD40–CD40L interaction after beta-amyloid stimulation. Science 286: 2352–2355PubMedCrossRefGoogle Scholar
  63. Wada R, Tifft CJ, Proia RL (2000) Microglial activation precedes acute neurodegeneration in Sandhoff disease and is suppressed by bone marrow transplantation. Proc Natl Acad Sci USA 97: 10954–10959PubMedCrossRefGoogle Scholar
  64. Wietgrefe S, Zupancic M, Haase A, Chesebro B, Race R, Frey W, Rustan T, Friedman RL (1985) Cloning of a gene whose expression is increased in scrapie and in senile plaques in human brain. Science 230: 1177–1179PubMedCrossRefGoogle Scholar
  65. Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, Poser S, Pocchiari M, Hofman A, Smith PG (1996) A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 347: 921–925PubMedCrossRefGoogle Scholar
  66. Williams AE, Lawson LJ, Perry VH, Fraser H (1994) Characterization of the microglial response in murine scrapie. Neuropathol Appl Neurobiol 20: 47–55PubMedCrossRefGoogle Scholar
  67. Williams A, Van Dam AM, Ritchie D, Eikelenboom P, Fraser H (1997) Immunocytochemical appearance of cytokines, prostaglandin E2 and lipocortin-1 in the CNS during the incubation period of murine scrapie correlates with progressive PrP accumulations. Brain Res 754: 171–180PubMedCrossRefGoogle Scholar
  68. Xia MQ Hyman BT (1999) Chemokines/chemokine receptors in the central nervous system and Alzheimer’s disease. J Neurovirol 5: 32–41PubMedCrossRefGoogle Scholar
  69. Zhou A, Paranjape J, Brown TL, Nie H, Naik S, Dong B, Chang A, Trapp B, Fairchild R, Colmenares C, Silverman RH (1997) Interferon action and apoptosis are defective in mice devoid of 2, 5-oligoadenylate-dependent RNase L. EMBO J 16: 6355–6363Google Scholar

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© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • C. Riemer
  • D. Simon
  • S. Neidhold
  • J. Schultz
  • A. Schwarz
  • M. Baier

There are no affiliations available

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