PROJECT SUMMARY At present, there is no treatment that prevents or even slows the progression of Alzheimer's disease (AD), which is the most prevalent neurodegenerative disorder. The Animal Core (Core C) will provide normal and genetically modified mice or rats and will conduct the experiments described in Projects 1, 2, and 3. Rodent models that express human proteins involved in neurodegenerative disease proved key in the discovery of misfolded forms of normal proteins, called prions, as new principles of disease. AD involves two prions, tau and Abeta. Cellular assays allow measurement of human tau and Abeta prions in culture, but transfer of disease from humans to mice will provide essential validation. Inoculation of brain homogenates into specific regions of the rodent brain and subsequent diagnosis of disease requires exceptionally skilled animal technicians who also assess disease onset by evaluating clinical signs and by bioluminescence as a marker of disease-induced gliosis in transgenic models specifically bred for this purpose (Projects 1 and 2). The stability of tau and Abeta prion strains or conformations also will be tested by repeated passage in mice (Project 2). Exceptionally high resolution structures (Project 3) can be determined by cryo-electron microscopy using material provided by Core C. The experiments executed in Core C ultimately will provide models to test therapies that halt disease progression.