This project will use a variety of techniques to evaluate mitochondrial effects of potential therapeutic agents for treatment of Alzheimer's disease (AD). AD has been associated with a variety of mitochondrial abnormalities including electron transport chain abnormalities (cytochrome oxidase). These abnormalities result in production of free radicals which may be important in the pathogenesis of AD. We will initially investigate the role of the therapeutic agent acetyl-L-carnitine (ALC), as a suppressor of hydroxy radical formation and specifically evaluate the hypothesis that ALC functions as an iron chelator thereby inhibiting the iron catalyzed formation of hydroxy radicals (Fenton reaction). We will evaluate biochemical effects of ALC on mitochondria and in conjunction with project #2 we will directly quantitate free radical production by spin trapping. We will accomplish this in several experimental systems. We will utilize chronic infusion of sodium azide into rats to create an animal model of cytochrome oxidase deficiency and evaluate beneficial changes induced by ALC administration. We will culture skin fibroblasts from AD and control patients in the presence of a proton ionophoric uncoupler in order to induce free radical production and peroxidative damage and evaluate the protective effects of ALC. We will evaluate changes in platelet mitochondrial metabolism in human AD patients taking ALC. In conjunction with project #3 we will evaluate mitochondrial effects of nerve growth factor (NGF) in a cultured cell system. This work will explore a new hypothesis regarding the mode of action of ALC, generate data on the role of free radicals in the pathogenesis of AD, provide a better understanding of the mitochondrial effects of ALC and NGF, and result in the development of new model systems and methods for evaluation of new AD drugs.
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