Abstract
Amphotericine B (AmB), a macrolide polyene antibiotic, is one of a few drugs that has shown therapeutic properties in scrapie-infected hamster. Its beneficial effect on survival time is mostly marked when animals are treated with its derivative MS-8209. To explore the MS-8209 effect at the cellular level, we investigated at the light and electron microscopy levels, the sequential appearance and distribution of PrP concurrently with histopathological changes in hamsters that were infected intracerebrally with the 263 K scrapie strain and treated or not with the drug. The first histopathological modifications and PrP immunostaining were observed in the thalamus and at the inoculation site where the drug caused a delay in the appearance of lesions and PrP accumulation. Using immunoelectron microscopy, at 70 d postinfection, the inoculation site of untreated animals showed an accumulation of PrP in plaque areas constitued by filaments mixed with alterated membrane structures and in developed lysosomal system of reactive astrocytes. Most of the numerous lysosomes containing PrP showed intra-organelle filaments. In contrast, in MS-8209 treated animals, the number of lysosomes was significantly lower (p<0.0038), with very few organelles harboring PrP. Our results suggest that in this scrapie model, MS-8209 treatment delays the disease by preventing the replication of the scrapie agent at the inoculation site where the astrocytes appear to be the first cells producing abnormal PrP. The lysosomal system of these astrocytes could constitute a privileged target for MS-8209.
Similar content being viewed by others
References
Adjou K.T., Privat N., Demart S, Deslys J.P., Seman M., Hauw J.J., and Dormont D. (2000) MS-8209, an amphotericin B analogue, delays the appearance of spongiosis, astrogliosis and PrPres accumulation in the brain of scrapie-infected hamsters. J. Comp. Pathol. 122, 3–8.
Adjou K.T., Demaimay R., Deslys J.P., Lasmezas C.I., Beringue V., Demart S., et al. (1999) MS-8209, a water-soluble amphotericin B derivative, affects both scrapie agent replication and PrPres accumulation in Syrian hamster scrapie. J. Gen. Virol. 80, 1079–1085.
Adjou K.T., Deslys J.P., Demaimay R., and Dormont D. (1997) Probing the dynamics of prion diseases with amphotericin B. Trends Microbiol. 5, 27–31.
Arnold J.E., Tipler C., Laszlo L., Hope J., Landon M., and Mayer R.J. (1995) The abnormal isoform of the prion protein accumulates in late-endosome-like organelles in scrapie-infected mouse brain. J. Pathol. 176, 403–411.
Brown D.R., Qin K., Herms J.W., Madlung A., Manson J., Strome R., et al. (1997) The cellular prion protein binds copper in vivo. Nature (London) 390, 684–687.
Brown D.R. (2001) Prion and prejudice: normal protein and the synapse. Trends Neurosci. 24, 85–90.
Bolton D.C., Rudelli R.D., Currie J.R., and Bendheim P.E. (1991) Copurification of Sp33–37 and scrapie agent from hamster brain prior to detectable histopathology and clinical disease. J. Gen. Virol. 72, 2905–2913.
Caughey B. and Raymond G. J (1991) The scrapie-associated form of PrP is made from a cell surface precursor that is both protease and phopholipase sensitive. J. Biol. Chem. 266, 18217–18223.
Caughey B., Raymond G.J., Ernst D., and Race RE. (1991) N-terminal truncation of the scrapie-associated form of PrP by lysosomal protease(s): implications regarding the site of conversion of PrP to the protease-resistant state. J. Virol. 65, 6597–6603.
DeArmond S.J., McKinley M.P., Barry R.A., Braunfeld M.B., McColloch J.R., and Prusiner S.B. (1985) Identification of prion amyloid filaments in scrapie-infected brain. Cell 41, 221–235.
DeArmond S.J., Mobley W.C., DeMott D.L., Barry R.A., Beckstead J.H., and Prusiner S.B. (1987) Changes in the localization of brain prion proteins during scrapie infection. Neurology 37, 1271–1280.
Demaimay R., Adjou K., Lasmezas C., Lazarini F., Cherifi K., Seman M., et al. (1994) Pharmacological studies of a new derivative of amphotericin B, MS-8209, in mouse and hamster scrapie. J. Gen. Virol. 75, 499–503.
Diedrich J.F., Minnigan H., Carp R.I., Whitaker J.N., Race R., Frey W., and Haase A.T. (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, 4759–4768.
Doh-Uva K., Iwaki T., and Caughey B. (2000) Lysosomotropic agents and cystein protease inhibitors inhibit scraple-associated prion protein accumulation. J. Virol. 74, 4894–4897.
Fournier J.G., Escaig-Haye F., Billette de Villemeur T., and Robain, O. (1995) Ultrastructural localization of cellular prion protein (PrPc) in synaptic boutons of normal hamster hippocampus. C.R. Acad. Sci. Paris 318, 339–344.
Fournier J.G. and Escaig-Haye F. (1999) In situ molecular hybridization techniques for ultra-thin sections, in Electron Microscopy, Methods and Protocols. Methods in Molecular Biology (Hajibagheri, M.A., ed.), Humana Press, Totowa, NJ, pp. 167–182.
Fournier J.G., Escaig-Haye F., and Grigoriev V. (2000) Ultrastructural localization of prion proteins: physiological and pathological implications. Microsc. Res. Tech. 50, 76–88.
Grigoriev V.B., Escaig-Haye F., Streichenberger N., Kopp N., Langeveld J., Brown P., and Fournier J.-G. (1999) Submicroscopic immunodetection of PrP in the brain of a patient with a new-variant of Creutzfeldt-Jakob disease. Neurosci. Lett. 263, 59–63.
Haeberlé A., Ribaut-Barassin C., Bombarde G., Mariani J., Hunsmann G., Grassi J., and Bailly Y. (2000) Synaptic prion protein immuno-reactivity in the rodent cerebellum. Microsc. Res. Tech. 50, 66–75.
Herms J., Tings T., Gall S., Madlung A, Giese A., Siebert H., et al. (1999) Evidence of presynaptic localization and function of the prion protein. J. Neurosci. 19, 8866–8875.
Ingrosso L., Ladogana A., and Pocchiari M. (1995) Congo red prolongs the incubation period in scrapie-infected hamsters. J. Virol. 69(1), 506–508.
Jeffrey M., McGovern G., Goodsir C.M., Brown K.L., and Bruce M.E. (2000) Sites of prion protein accumulation in scrapie-infected mouse spleen revealed by immuno-electron microscopy. J. Pathol. 191, 323–332.
Joly V., Saint-Pierre-Chazalet M., Saint-Julien L., Bolard J., Carbon C., and Yeni P. (1992) Inhibiting cholesterol synthesis reduces the binding and toxicity of amphotericin B against rabbit renal tubular cells in primary culture. J. Infect. Dis. 165, 337–343.
Keshet G.I., Bar-Peled O., Yaffe D., Nudel U., and Gabizon R. (2000) The cellular prion protein colocalizes with the dystroglycan complex in the brain. J. Neurochem. 75, 1889–1897.
Kordek R., Hainfellner J.A., Liberski P.P., and Budka H. (1999) Deposition of the prion protein (PrP) during the evolution of experimental Creutzfeldt-Jakob disease. Acta Neuropathol. 98, 597–602.
Laszlo L., Lowe J., Self T., Kenward N., Landon M., McBride T., et al. (1992) Lysosomes as key organelles in the pathogenesis of prion encephalopathies. J. Pathol. 166, 333–341.
Mc Kinley M.P., Taraboulos A., Kenaga L., Serban D., Steiber A., DeArmond S.J., et al. (1991) Ultrastructural localization of scrapie prion proteins in cytolasmic vesicles of infected cultured cellules. Lab. Invest. 65, 622–630.
Manueledis L., Fritch W., and Zaitsev I. (1998) Dapsone to delay symptoms in Creutzfeldt-Jakob disease. Lancet 352, 456.
Mayer R.J., Landon M., Laszlo L., Lennox G., and Lowe J. (1992) Protein processing in lysosomes: the new therapeutic target in neurodegenerative disease. Lancet 340, 156–159.
Moser M., Colello R.J., Pott U., and Oesch B. (1995) Developmental expression of the prion protein gene in glial cells. Neuron 14, 509–517.
Palacios J. and Serrano R. (1978) Proton permeability induced by polyene antibiotics. A plausible mechanism for their inhibition of maltose fermentation in yeast. FEBS Lett. 91, 198–201.
Pocchiari M., Schmittinger S., and Masullo C. (1987) Amphotericin B delays the incubation period of scrapie in intracerebrally inoculated hamsters. J. Gen. Virol. 68, 219–223.
Pocchiari M., Casaccia P., and Ladogana A. (1989) Amphotericin B: a novel class of antiscrapie drugs. J. Infect. Dis. 160, 795–802.
Raeber A.J., Race R.E., Brandner S., Priola S.A., Sailer A., Bessen R.A., et al. (1997) Astrocyte-specific expression of hamster prion protein (PrP) renders PrP knockout mice susceptible to hamster scrapie. EMBO J. 16, 6057–6065.
Salès N., Rodolfo K., Hassig R., Faucheux B., Di Giamberardino, L., and Moya K.L. (1998) Cellular prion protein localization in rodent and primate brain. Eur. J. Neurosci. 10, 2464–2471.
Tagliavini F., McArthur R.A., Canciani B., Giaccone G., Porro M., Bugiani M. et al. (1997) Effectiveness of Anthracycline against experimental prion disease in Syrian hamsters. Science 276, 1119–1122.
Vertut-Doi A., Ohnishi S.I., and Bolard J. (1994) The endocytic process in CHO cells, a toxic pathway of the polyene antibiotic amphotericin B. Antimicrob. Agents Chemother. 38, 2373–2379.
Vey M., Pilkuhn S., Wille H., Nixon R., DeArmond S.J., Smart E.J., et al. (1996) Subcellular colocalization of the cellular and scrapie prion proteins in caveolae-like membranous domains. Proc. Natl. Acad. Sci. USA 93, 14945–14949.
Vorberg I., Chan K., and Priola SA. (2001) Deletion of beta-strand and alpha-helix secondary structure in normal prion protein inhibits formation of its protease-resistant isoform. J. Virol. 75, 10024–10032.
Wiley C.A., Burrola P.G., Buchmeier M.J., Wooddell M.K., Barry R.A., and Prusiner S.B. (1987) Immunogold localization of prion filaments in scrapie-infected hamster brain. Lab. Invest. 57, 646–656.
Ye X., Scallet A.C., Kascsak R.J., and Carp R.I. (1998) Astrocytosis and amyloid deposition in scrapie-infected hamsters. Brain Res. 809, 277–287.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Grigoriev, V.B., Adjou, K.T., Salès, N. et al. Effects of the polyene antibiotic derivative MS-8209 on the astrocyte lysosomal system of scrapie-infected hamsters. J Mol Neurosci 18, 271–281 (2002). https://doi.org/10.1385/JMN:18:3:271
Issue Date:
DOI: https://doi.org/10.1385/JMN:18:3:271