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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects the cognitive function and memory of those affected. It results from plaques formed by the abnormal cleavage of the Amyloid Precursor Protein (APP), which result in the formation of a 42 amino acid polypeptide, also known as amyloid beta 42 (Aβ42). Accumulation of these hydrophobic Aβ42 plaques triggers neuronal cell death in the central nervous system. However, the reason for this abnormal cell death still remains unknown. A possible explanation involves the role of mitochondrial dysfunction, as mitochondria carry out many vital cellular functions in a cell, including ATP production, reactive oxygen species production, and apoptosis. This study uses Drosophila melanogaster - the fruit fly – as the model organism, as 75% of the genetic machinery is conserved between flies and humans and much of the information generated using this model can be extrapolated to humans. This study uses an AD fly model in which human Aβ42 peptides can be misexpressed in the Drosophila eye using the GAL4/UAS system. In our study, we have identified (1) alpha-ketoglutarate dehydrogenase and (2) pyruvate dehydrogenase as potential enzymatic modifiers of the human Aβ42 neurodegeneration. To investigate their effect on Alzheimer’s, we used the GAL4/UAS system, and misexpressed the GOF/LOF forms of the genes coding these enzymes along with human Aβ42 in the fly eye and checked the resultant phenotypes in both larval eye antennal imaginal discs and in adults. Our results showed partial rescue in the LOF of alpha-ketoglutarate dehydrogenase, which clearly indicates that the enzyme plays a major role in AD progression. In the future, we will test the GOF of both enzymatic modifiers in further experiments. This study has significant bearings on understanding how certain enzymatic mitochondrial machinery and metabolism affects AD progression.
Primary Advisor's Department
Stander Symposium poster
"Investigation of the Role of Mitochondrial Dysfunction as a Trigger for Neurodegeneration in Alzheimer’s disease" (2018). Stander Symposium Posters. 1360.