Neurodegenerative disorders are affecting larger and larger proportions of our population as lifespan increases. Thus, the means to prevent or reduce the rate of these disorders is a high priority for medical research. The goal of this project is to gain understanding of the neuroprotective mechanisms of Ginkgo biloba extract EGb761. EGb761 has become one of the most popular preparations, especially for the prevention and treatment of primary neurodegenerative dementias associated with aging and Alzheimer's disease. Substantial experimental evidence supports neuroprotective properties of EGb761, but the actual mechanisms of its action(s) is yet unknown. We will test the hypothesis that the standardized extract EGb761 has multiple sites of action for neuroprotection, which is, at least in part, achieved by interaction of antioxidative, anti-amyloidogenic, and anti-apoptotic mechanisms. The specific aims of the present project are: 1. Evaluate antioxidative and anti-amyloidogenic mechanisms of EGb761, 2. Identify cell survival pathways of EGb761. Cultured hippocampal slices and neuronal cells will be used as models of oxidative stress and neurotoxicity. State-of-the art molecular and cellular techniques and pharmacological application of inhibitors and activators will be used to define the potential pathways of EGb761 neuroprotection. All of the required methodologies are in place in the PI's laboratory and in those of the collaborators. Results from these experiments can be applied to animal models and human studies. Better understanding of the mechanisms of neuroprotection by EGb761 will be important not only for design of rational "mechanism-based" strategies that target age-related neurodegenerative disorders, but also for basic understanding of the underlying neurodegenerative processes themselves.