Statins can reduce A? generation both in vitro and in vivo, which provides a possible explanation for their clinical benefits in Alzheimer's disease (AD) prevention. However, it has been shown that the levels of cholesterol and A? are not correlated in the brain of transgenic AD mouse models treated with atorvastatin or in mice genetically engineered to have low blood cholesterol levels. Therefore, the notion that statins act simply via cholesterol-lowering may need to be examined more carefully. As inhibitors of HMG-CoA reductase, statins inhibit the biosynthesis of many metabolites downstream of mevalonate, including cholesterol and isoprenoids. We have found that geranylgeranyl pyrophosphate (GGPP), an isoprenoid generated in the mevalonate biosynthetic pathway, preferentially increases the levels of amyloidogenic A?42 through the activation of Rho/Rock signaling. We have also found that the cleavage of APP fragments by secretase is GGPP dependent. Furthermore, supplement of GGPP can fully reverse statin-mediated A? reduction. Based on our findings, we hypothesize that cellular GGPP may play an important role in the amyloidogenesis of AD; and through inhibiting the synthesis of GGPP, statins reduce A? generation. To test this hypothesis, we will first determine the relation between cellular GGPP levels and and A? generation in specific aim #1. We will then investigate whether the inhibition of Rho/Rock signaling is a mechanism of statin-mediated changes in APP-CTF processing and A? generation in specific aim #2. The information generated by the proposed studies will broaden our knowledge of the mechanisms of statins in the treatment of AD and provide more specific drug targets. Our studies will also set a start point for future research to develop novel therapeutic approaches to prevent AD based on the regulation of isoprenoids and Rho/Rock signaling. Statins, which have been shown to reduce the prevalence of Alzheimer's disease, inhibit the synthesis of both cholesterol and GGPP. We have found that GGPP alters the metabolism of APP and promote the synthesis amyloid-?-peptide, a protein important in the development of the disease. We will be able to define the underlying mechanisms through proposed studies, thus providing new drug targets for the prevention and treatment of Alzheimer's disease. ? ? ?
