The objective is to determine the role of NADPH-cytochrome P450 reductase (CPR) in the pathogenesis of Alzheimer's disease (AD). The hypothesis is that CPR may contribute to the amyloid beta (A beta) protein-induced neuropathology in AD through its activities in the production of reactive oxygen species (ROS). CPR has long been known to be involved in ROS production. The current proposal for a 2-year, pilot study will focus on the development and characterization of an amyloid precursor protein (APP) transgenic mouse model with defective expression of CPR. This model will be generated by cross-breeding 2 existing single transgenic mice, 1 expressing transgenic APP and the other having greater than 75% decreases in the level of CPR expression throughout the major organs, including the brain. The latter mouse model has been generated in preliminary studies. The potential involvement of CPR in APP-induced neuropathology is supported by a recent finding on the induction of CPR proteins surrounding A beta deposits in the APP-transgenic mice and within the cortical neurons from the brains of human AD patients. Preliminary studies also indicated a decrease in the levels of amyloid plaques in the brains of APP mice with defective expression of CPR. Thus, a drastic decrease in CPR expression may lead to a significant reduction in A beta-mediated oxidative stress and alleviate neurodegenerative changes in AD. The new mouse model will be characterized to determine whether there will be a lower expression of markers of oxidative stress and a less extent of neuropathological and behavioral manifestations in the double transgenic mice than in the parental APP-transgenic mice. The outcome of this study could be the first direct evidence for the role of CPR in pathogenesis of AD in a transgenic mouse model. It will provide a better understanding of the molecular basis of pathogenesis of AD. ? ?
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