NR AXWZ
AU Spilman,P.; Bush,C.; Sattavat,M.; Tousseyn,T.; Lessard,P.; Golde,T.; Huang,E.; Prusiner,S.; DeArmond,S.
TI Treatment of Scrapie-Infected Mice with The gamma-Secretase Inhibitor LY411,575 and Quinacrine Prevents Spread of PrPsc and Neuropathology
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Pathology and Pathogenesis P03.160
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB PrPsc is linked to dendrite loss in prion disease by activation of Notch-1 signaling pathways. Notch-1 activation is a multistep process culminating in release of its Intracellular Domain NICD by g-secretase cleavage. Here we tested the hypothesis that dendritic degeneration is primarily the result of PrPsc-driven activation of Notch-1 signaling pathways. CD1 mice were intra-thalamically inoculated with RML prions. Mice were treated with g-secretase inhibitor (G) alone or in combination with quinacrine (Q). The drugs were given ad libitum in chocolate drink continuously for 60 days beginning 50 days postinoculation. Results: (1) PrPsc: Q alone did not reduce neocortical (Nc), hippocampal (Hp), or thalamic (Th) PrPsc. In Nc, G alone produced ~50% decrease in PrPsc and G+Q a significant 95% decrease. In Th, G alone increased PrPsc by ~30%, which taken together with the ~50% decrease in Nc, argue that G represses axonal transport of PrPsc. (2) NICD: In Nc, G reduced NICD levels ~90% relative to untreated RML-infected mice, consistent with its known effects on gsecretase activity. In Th, no significant effects were found, although G alone reduced NICD to levels seen in uninfected controls. (3) Dendrite loss: Golgi silver stained dendrites were quantified. G did not prevent dendrite loss in any region, even though it reduced NICD by 90%. This argues that the Notch-1 repressor pathway is not the only cause of dendritic degeneration. Q prevented 80% of the dendrite loss, suggesting that Q affects non-Notch-1 pathways which mediate dendrite degeneration. Dual G+Q treatment increased the number of dendrites 10-20% above that in uninfected controls in all regions studied, suggesting that it not only prevented dendrite loss but also stimulated new growth. These results argue that G+Q act synergistically to prevent spread of scrapie in the brain. (Supported by: NIH Grants AG021601, AG02132, AG10770, and AG023501 and by the Stephen C. and Patricia A. Schott Foundation).
AD P. Spilman, C. Bush, M. Sattavat, T. Tousseyn, E. Huang, S. DeArmond, University of California, Department of Pathology, USA; P. Lessard, S. Prusiner, University of California, Institute for Neurodegenerative Diseases, USA; T. Golde, Mayo Clinic College of Medicine, Department of Neuroscience, USA
SP englisch
PO Schottland
EA pdf-Datei und Poster (Posterautoren: P. Spilman, M. Sattavat, P. Lessard, E. Huang, S.B. Prusiner und S.J. DeArmond; Postertitel: Treatment of Scrapie-Infected Mice with the Gamma-Secretase Inhibitor LY411,575 plus Quinacrine Profoundly Reduces PrPsc and Neuropathological Changes in the CNS)