The activity of amyloid beta binding alcohol dehydrogenase in Alzheimer's disease
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The mitochondria are a vibrant hub for many problems that occur in Alzheimer’s disease. The enzyme amyloid-ß binding alcohol dehydrogenase (ABAD) and Cyclophilin D (CypD) are two key mitochondrial proteins that have essential functions in Alzheimer’s disease. ABAD is crucial in the generation of energy via the ß-oxidation of fatty acids, and CypD has been linked to Alzheimer’s disease through the initiation of necrosis. Changes in glucose metabolism have been observed in the brains of Alzheimer’s disease sufferers. This suggests that neurons require an alternative energy source that can bypass glycolysis in order to produce energy. The oxidation of fatty acids is crucial at this point as the products of this catabolism can feed into the second stage of the respiratory cycle. In Alzheimer’s disease, Amyloid-ß (Aß) has been found to bind to ABAD distorting the catalytic site changing its activity. The first objective of this thesis was to investigate a potential previously reported interaction between ABAD and CypD. To explore this further, FRET analysis and immunoprecipitation studies were conducted. Though no strong interactions were observed from the immunoprecipitation studies, live cell FRET analysis did reveal a small/weak interaction between CypD and ABAD. Additional studies also showed a decrease in ABAD activity in the presence of CypD, suggesting that there could be functional consequences from this interaction between CypD and ABAD.I also explored the effect of changing cellular energy sources on the activity of ABAD. ABAD activity was found to increase under conditions of reduced glucose in both HEK 293 and SK-N-SH cells expressing ABAD. In addition, Alois Alzheimer initially reported changes in lipids. These reported changes in lipids were explored under conditions where there was increased expression of ABAD and in the presence of Aß. On the whole, the changes suggested that there was a shift in the metabolism of fatty acids when ABAD was expressed further implying a change in energy sources in the Alzheimer’s disease brain.
Thesis, MPhil Master of Philosophy
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