application) Defective energy metabolism and subsequent increased oxidative stress may be a mechanism of cell death in Alzheimer's disease (AD), a neurodegenerative disorder affecting as many as 50% of persons over age 85. Mitochondrial energy metabolism involves electron transfers, and interference with this process generates free radicals. These free radicals can damage proteins, lipids, and DNA, and lead eventually to cell death. Evidence is accumulating which implicates this process in AD. However, few studies on AD directly address this hypothesis. The long term objective of this proposal is to examine systematically the hypothesis that a primary abnormality in energy metabolism may contribute to 1) oxidative stress, 2) cell death, and 3) altered APP processing. Decreased activity of electron transport chain complex IV has recently been reported in AD, and may be due to mutations in the mitochondrial DNA (mtDNA). The functional consequences of such mtDNA mutations can be explored using cytoplasmic hybrids (cybrids) derived from AD cases or controls. Cybrids are formed by using mtDNA from platelets to repopulate a host cell from which the mtDNA has been removed. Mitochondrial abnormalities from patients are thereby directly transferred into cell culture, where they can be studied systematically. This system will be used to study the consequences of defective energy metabolism in AD.
The specific aims of this project are: 1) to determine whether AD cybrids show increased oxidative damage to proteins, lipids, and DNA compared to control cybrids, 2) to determine whether AD cybrids are more susceptible to exogenous toxins compared to control cybrids, and to assess potential neuroprotective strategies, and 3) to detemine whether AD cybrids have increased AB production compared to control cybrids, and to assess potential neuroprotective strategies.
