The incidence of Alzheimer's disease (AD) has steadily increased in the United States as our average lifespan has lengthened. Thus, the means to prevent or reduce the rate of this disorder is a high priority for medical research. A standardized extract of Ginkgo biloba leaves (EGb 761) has been used for treatment of certain cerebral dysfunctions and dementias associated with aging and AD. Substantial evidence indicates that EGb 761 has neuroprotective effects. The action mechanisms of the extract are, however, poorly understood. Our previous studies funded by the National Institutes of Health provided evidence for the anti-amyloid beta (A beta) aggergation and anti-apoptotic properties of EGb 761 in vitro, which hold promise as potentially important neuroprotective mechanisms of action. The goal of this interdisciplinary project is to further our understanding of the neuroprotective mechanisms of EGb 761 in vivo. We will continue to test the hypothesis that the neuroprotective effect of EGb 761 is achieved by inhibition of A beta oligomerization, antioxidative properties and augmentation of an organism's endogenous stress-response. We will use transgenic C. elegans models in conjunction with a transgenic mouse model of AD to study possible links between A beta aggregation, oxidation and toxicity.
The specific aims of the present project are: 1) to correlate effects of EGb 761 on A beta aggregation and toxicity through fluorescence staining of A beta deposits and behavioral analysis of A beta-induced paralysis in the transgenic C. elegans expressing human A beta; 2) to define activities of single constituents of EGb 761 against A beta-induced oxidation through kinetic study of protein carbonyls in an inducible transgenic C. elegans; 3) to implicate changes in gene transcription profile induced by EGb 761 in the wild type and the transgenic C. elegans, using DNA microarray method, 4) to determine effects of EGb 761 on cognitive _mpairment through testing hippocampus-dependent spatial learning in a transgenic mouse model of AD. Previous results and preliminary data show the feasibility of this project. A better understanding of the 'mechanisms of EGb 761 neuroprotection will be important for understanding of the underlying neurodegenerative processes and for designing therapeutic strategies that target neurodegenerative disorders.
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