Neurodegenerative diseases of the brain such as Alzheimer's disease and Parkinson's disease are major public health problems in the United States. These diseases involve a complex orchestration of advancing age, genetics, and environmental factors and biochemical features such as oxidative damage and mitochondrial abnormalities. The long term objective of this project is to elucidate this relationship by focusing on the following components: environmental toxicants, age, lipid peroxidation, and mitochondrial dysfunction. The hypotheses of this project are 1) reactive alkenal products of lipid peroxidation, such as HNE, HHE, and acrolein, contribute to the pathogenesis of neurodegenerative disease by promoting mitochondrial dysfunction, and 2) exposure to environmental toxicants prevent mitochondrial alkenal detoxification. These hypotheses will be tested through successful completion of the following specific aims: a) define the effects of alkenals on brain mitochondrial functions and develop novel protective alkenal scavengers; b) determine whether alkenals enhance brain mitochondrial free radical generation; and, c) establish the environmental and age-related influences on brain mitochondrial alkenal detoxifying pathways. Successful completion of these experiments will provide fundamental information concerning the relationship of environmental factors, oxidative damage, and mitochondrial dysfunction in age-related neurodegenerative disease. With this knowledge, novel therapeutic interventions or preventative strategies may be designed for these diseases.
