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Research output: Thesis › Master's Thesis
Research output: Thesis › Master's Thesis
}
TY - THES
T1 - Determining the mechanism of dichloroacetate-regulated processing of the Alzheimer’s disease-related amyloid precursor protein
AU - Simmons, Hannah
PY - 2019
Y1 - 2019
N2 - Alzheimer’s disease (AD) is the most common form of dementia caused, arguably, by the accumulation in the brain of ‘sticky’ protein fragments called amyloid beta (A)-peptides. These fragments are formed through the proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. However, in an alternate non-amyloidogenic pathway, α-secretase (ADAM10) cleaves APP within the A-domain thereby precluding the formation of intact toxic peptides. We have recently shown that orphan drug dichloroacetate (DCA) can inhibit the detrimental amyloidogenic APP processing pathway whilst boosting the beneficial non-amyloidogenic processing pathway. However, the mechanism(s) by which DCA exerts these effects are, as yet, unknown and, therefore, the current study aims to elucidate these mechanisms. Hence, through manipulating pH, p53 levels, lactate dehydrogenase (LDH) activity, pyruvate and lactate levels, mitochondrial autophagy and oxidative stress, we aimed to investigate each potential mechanism by characterising the resultant effects on APP expression and proteolysis. Furthermore, we also investigated the potential effects of DCA on the subcellular localisation of APP and the activity of BACE1. However, none of these potential mechanisms proved to be involved in the DCA mechanism of action. Therefore, in conclusion, the mechanism(s) behind DCA-mediated changes in APP proteolysis/expression have not yet been identified but could still provide valuable insights in relation to future potential AD treatments.
AB - Alzheimer’s disease (AD) is the most common form of dementia caused, arguably, by the accumulation in the brain of ‘sticky’ protein fragments called amyloid beta (A)-peptides. These fragments are formed through the proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. However, in an alternate non-amyloidogenic pathway, α-secretase (ADAM10) cleaves APP within the A-domain thereby precluding the formation of intact toxic peptides. We have recently shown that orphan drug dichloroacetate (DCA) can inhibit the detrimental amyloidogenic APP processing pathway whilst boosting the beneficial non-amyloidogenic processing pathway. However, the mechanism(s) by which DCA exerts these effects are, as yet, unknown and, therefore, the current study aims to elucidate these mechanisms. Hence, through manipulating pH, p53 levels, lactate dehydrogenase (LDH) activity, pyruvate and lactate levels, mitochondrial autophagy and oxidative stress, we aimed to investigate each potential mechanism by characterising the resultant effects on APP expression and proteolysis. Furthermore, we also investigated the potential effects of DCA on the subcellular localisation of APP and the activity of BACE1. However, none of these potential mechanisms proved to be involved in the DCA mechanism of action. Therefore, in conclusion, the mechanism(s) behind DCA-mediated changes in APP proteolysis/expression have not yet been identified but could still provide valuable insights in relation to future potential AD treatments.
U2 - 10.17635/lancaster/thesis/564
DO - 10.17635/lancaster/thesis/564
M3 - Master's Thesis
PB - Lancaster University
ER -