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Prion infections of the central nervous system (CNS) are characterised by a reactive gliosis and the subsequent degeneration of neuronal tissue. The activation of glial cells, which precedes neuronal death, is likely to be initially caused by the deposition of misfolded, proteinase K-resistant, isoforms (termed PrP(res)) of the prion protein (PrP) in the brain. Cytokines and chemokines released by PrP(res)-activated glia cells may contribute directly or indirectly to the disease development by enhancement and generalisation of the gliosis and via cytotoxicity for neurons. However, the actual role of prion-induced glia activation and subsequent cytokine/chemokine secretion in disease development is still far from clear. In the present work, we review our present knowledge concerning the functional biology of cytokines and chemokines in prion infections of the CNS.

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Neuropathological, epidemiological and experimental data indicate a potential interrelationship between Alzheimer's disease and prion diseases. Proteolytic processing of amyloid precursor protein (APP) by beta-secretase was recently suggested to be controlled by prion protein expression. Here, we characterized the prion infection of Tg2576 mice, which overexpress the human APP(Swe) protein. Prion infection of Tg2576-mice led to an early death of the animals, which was preceded by a relatively short symptomatic stage. However, disease-associated gliosis and deposition of misfolded prion protein PrP(Sc) were identical in infected Tg2576-mice and non-transgenic littermate controls. To analyze the effect of prion infection on APP processing and generation of beta-amyloid we determined cortical levels of SDS- and formic acid (FA)-extractable forms of beta-amyloid (1-40) and (1-42) by ELISA. Formic acid-extractable Abeta (1-42) levels were 10-fold higher in infected versus uninfected Tg2576 mice whereas other forms of Abeta were essentially unaffected by the prion infection. Hence, the experimental model demonstrates that a prion infection of the CNS promotes selectively formation of FA-extractable Abeta(1-42) in Tg2576 mice.

21039 Background: For cellular prion protein (PrPc) putative roles in many cellular processes including signalling, survival, adhesion, proliferation and differentation have been proposed. The hallmarks of cancer include some of these traits and in human tumors both increased and decreased levels of PrPc have been observed. However PrPc deficient mice show no increased rate of tumor formation. To characterize the possible role of PrPc in tumorigenesis we generated PrPc-/-/p53-/- mice. Methods: Organ and tumor samples were surgically removed post mortem and processed for histological analysis. Time to death was defined as the latency between birth and spontaneous death or a terminal disease state as indicated by tumor burden and other symptoms of severe disease. Results: As reported previously lymphomas are the most frequent tumors in p53-/- mice [5 out of 7 (71 %)]. In contrast, sarcomas predominate in PrPc-/-/p53-/- mice [9 out of 21 (43 %)]. This was accompanied by a decrease in the incidence of lymphomas in PrPc-/-/p53-/- mice [7 out of 21 (33 %)]. Conclusions: These results indicate for PrPc, in the context of p53 deficiency, a role in sarcoma tumorigenesis and the PrPc-/-/p53-/- mice might provide a clinical relevant model for the study of sarcomas. No significant financial relationships to disclose.

Disinfectants containing 3-methyl-4-chlorophenol were tested for their capacity to inactivate the infectious agent of scrapie. Coincubation of brain homogenates prepared from terminally ill scrapie-infected hamsters with the disinfectants rendered the prion protein PrP(Sc) sensitive to proteinase K digestion. Inoculation of hamsters with disinfectant-treated samples indicated a reduction in infectivity levels to below the limit of detection.