Oxidative stress and a key metabolic enzyme in Alzheimer brains, cultured cells, and an animal model of chronic oxidative deficits.

Oxidative stress and diminished metabolism occur in several neurodegenerative disorders. Brains from Alzheimer's disease (AD) patients exhibit several indicators of oxidative stress and have reduced activities of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a key mitochondrial enzyme. Whether these abnormalities are secondary to neurodegenerative processes or are inherent properties of the cells cannot be determined in autopsy brain. Studies in cultured fibroblasts suggest that AD-related differences in oxidative stress and KGDHC reflect inherent properties of AD cells. KGDHC is sensitive to oxidative stress whether the enzyme is studied in cells, in purified mitochondria, or as an isolated protein. Reductions of brain KGDHC in living rodents lead to oxidative stress and selective cell death. The results suggest that KGDHC participates in a deleterious cascade of events related to oxidative stress that are critical in selective neuronal loss in neurodegenerative diseases.