This study has examined the distribution of PrP(Sc) in sheep by immunocytochemistry of tissues recovered from terminally affected animals following their experimental infection by the oral route with BSE. Despite a wide range of incubation period lengths, affected sheep showed a similar distribution of high levels of PrP(Sc) throughout the central nervous system. PrP(Sc) was also found in the lymphoid system, including parts of the digestive tract, and some components of the peripheral nervous system. These abundant PrP(Sc) deposits in sheep in regions outside the central nervous system are in direct contrast with cattle infected with BSE, which show barely detectable levels of PrP(Sc) in peripheral tissues. A number of genetically susceptible, challenged animals appear to have survived.

Although the ultimate target of infection is the central nervous system (CNS), there is evidence that the enteric nervous system (ENS) and the peripheral nervous system (PNS) are involved in the pathogenesis of orally communicated transmissible spongiform encephalopathies. In several peripherally challenged rodent models of scrapie, spread of infectious agent to the brain and spinal cord shows a pattern consistent with propagation along nerves supplying the viscera. We used immunocytochemistry (ICC) and paraffin-embedded tissue (PET) blotting to identify the location and temporal sequence of pathological accumulation of a host protein, PrP, in the CNS, PNS, and ENS of hamsters orally infected with the 263K scrapie strain. Enteric ganglia and components of splanchnic and vagus nerve circuitry were examined along with the brain and spinal cord. Bioassays were carried out with selected PNS constituents. Deposition of pathological PrP detected by ICC was consistent with immunostaining of a partially protease-resistant form of PrP (PrPSc) in PET blots. PrPSc could be observed from approximately one-third of the way through the incubation period in enteric ganglia and autonomic ganglia of splanchnic or vagus circuitry prior to sensory ganglia. PrPSc accumulated, in a defined temporal sequence, in sites that accurately reflected known autonomic and sensory relays. Scrapie agent infectivity was present in the PNS at low or moderate levels. The data suggest that, in this scrapie model, the infectious agent primarily uses synaptically linked autonomic ganglia and efferent fibers of the vagus and splanchnic nerves to invade initial target sites in the brain and spinal cord.

Variant Creutzfeldt-Jakob disease (CJD) probably results from exposure to the bovine spongiform encephalopathy agent. There is no treatment to slow or halt variant CJD, and the diagnosis is usually made when patients are terminally ill. During the long incubation period when there are no symptoms, there is a potential but unknown risk of transfer of infection by blood transfusion, treatment with blood products, transplantation, or reuse of surgical instruments.

The present study investigated the relationship among PrP deposition, microglial activation, vacuolation, and neuronal death in the hippocampus of the 301V/VM murine scrapie model (mean incubation period 117 +/- 1 days). PrP deposition was first detected after 30 days and microglial activation after 60 days. Vacuolation in the CA1 and CA2 pyramidal layer was present from 90 days onward. Only occasional in situ end labeling (ISEL)-positive neurons were present in the hippocampus of scrapie-infected mice from 75 days postinoculation (d.p.i.), except at 105 d.p.i. when relatively large numbers of apoptotic, ISEL-positive neurons in the CA1 hippocampal region were observed. Terminally ill animals showed almost complete loss of CA1 pyramidal neurons. Electron microscopy of the CA1 region at 105 days confirmed that these neurons were dying by apoptosis. These data suggest that microglial activation in scrapie is a response to abnormal PrP deposition rather than a response to neuronal cell loss.

Veterinary RecordVolume 138, Issue 22 p. 546-548 Short Communication Detection of BSE infectivity in brain and spleen of experimentally infected sheep J. D. Foster, J. D. Foster Institute for Animal Health, BBSRC and MRC Neuropathogenesis Unit, Ogston Building, Edinburgh, EH9 3JFSearch for more papers by this authorM. Bruce, M. Bruce Institute for Animal Health, BBSRC and MRC Neuropathogenesis Unit, Ogston Building, Edinburgh, EH9 3JFSearch for more papers by this authorI. McConnell, I. McConnell Institute for Animal Health, BBSRC and MRC Neuropathogenesis Unit, Ogston Building, Edinburgh, EH9 3JFSearch for more papers by this authorA. Chree, A. Chree Institute for Animal Health, BBSRC and MRC Neuropathogenesis Unit, Ogston Building, Edinburgh, EH9 3JFSearch for more papers by this authorH. Fraser, H. Fraser Institute for Animal Health, BBSRC and MRC Neuropathogenesis Unit, Ogston Building, Edinburgh, EH9 3JFSearch for more papers by this author J. D. Foster, J. D. Foster Institute for Animal Health, BBSRC and MRC Neuropathogenesis Unit, Ogston Building, Edinburgh, EH9 3JFSearch for more papers by this authorM. Bruce, M. Bruce Institute for Animal Health, BBSRC and MRC Neuropathogenesis Unit, Ogston Building, Edinburgh, EH9 3JFSearch for more papers by this authorI. McConnell, I. McConnell Institute for Animal Health, BBSRC and MRC Neuropathogenesis Unit, Ogston Building, Edinburgh, EH9 3JFSearch for more papers by this authorA. Chree, A. Chree Institute for Animal Health, BBSRC and MRC Neuropathogenesis Unit, Ogston Building, Edinburgh, EH9 3JFSearch for more papers by this authorH. Fraser, H. Fraser Institute for Animal Health, BBSRC and MRC Neuropathogenesis Unit, Ogston Building, Edinburgh, EH9 3JFSearch for more papers by this author First published: 01 June 1996 https://doi.org/10.1136/vr.138.22.546Citations: 20Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume138, Issue22June 1996Pages 546-548 RelatedInformation

The transmissible neurodegenerative diseases, of which scrapie is the archetype, are caused by unconventional infectious agents. Prion protein (PrP), a widespread host coded, cell surface sialoglycoprotein, is thought to be an essential or, controversially, sole component of these agents. During infection, disease specific accumulations of PrP may be observed in immunostained brain sections of mice infected with the 87V scrapie strain as amyloid plaques or as diffuse or granular foci within the neuropil. Using serial light and electron microscopical preparations we determined immunocytochemically that infection specific PrP is present in amyloid fibrils, and accumulates on the plasmalemma of neurites at the periphery of plaques and in the neuropil, irrespective of the morphological form of PrP accumulation when viewed by light microscopy. In some brain areas with dense granular PrP expression complete disruption of neuropil with loss of neurites was associated with fibrils lying free in expanded extracellular space. These results suggest that normal PrP may be converted to its pathological form at the neuronal plasmalemma or in the extracellular space and, furthermore, that amyloid fibrils are formed following the accumulation and aggregation of subunit proteins at these sites.

Transmission from four cases of bovine spongiform encephalopathy (BSE) to mice resulted in neurological disease in 100% of recipient animals, after incubation periods of between 265 and 700 days post-injection. The results from the four cases were very similar to one another. There were major differences in the incubation period between the four inbred strains of mice tested, and even between strains of the same Sinc genotype, and the incubation periods of Sinc heterozygote mice were much longer than those for any of the inbred strains. Transmission from a case of natural scrapie differed in two important respects: there were no differences in the incubation period between mouse strains of the same Sinc genotype, and that of the heterozygotes was between those of the Sinc homozygotic parental strains. The distribution of vacuolar degeneration in the brains of mice infected with scrapie also differed from those infected with the BSE isolates. Transmission was also achieved from formol-fixed BSE brain. These results show that the same strain of agent caused disease in the BSE cases, and that the relationship of BSE to scrapie in sheep is unclear.

In an immunohistochemical study of naturally-occurring and experimental scrapie in sheep, deposits of cerebrovascular amyloid were found to react with antibodies to hamster scrapie prion protein (PrP 27–30), but not with antibodies to the amyloid β-protein of Alzheimer's disease. It is concluded that this vascular amyloid is formed from PrP and is therefore closely associated with scrapie infection. It is likely that this amyloid is formed from a host precursor protein as a specific pathological consequence of invasion by the scrapie agent.

A biochemical study has been carried out on a series of sputum specimens from 9 patients with cystic fibrosis. The mucus was centrifuged at 120,000 g for 3+ hr at 4°C to separate the sol and gel phases. The concentration of various high molecular weight components in the sol phase was determined by cellulose acetate electrophoresis and by cross electrophoresis. The average proportion of mucus that separated as sol phase was closely similar to that of sputum specimens from patients with asthma and bronchitis. The relative concentration of albumin in the high molecular weight components of the sol phase of bronchial mucus from cystic fibrosis patients was similar to that found in the sol phase of sputum from patients with asthma rather than those suffering from chronic bronchitis. This resemblance to the sputum of patients with asthma was also borne out by the plasma protein composition of the sol phase of cystic fibrosis mucus. Humoral factors involved in non-specific and specitic immune defence do not seem to be lacking in cystic fibrosis mucus as judged by the levels of lysozyme, lactoferrin, IgA and IgG. The soluble secretory proteins of cystic fibrosis mucus appear to be closely similar to those of patients with other chronic chest diseases. The plasma protein composition of the sol phase of cystic fibrosis mucus, however, seems to suggest that a degree of inflammation is occurring that is in excess of that expected from repeated bacterial infection.