X/Partial The Neuropathology Core (NP Core) is a component of the DeArmond Neuropathology Research Laboratory (NRL). NP Core directed by S. DeArmond is part of a remarkably productive collaboration with Stanley Prusiner for the past 24 years. The NP Core is particularly enthusiastic about this PPG proposal because of the results of a drug trial recently completed by the NRL in which PrPSc formation, axonal transport of PrPSc and dendrite degeneration were prevented by oral doses of a y-secretase inhibitor plus quinacrine. Residual PrPSc remained in brain regions that were the first to become infected by inoculation with prions and had accumulated high levels of PrPSc before treatment was begun. Such sites were niduses for restart of PrPSc formation. The NP Core will fulfill three basic functions: First, it will perform full autopsies on CJD patients and related controls. The basic goals are to verify the diagnosis and the immediate cause of death, and to dissect samples from the CNS, muscle, visceral organs and other sites as needed in Project 3. Second, quantitative morphological and neurochemical analysis of dissected brain regions during the course of CJD and other human prion diseases transmitted to guinea pigs and transgenic (Tg) mice will correlate the kinetics of PrPSc formation and accumulation in each brain region with the vacuolation, dendrite and presynaptic bouton degeneration;reactive astrocytic gliosis;activation of microglia;and nerve cell loss. These data will be correlated with non-invasive tests for PrPSc in blood and other systemic sites. The rodent models of human prion diseases will also allow us to test whether non-invasive peripheral measurements of abnormal PrPs or other proteins predict and correlate well with beneficial effects of emerging treatments of prion diseases that clear PrPSc from the brain and prevent neurodegeneration. Third, neuropathological verification of prion disease in hamsters, wild-type mice and Tg mice will be performed for Projects 1 and 2, which focus on the structure of PrPSc.

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