eISSN: 1509-572x
ISSN: 1641-4640
Folia Neuropathologica
Current issue Archive Manuscripts accepted About the journal Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
1/2012
 
Share:
Share:
more
 
 

Review article
Ultrastructural findings in pigs experimentally infected with bovine spongiform encephalopathy agent

Pawel P. Liberski, Beata Sikorska, Gerald A.H. Wells, Steve A.C. Hawkins, Michael Dawson, Marion M. Simmons

Folia Neuropathol 2012; 50 (1): 89-98
Article file
 
 
Bovine spongiform encephalopathy (BSE) is a transmissible neurodegenerative disorder previously epidemic among cattle in the United Kingdom, with subsequent cases worldwide and which has now declined to a very low incidence due to rigorous controls [8,24,73,92].

Like other scrapie-like transmissible spongiform ence­pha­lopathies (TSE) [48], BSE is caused by an elusive pat­hogen which has historically been variously termed “a slow unconventional virus” [23], “virino” [33] and more recently, a “prion” [74]. Originally transmitted to cattle via meat-and-bone meal in commercial feedstuffs [91], BSE has been transmitted in primary inoculum to a wide range of food animal species [82] and in addition to mice [10,20,22], mink [75] and the common marmoset [2].

Neuropathologically, both natural and experimental BSE is characterized by spongiform change and astrocytosis in the neuropil and vacuolation of selected nuclei of the brain stem [81,84,85,88,90,91] and accumulation of the proteinase-resistant isoform of PrP (PrPSc) [83,84]. Scrapie-associated fibrils (SAF) or “prion rods” which are visualized by negative-staining electron microscopy in brain extracts [9,29,77] are also associated with disease, and there is a good correlation between degree of pathology and SAF yield [89].

To date, ultrastructural studies of spongiform en­ce­phalopathies have been conducted in primates, including humans [37,38,41,51,53,60]; ruminants (cattle, sheep, mule deer and elk) [4-6,16-18,26,27,46,66,67] and laboratory rodents [12,31,32,47,64,65,70; for review: 30,66,67]. The successful transmission of BSE to do­mestic pigs [14,86], which belong to the order Artiodactyla (even-toed hoofed animals), made it possible to study the pathology of this disease in another spe­cies and to test whether tubulovesicular structures, the only disease-specific structures observed in situ [49,53, 55,59,62,65] occur also in BSE-affected pig brain.

Material and methods



Experiment design and inoculation procedure

The pigs were infected at 1-2 weeks of age by multiple-route parenteral inoculation with a homogenate of bovine brain from natural BSE cases, as described in full previously [76,86,87]. All challenges were carried out in accordance with the Animals (Scientific Procedures) Act, 1986, under licence from the UK Home Office. Animals were sedated with azoperone (Stresnil; Janssen Animal Health) and killed by the intravenous injection of pentobarbitone sodium followed by exsanguination. When clinical disease developed, animals were killed and samples collected immediately post-mortem.

Electron microscopy

Multiple samples, comprised 2-3 mm3, of cerebral cortex, brain stem at the level of vestibular nuclei, ventral horns of the spinal cord, cerebellum and dorsal root ganglia, selected on the basis of the previously determined prevalence of light-microscopy changes [76,87], were fixed immediately after dissection in 2.5% glutaraldehyde, freshly prepared in phosphate buffer (pH 7.4), then postfixed in 1% osmium tetroxide and processed for routine electron microscopy. Comparable areas of brain from uninoculated pigs served as controls.

Results



In general, the ultrastructural features of BSE-affected pig brain were similar to those of BSE-affected cattle [46,66,67] and humans with TSEs [60,61]. Spongiform change in the form of membrane-bound vacuoles (Fig. 1) separated by membranes curled into secondary chambers dominated the pathology. A dense astrocytic reaction was accompanied by abundant elongated microglial cells. Of particular note was the finding of numerous astrocytic processes in close conjunction with microglial cells. Neuronal degeneration presented as either neuroaxonal dystrophy, as evidenced by dystro­phic neurites, or autophagic vacuoles. Dystrophic neu­rites accumulated altered subcellular organelles: mitochondria (Fig. 1B), electron-dense bodies, neurofilaments and “branching-cisterns” (Fig. 2). Autopha­gic vacuoles appeared as a part or parts of the neuronal cytoplasm sequestrated by intracytoplasmic membranes (Fig. 3). Sequestrated cytoplasm was of higher electron density than the remaining cytosol. Discontinuity of plasma membranes was occasionally seen (Fig. 3B, arrow). Tubulovesicular structures (TVS) were numerous with the highest number of affected processes in the cerebellum (Fig. 4). Many large multivesicular bodies were seen (Fig. 5).

Discussion



Not unexpectedly, the overall neuropathology of experimental BSE in pigs resembled the main ultrastructural features of BSE in cattle and other TSEs [for review: 42,43,48,78,79]. However, the distribution of lesions in pigs was different from that in cattle. In particular, the cerebral and cerebellar cortices in pigs were more heavily involved. These quantitative differences in pathology are not unprecedented, as it is well established that the topography of lesions differs between species or between strains of the agent passaged in one species [3,15,21]. It remains unclear to what extent such differences are explicable in terms of targeting of the agent to different anatomical regions [11] or selective vulnerability of different neuronal populations, but both phenomena are considered to be important.

The observation of TVS in the pig established their occurrence in another animal model of experimental spongiform encephalopathy and in a mammalian spe­cies not previously used in TSE research. The molecular composition and the biological significance of TVS remains unknown [49,55]. TVS have been found in all naturally occurring and experimentally induced spongiform encephalopathies in which the appropriate examinations have been made [35]. Examples include natural Creutzfeldt-Jakob disease [1,53,55,60], Gerstmann-Sträussler-Scheinker disease (GSS) [51], BSE [46,66,67], and natural and experimental scrapie [4,62, 65,69,70]. This comprehensive association suggests that they represent a morphological component closely linked to the basic disease pathomechanism. This is further supported by the observation that TVS appear early in the incubation period. For example, in hamsters infected with the 263K strain of scrapie, in which the incubation period lasts approximately 8 weeks, TVS were observed 3 weeks postinoculation [62]. Additionally, the number of neuronal processes containing TVS generally correlates well with the infectivity titre [62]. Thus, the highest number of processes involved was seen in hamsters infected with the 263K strain of scrapie, followed by the next highest frequency in hamsters infected with the 22C strain of scrapie and in mice infected with the Fujisaki strain of CJD [62]. This corresponds to infectivity titres in brains of 104 LD50 for hamsters infected with the 263K strain of scrapie agent and 3.1 x 104 LD50 in CJD virus-infected mice, respectively. In contrast, the lowest number of neuronal processes containing TVS is reported for natural diseases like scrapie [4], BSE [46,66,67] or CJD and GSS [51,53,55,60,61]. The frequency of TVS-containing pro­cesses in BSE-affected pig brains was high but, as the titre there is unknown, it is impossible to judge wheth­er this finding represents a true correlation or a coincidental finding. In conclusion, irrespective of what TVS represent, the necessity for further studies is obviously clear.

Autophagy is an important component of the ultra­­structural picture of TSE [50,57,58,80], but its exact role and whether it is protective or destructive is not well established [39]. Autophagy was initially shown in scra­pie-infected hamsters [7,63] and later in CWD-infected cervids [26], and the present authors consider it to be a deleterious process leading to neurodegeneration [56].

Different types of autophagy have been described: macroautophagy (here called just “autophagy”), micro­autophagy and chaperon-mediated autophagy [34].

One of these is macroautophagy, which is the intracellular bulk degradation of organelles. Its stages comprise the formation of semi-circular membrane elongations which engulf a target portion of the cytoplasm (a cargo), forming a membrane sac which fuses with a lysosome to form an autophagosome. Such membra­nes are observed readily in scrapie-affected hamster brain [63] but not so readily in different models.

Several investigators have suggested that auto­phagy plays a beneficial role in prion infection [28]. For instance, imatinib, an autophagy inducer [93], not only delays the onset of clinical disease following peripheral ino-culation but also clears PrPSc from scrapie-infected cultures [19]. Rapamycin, acting through the target of rapa­mycin (TOR) reduced the level of PrPSc and prolonged the incubation when given in the last third of the ex­pected incubation period [28]. Recent observations suggest a “double-edged” role for autophagy [13]. For example, in Alzheimer’s disease (AD), another protein-misfolding disorder, upregulation of autophagy contribu­tes to beta-amyloid pathology [68]. This upregulation of autophagy may result in cell-death through distortion of neuronal metabolism or loss of synapses and dendrites. The abundance of dystrophic neurites containing abundant autophagic vacuoles and lysosomal dense bodies has been shown repeatedly in prion diseases and other protein-misfolding diseases [25,36,40, 44,45,52,54,71,72]. In Drosophila transfected with Ab42 (a major amyloidogenic peptide AD plaque forming), Ling et al. [68] found increased macroautophagy and dystrophic neurites typical of AD. Rapamycin increased the number of autophagic vacuoles and electron-lucent areas in dystrophic neurites, probably reflecting en­zyme leakage from post-lysosomal autophagic vacuoles, which may lead to neurodegeneration. Also, membrane erosion was seen in A42-Drosophila and we also observed membrane discontinuity in dystrophic neurites in this study. Collectively, the very presence of dystrophic neurites may suggest that autophagy, over certain threshold tolerated by the brain may become deleterious.

Acknowledgements



This paper was presented, in part, at the Meeting of the Association of Polish Neuropathologists, held in Warsaw, in June 1993. Professor Pawel P. Liberski was a recipient of support from the British Council while staying in the United Kingdom. Mr R. Kurczewski, Ms Elz­bieta Naganska, Ms L. Romanska and Mr K. Smoktunowicz are kindly acknowledged for skilful technical assistance and Ms. Ewa Skarżyńska for editorial work.

References



 1. Armstrong RA. Dispersion of prion protein deposits around blood vessels in variant Creutzfeldt-Jakob disease. Folia Neuropathol 2010; 48: 150-158.

 2. Baker HF, Ridley RM, Wells GAH. Experimental transmission of BSE and scrapie to the common marmoset. Veterinary Record 1993; 132: 403-406.

 3. Béringue V, Vilotte JL, Laude H. Prion agent diversity and species barrier. Vet Res 2008; 39: 47.

 4. Bignami A, Parry HB. Aggregations of 35-nanometer particle as­sociated with neuronal cytopathic changes in natural scrapie.

Science 1971; 171: 389-390.

 5. Bignami A, Parry HB. Electron microscopic studies of the brain of sheep with natural scrapie. I. The fine structure of neuronal va-cuolation. Brain 1972; 95: 319-326.

 6. Bignami A, Parry HB. Electron microscopic studies of the brain of sheep with natural scrapie. Brain 1972; 95: 487-494.

 7. Boellaard JW, Schlote W, Tateishi J. Neuronal autophagy in experimental Creutzfeldt-Jakob's disease. Acta Neuropathol 1989; 78: 410-418.

 8. Bradley R, Liberski PP. Bovine spongiform encephalopathy (BSE): the end of the beginning or the beginning of the end? Folia Neuropathol 2004; 42 Suppl A: 55-68.

 9. Brown P, Liberski PP, Wolff A, Gajdusek DC. Resistance of scrapie infectivity to steam autoclaving after formaldehyde fixation and limited survival after ashing at 360 degrees C: practical and the­o­retical implications. J Infect Dis 1990; 161: 467-472.

10. Bruce ME, Chree A, McConnell I, Foster J, Pearson G, Fraser H. Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and the sepcies barrier. Philos Trans R Soc Lond B Biol Sci 1994; 343: 405-411.

11. Bruce ME, McBride PA, Farquhar CF. Precise targeting of the patho-logy of the sialoglycoprotein, PrP, and vacuolar degeneration in mouse scrapie. Neurosci Lett 1986; 102: 1-6.

12. Chandler RL. Ultrastructural pathology of scrapie in the mouse:

an electron microscopic study of spinal cord and cerebellar areas. Br J Exp Pathol 1968; 49: 52-59.

13. Cherra SJ 3rd, Dagda RK, Chu CT. Review: autophagy and neuro­degeneration: survival at a cost? Neuropathol Appl Neurobiol 2010; 36: 125-132.

14. Dawson M, Wells GAH, Parker BNJ, Scott AC. Primary parenteral transmission of bovine spongiform encephalopathy to the pig.

Vet Rec 1990; 127: 338.

15. DeArmond SJ, Yang S-L, Lee A, Bowler R, Taraboulos A Groth D, Prusiner SB. Three scrapie prion isolates exhibit different accumulation patterns of the prion protein scrapie isoform. Proc Natl Acad Sci U S A 1993; 90: 6449-6453.

16. Ersdal C, Goodsir CM, Simmons MM, McGovern G, Jeffrey M. Abnormal prion protein is associated with changes of plasma membranes and endocytosis in bovine spongiform encephalopathy (BSE)-affected cattle brains. Neuropathol Appl Neurobiol 2009; 35: 259-271.

17. Ersdal C, Simmons MM, González L, Goodsir CM, Martin S, Jeffrey M. Relationships between ultrastructural scrapie pathology and patterns of abnormal prion protein accumulation. Acta Neuropathol 2004; 107: 428-438.

18. Ersdal C, Simmons MM, Goodsir C, Martin S, Jeffrey M. Sub-cellu­lar pathology of scrapie: coated pits are increased in PrP codon 136 alanine homozygous scrapie-affected sheep. Acta Neuro­pathol 2003; 106: 17-28.

19. Ertmer A, Gilch S, Yun SW, Flechsig E, Klebl B, Stein-Gerlach M,

Klein MA, Schätzl HM. The tyrosine kinase inhibitor STI571 indu­ces cellular clearance of PrPSc in prion-infected cells. J Biol Chem 2004; 279: 41918-41927.

20. Fraser H, Bruce ME, Chree A, McConnell I, Wells GAH. Transmission of bovine spongiform encephalopathy and scrapie to mice. J Gen Virol 1992; 73: 1891-1897.

21. Fraser H, Dickinson AG. Scrapie in mice. Agent-strain differences in the distribution and intensity of grey matter vacuolation. J Comp Pathol 1973; 83: 29-40.

22. Fraser H, McConnell I, Wells GAH, Dawson M. Transmission of bovine spongiform encephalopathy to mice. Vet Rec 1988; 123: 472.

23. Gajdusek DC. Unconventional viruses and the origin and disappearance of kuru. Science 1977; 197: 943-960.

24. Gavier-Widén D, Stack MJ, Baron T, Balachandran A, Simmons M. Diagnosis of transmissible spongiform encephalopathies in animals: a review. J Vet Diagn Invest 2005; 17: 509-527.

25. Gibson PH, Liberski PP. An electron and light microscopic study of the numbers of dystrophic neurites and vacuoles in the hippo­campus of mice infected intracerebrally with scrapie. Acta Neuropathol 1987; 73: 379-382.

26. Guiroy DC, Williams ES, Liberski PP, Gajdusek DC. Electron Microscopic findings in brain of Rocky Mountain elk with chronic wasting disease. Folia Neuropathol 1994; 32: 171-173.

27. Guiroy CG, Williams ES, Liberski PP, Wakayama I, Gajdusek DC. Ultrastructural neuropathlogy of chronic wasting disease in captive mule deer. Acta Neuropathol (Berl) 1992; 85: 437-444.

28. Heiseke A, Aguib Y, Schatzl HM. Autophagy, prion infection and their mutual interactions. Curr Issues Mol Biol 2010; 12: 87-97.

29. Hope J, Reekie LJ, Hunter N, Multhaup G, Beyreuther K, White H, Scott AC, Stack MJ, Dawson M, Wells GA. Fibrils from brains of cows with new cattle disease contain scrapie-associated protein. Nature 1988; 336: 390-392.

30. Jeffrey M, McGovern G, Sisó S, González L. Cellular and sub-cellular pathology of animal prion diseases: relationship between morphological changes, accumulation of abnormal prion protein and clinical disease. Acta Neuropathol 2011; 121: 113-134.

31. Kim JH, Manuelidis EE. Serial ultrastructural study of experimental Creutzfeldt-Jakob disease in guinea pigs. Acta Neuropathol (Berl) 1986; 69: 81-90.

32. Kim JH, Manuelidis EE. Ultrastructural findings in experimental Creutzfeldt-Jakob disease in guinea pigs. J Neuropathol Exp Neurol 1983; 42: 29-43.

33. Kimberlin RH. Scrapie and possible relationships with viroids. Semin Virol 1990; 1: 153-162.

34. Klionsky DJ, Baehrecke EH, Brumell JH, Chu CT, Codogno P, Cuer­vo AM, Debnath J, Deretic V, Elazar Z, Eskelinen EL, Finkbeiner S, Fueyo-Margareto J, Gewirtz D, Jäättelä M, Kroemer G, Levine B, Melia TJ, Mizushima N, Rubinsztein DC, Simonsen A, Thorburn A, Thumm M, Tooze SA. A comprehensive glossary of autophagy-related molecules and processes. 2nd ed. Autophagy 2011; 7: 1273-1294.

35. Kovacs GG, Budka H. Molecular pathology of human prion diseases. Int J Mol Sci 2009; 10: 976-999.

36. Lampert PW. A comparative electron microscopic study of reactive, degenerating, regenerating, and dystrophic axons. J Neuro­pathol Exp Neurol 1967; 26: 345-368.

37. Lampert PW, Earle KM, Gibbs CJ Jr., Gajdusek DC. Experimental kuru encephalopathy in chimpanzees and spider monkeys. Electron microscopic studies. J Neuropathol Exp Neurol 1969; 28: 353-370.

38. Lampert PW, Gajdusek DC, Gibbs CJ Jr. Experimental spongiform encephalopathy (Creutzfeldt-Jakob disease) in chimpanzees. Electron microscopic studies. J Neuropathol Exp Neurol 1971; 30: 20-32.

39. Lansbury PT, Lashuel HA. A century-old debate on protein aggregation and neurodegeneration enters the clinic. Nature 2006; 443: 774-779.

40. Liberski PP. Degenerative neurites in experimental scrapie.

Neuro­patol Pol 1986; 24: 79-88.

41. Liberski PP. Kuru and D. Carleton Gajdusek: a close encounter. Folia Neuropathol 2009; 47: 114-137.

42. Liberski PP. Light and Electron Microscopic Neuropathology of Slow Virus Diseases. CRC Press, Boca Raton, 1992.

43. Liberski PP. Spongiform change – an electron microscopic view.

Folia Neuropathol 2004; 42 Suppl B: 59-70.

44. Liberski PP. The transmissible brain amyloidoses: a comparison with the non transmissible brain amyloidoses of Alzheimer type. Acta Neurobiol Exp (Wars) 1993; 53: 337-349.

45. Liberski PP. Transmissible cerebral amyloidoses as a model for Alz­heimer’s disease. An ultrastructural perspective. Mol Neurobiol 1994; 8: 67-77.

46. Liberski PP. Ultrastructural neuropathologic features of bovine spongiform encephalopathies. J Am Vet Med Assoc 1990; 196: 1682-1683.

47. Liberski PP, Asher DM, Yanagihara R, Gibbs CJ Jr., Gajdusek DC. Se­rial ultrastructural studies of scrapie in hamsters. J Comp Pathol 1989; 101: 429-442.

48. Liberski PP, Brown P. Astrocytes in transmissible spongiform en­ce­phalopathies (prion diseases). Folia Neuropathol 2004; 42 Suppl B: 71-88.

49. Liberski PP, Brown P. Disease-specific particles without prion protein in prion diseases – phenomenon or epiphenomenon? Neuro­pathol Appl Neurobiol 2007; 33: 395-397.

50. Liberski PP, Brown DR, Sikorska B, Caughey B, Brown P. Cell death and autophagy in prion diseases (transmissible spongiform encephalopathies). Folia Neuropathol 2008; 46: 1-25.

51. Liberski PP, Budka H. Tubulovesicular structures in gerstmann-Straussler-Scheinker disease. Acta Neuropathol (Berl) 1994; 88:

491-492.

52. Liberski PP, Budka H. Ultrastructural pathology of Gerstmann-Sträussler-Scheinker disease. Ultrastruct Pathol 1995; 19: 23-36.

53. Liberski PP, Budka H, Sluga E, Barcikowska M, Kwiecinski H. Tubu­lovesicular structures in human and experimental Creutzfeldt-Jakob disease. Eur J Epidemiol 1991; 7: 551-555.

54. Liberski PP, Budka H, Yanagihara R, Gajdusek DC. Neuroaxonal dystrophy in experimental Creutzfeldt-Jakob disease: electron microscopical and immunohistochemical demonstration of neurofilament accumulations within affected neurites. J Comp Pathol 1995; 112: 243-255.

55. Liberski PP, Budka H, Yanagihara R, Gibbs CJ Jr., Gajdusek DC. Tubulovesicular structures. In: Liberski PP (ed.). Light and Electron Microscopic Neuropathology of Slow Virus Diseases. CRC Press, Boca Raton 1992, pp. 373-392.

56. Liberski PP, Gajdusek DC, Brown P. How do neurons degenerate in prion diseases or transmissible spongiform encephalopathies (TSEs): neuronal autophagy revisited. Acta Neurobiol Exp (Wars) 2002; 62: 141-147.

57. Liberski PP, Sikorska B, Bratosiewicz-Wasik J, Gajdusek DC, Brown P. Neuronal cell death in transmissible spongiform ence­phalopathies (prion diseases) revisited: from apoptosis to auto­phagy. Int J Biochem Cell Biol 2004; 36: 2473-2490.

58. Liberski PP, Sikorska B, Gibson P, Brown P. Autophagy contri­butes to widespread neuronal degeneration in hamsters infected with the Echigo-1 strain of Creutzfeldt-Jakob disease and mice infected with the Fujisaki strain of Gerstmann-Sträussler-Scheinker (GSS) syndrome. Ultrastruct Pathol 2011; 35: 31-36.

59. Liberski PP, Sikorska B, Hauw JJ, Kopp N, Streichenberger N, Gi-

raud P, Budka H, Boellaard JW, Brown P. Tubulovesicular structures are a consistent (and unexplained) finding in the brains of hu­mans with prion diseases. Virus Res 2008; 132: 226-228.

60. Liberski PP, Sikorska B, Hauw JJ, Kopp N, Streichenberger N, Gi­raud P, Boellaard J, Budka H, Kovacs GG, Ironside J, Brown P. Ultrastructural characteristics (or evaluation) of Creutzfeldt-Jakob di­sease and other human transmissible spongiform encephalo­pathies or prion diseases. Ultrastruct Pathol 2010; 34: 351-361.

61. Liberski PP, Streichenberger N, Giraud P, Soutrenon M, Meyronnet D, Sikorska B, Kopp N. Ultrastructural pathology of prion diseases revisited: brain biopsy studies. Neuropathol Appl Neurobiol 2005; 31: 88-96.

62. Liberski PP, Yanagihara R, Gibbs CJ Jr., Gajdusek DC. Appearance of tubulovesicular structures in experimental Creutzfeldt-Jakob disease and scrapie preceeds the onset of clinical disease. Acta Neuropathol (Berl) 1990; 79: 349-354.

63. Liberski PP, Yanagihara R, Gibbs CJ Jr, Gajdusek DC. Neuronal autophagic vacuoles in experimental scrapie and Creutzfeldt-Jakob disease. Acta Neuropathol 1992; 83: 134-139.

64. Liberski PP, Yanagihara R, Gibbs CJ Jr., Gajdusek DC. Scrapie as a model for neuroaxonal dystrophy: ultrastructural studies. Exp Neurol 1989; 106: 133-144.

65. Liberski PP, Yanagihara R, Gibbs CJ Jr., Gajdusek DC. Tubulovesi-cular structures in experimental Creutzfeldt-Jakob disease and scrapie. Intervirology 1988; 29: 115-119.

66. Liberski PP, Yanagihara R, Wells GAH, Gibbs CJ Jr., Gajdusek DC. Comparative ultrastructural neuropathology of naturally occuring bovine spongiform encephalopathy and experimentally in­duced scrapie and Creutzfeldt-Jakob disease. J Comp Pathol 1992; 106: 361-381.

67. Liberski PP, Yanagihara R, Wells GAH, Gibbs CJ Jr., Gajdusek DC. Ultrastructural pathology of axons and myelin in experimental scrapie in hamsters and bovine spongiform encephalopathy in

cattle and a comparison with the panencephalopathic type of Creutzfeldt-jakob disease. J Comp Pathol 1992; 106: 383-398.

68. Ling D, Song HJ, Garza D, Neufeld TP, Salvaterra PM. Abeta42-induced neurodegeneration via an age-dependent autophagic-lysosomal injury in Drosophila. PLoS One 2009; 4: e4201.

69. Manuelidis L, Yu ZX, Barquero N, Mullins B. Cells infected with scrapie and Creutzfeldt-Jakob disease agents produce intracellular 25-nm virus-like particles. Proc Natl Acad Sci U S A 2007; 104:

1965-1970.

70. Narang HK, Asher DM, Pomeroy KL, Gajdusek DC. Abnormal tubu­lovesicular particles in brains of hamsters with scrapie. Proc Soc Exp Biol Med 1987; 184: 504-509.

71. Nixon RA. Autophagy, amyloidogenesis and Alzheimer disease.

J Cell Sci 2007; 120: 4081-4091.

72. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 2005; 64: 113-122.

73. Ortiz-Pelaez A, Stevenson MA, Wilesmith JW, Ryan JB, Cook AJ.

Case-control study of cases of bovine spongiform encephalopathy born after July 31, 1996 (BARB cases) in Great Britain. Vet Rec 2012 Jan 18 [Epub ahead of print].

74. Prusiner SB. Novel proteinaceous infection particles cause scrapie. Science 1982; 216: 136-144.

75. Robinson MM, Hadlow W, Huff TP, Wells GAH, Dawson M,

Marsh RF, Gorham JR. Experimental infection of mink with bovine spongiform encephalopathy. J Gen Virol 1994; 75: 2151-2155.

76. Ryder SJ, Hawkins SA, Dawson M, Wells GA. The neuropathology of experimental bovine spongiform encephalopathy in the pig.

J Comp Pathol 2000; 122: 131-143.

77. Scott AC, Wells GAH, Stack MJ, White H, Dawson M. Bovine spongiform encephalopathy: detection and quantitation of fibrils, fibril protein (PrP) and vacuolation in brain. Vet Microbiol 1990; 23:

295-304.

78. Sikorska B. Mechanisms of neuronal death in transmissible spongiform encephalopathies. Folia Neuropathol 2004; 42 Suppl B: 89-95.

79. Sikorska B, Hainfellner JA, Mori S, Bratosiewiczi J, Liberski PP, Budka H. Echigo-1: a panencephalopathic strain of Creutzfeldt-Jakob disease. II. Ultrastructural studies in hamsters. Folia Neuropathol 2004; 42 Suppl B: 167-175.

80. Sikorska B, Liberski PP, Brown P. Neuronal autophagy and aggresomes constitute a consistent part of neurodegeneration in experimental scrapie. Folia Neuropathol 2007; 45: 170-178.

81. Simmons MM, Harris P, Jeffrey M, Meek S, Blamire IWH, Wells GA. BSE in Great Britain: consistencies of the neurohistological findings in two random annual samples of clinical suspects. Vet Rec 1996; 138: 175-177.

82. Simmons MM, Spiropoulos J, Hawkins SAC, Bellworthy SJ, Ton-

gue SC. Approaches to investigating transmission of spongiform encephalopathies in domestic animals using BSE as an example. Vet Res 2008; 39: 34.

83. Simmons MM, Spiropoulos J, Webb PR, Spencer YI, Czub S, Muel-ler R, Davis A, Arnold ME, Marsh S, Hawkins SA, Cooper JA, Ko-

nold T, Wells GA. Experimental classical bovine spongiform ence­phalopathy: definition and progression of neural PrP immunolabeling in relation to diagnosis and disease controls. Vet Pathol 2011; 48: 948-963.

84. Stack MJ, Moore SJ, Davis A, Webb PR, Bradshaw JM, Lee YH, Chaplin M, Focosi-Snyman R, Thurston L, Spencer YI, Hawkins SA, Ar­nold ME, Simmons MM, Wells GA. Bovine spongiform encephalopathy: investigation of phenotypic variation among passive surveillance cases. J Comp Path 2011; 144: 277-288.

85. Wells GAH, Hancock RD, Cooley WA, Richards MS, Higgins RJ,

David GP. Bovine spongiform encephalopathy: diagnostic significance of vacuolar changes in selected nuclei of the medulla oblongata. Vet Rec 1989; 125: 521-524.

86. Wells GAH, Hawkins SAC, Austun AR, Ryder SJ, Done SH,

Green RB, Dexter I, Dawson M, Kimberlin RH. Studies of the transmissibility of the agent of bovine spongiform encephalopathy to pigs. J Gen Virol 2003; 84: 1021-1031.

87. Wells GAH, Hawkins SAC, Pohlenz J, Matthews D. Portrait of experimental BSE in pigs. In: Hornlimann B, Reisner D, Kretschmar H (eds.). Prions in Humans and Animals. De Gruyter, Berlin 2007; pp. 275-278.

88. Wells GAH, Scott AC, Johnson CT, Gunning RF, Hancock RD, Jeffrey M, Dawson M, Bradley R. A novel progressive spongiform encephalopathy in cattle. Vet Pathol 1987; 121: 419-420.

89. Wells GAH, Scott AC, Wilesmith J, Simmons MM, Matthews D. Correlation between the results of a histopathological examination and the detection of abnormal brain fibrils in the diagnosis of bovine spongiform encephalopathy. Res Vet Sci 1994; 56: 346-351.

90. Wells GAH, Wilesmith J, McGill IS. Bovine spongiform encephalopathy: a neuropathological perspective. Brain Pathol 1991; 1: 69-78.

91. Wells GAH, Wilesmith JW. The neuropathology and epidemiology of bovine spongiform encephalopathy. Brain Pathol 1995; 5:

91-103.

92. Wilesmith JW, Ryan JBM, Arnold ME, Stevenson MA, Burke PJ. Descriptive epidemiological features of cases of bovine spongiform encephalopathy born after July 31, 1996 in Great Bitain. Vet Rec 2010; 167: 279-286.

93. Yun SW, Ertmer A, Flechsig E, Gilch S, Riederer P, Gerlach M,

Schätzl HM, Klein MA. The tyrosine kinase inhibitor imatinib mesylate delays prion neuroinvasion by inhibiting prion propagation in the periphery. J Neurovirol 2007; 13: 328-337.
Copyright: © 2012 Mossakowski Medical Research Centre Polish Academy of Sciences and the Polish Association of Neuropathologists. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Quick links
© 2017 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe