Currently, there is not effective form of treatment for prion disease. The pathogenesis of prion disease is related to a conformational change of the normal prion protein, PrPC, to a form with a high beta sheet content, PrPSc. The increased beta sheet content of the disease-associated protein provides both a therapeutic target and allows development of ligands for specific imaging of the diseased brain or organs. Recently vaccination has been shown to be an effective therapy in transgenic Alzheimer's disease (AD) model mice. We have developed an immunological approach making it potentially safer for human use. Recently, we have used a similar immunotherapeutic approach for the prion disease and found that both active and passive vaccination delays the disease onset. Our further preliminary data shows that mucosal immunization can prevent infection by the natural oral route. We propose that both active and passive immunization approaches will be effective at preventing prion infection. PrP is a copper binding protein and copper has been found to be important in the conformational change to PrPSc. Our novel, preliminary data suggests that copper chelators also inhibit prion infection, suggesting this as an additional therapeutic approach which can be combined with the immunological therapies. A methodology to improve the diagnosis of prion disease is also needed. We have used ligands that are coupled to gadolinium which bind to the beta sheet rich amyloid deposits in AD transgenic mice. We show that similar techniques can be used to image prion related pathology. We also have preliminary data that non-toxic, Congo red analog ligands can be used to specifically image PrPSc amyloid deposits in vivo. In this proposal we will further develop our active and passive immunization, as well as metal chelation approaches utilizing peripherally infected prion model mice (using prion strains 139A and 87V), tissue culture models of prion infection and transgenic mice expressing either human or deer PrP. UMRI will be used to image T2 and gradient echo signal changes related to pre-symptomatic and symptomatic prion infection in model mice. We will also use non-toxic, PrP homologous peptides coupled to gadolinium which bind to PrPSc as ligands to visualize prion related amyloid deposits in vivo using uMRI. In vivo imaging will also be done with 2 photon microscopy and non-toxic, Congo red analogs. Our novel imaging techniques will be used to monitor our therapeutic experiments.