NR AXSY
AU Morales,R.; Estrada,L.; Castilla,J.; Soto,C.
TI Pathological Interaction Between Protein Misfolding Disorders: Prions and Alzheimer's Disease
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Protein Misfolding P01.34
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB Protein Misfolding Disorders (PMD) include several diverse diseases, such Alzheimer's, Parkinson's, Transmissible Spongiform Encephalopathies, Diabetes Type II and various systemic amyloidosis. The central event in these diseases is the accumulation of a misfolded, ß-sheet rich aggregated form of a naturally expressed protein. In vitro studies have shown that protein misfolding and aggregation follows a seedingnucleation mechanism similar to the process of crystallization. In this model, the limiting step is the formation of small oligomeric intermediates that act as seeds to catalyze the polymerization process. The seeding-nucleation model provides a rationale and plausible explanation for the infectious nature of prions. Infectivity lies on the capacity of preformed stable misfolded oligomeric proteins to act as a seed to catalyze the misfolding and aggregation process. The mechanism of misfolding and aggregation is similar in all PMD suggesting that misfolded aggregates have an inherent capability to be transmissible. Moreover, it has been shown that oligomeric seeds formed by one protein can accelerate the misfolding and aggregation of another protein, by a process termed cross-seeding. Our current study aims to assess the potential molecular cross-talk among PMD in vivo. For this purpose we inoculated with prions a transgenic mice model of Alzheimer's disease (tg2576) that develops typical amyloid plaques over time. 45, 303 and 365 days old transgenic and wild type mice were inoculated intraperitoneally with RML prions. We found significant diminution in prion incubation periods for tg2576 mice compared to age matched wild type controls. Moreover, a time dependent effect was observed, where the shorter incubation period was observed in animals containing larger number of amyloid plaques. Inoculation of tg2576-RML prions into wild type mice showed incubation periods similar to the original infectious material, suggesting that strains characteristics are maintained. In vitro data showed cross-seeding aggregation between PrPsc and Aß. Our findings suggest an interaction between Alzheimer's and prion pathologies, indicating that one protein misfolding process may be an important risk factor for the development of a second perhaps more prevalent disease.
AD R. Morales, L. Estrada, J. Castilla, C. Soto, University of Texas Medical Branch, Neurology, USA
SP englisch
PO Schottland