Investigation of Ketogenic Diet Metabolites as a Therapeutic for Alzheimer’s Disease in a Drosophila Model of Glial Tauopathy

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dc.contributorBroaders, Kyle
dc.contributorArango, Alexi
dc.contributor.advisorTanner, Geoffrey
dc.contributor.advisorWoodard, Craig
dc.contributor.authorO'Leary, Emma
dc.date.accessioned2016-04-29T12:56:20Z
dc.date.available2016-04-29T12:56:20Z
dc.date.gradyear2016en_US
dc.date.issued2016-04-29
dc.description.abstractAlzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by progressive neuronal and synaptic degeneration, as well as decreased cognition over time. AD is prevalent in today’s society, comprising 60-80% of dementia cases, and therefore it is an essential disease to study. Although extensive research has been done, the cause and progression of the disease is still unknown. However, one of the hallmarks of AD is intracellular neurofibrillary tangles (NFTs), which are composed of the protein tau. High tau concentrations have been shown to correlate with fast cognitive decline; therefore, it is hypothesized that lowering overall tau levels in the brain will reduce AD symptoms. Moreover, there is evidence that AD patients have a reduced glycolytic metabolism, so it is predicted that administration of a ketogenic diet – which produces ketone bodies that bypass glycolysis to enter mitochondrial metabolism directly- will ameliorate tau toxicity. This hypothesis was tested by feeding the ketone body β-hydroxybutyrate (βHB) to Drosophila overexpressing human wild-type tau in their glia, and quantifying the level of tau in their brains with Western blot. Furthermore, since ketone bodies have been shown to modulate ATP-sensitive potassium (KATP) channel activity, the role of KATP channels was investigated by administering the allosteric KATP inhibitor tolbutamide. Our results found that: 1) Administration of βHB lowers overall tau in the brain as long as the flies are raised on the diet 2) Reduction in relative tau levels is more pronounced after four weeks on βHB 3) Tolbutamide indirectly increases the amount of tau in the brain and reverses the effects of the ketogenic diet, indicating that KATP channels may have a mechanistic role in regulating tau expression and neuroexcitability.en_US
dc.description.sponsorshipBiochemistryen_US
dc.identifier.urihttp://hdl.handle.net/10166/3738
dc.language.isoen_USen_US
dc.rights.restrictedrestricteden_US
dc.subjectAlzheimer's diseaseen_US
dc.subjectketogenic dieten_US
dc.subjectketone bodyen_US
dc.subjecttauen_US
dc.subjectamyloid betaen_US
dc.subjectDrosophila melanogasteren_US
dc.subjecttauopathyen_US
dc.subjectgliaen_US
dc.titleInvestigation of Ketogenic Diet Metabolites as a Therapeutic for Alzheimer’s Disease in a Drosophila Model of Glial Tauopathyen_US
dc.typeThesis
mhc.degreeUndergraduateen_US
mhc.institutionMount Holyoke College

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