Master of Science
Dr. Robert Cumming
Alzheimer’s disease is a progressive, neurodegenerative disorder characterized by the accumulation of amyloid β (Aβ) plaques in affected brain regions. Strong evidence indicates that Aβ exerts neurotoxic effects by promoting mitochondrial dysfunction and ROS production, leading to widespread oxidative damage and activation of pro-apoptotic mechanisms. Past investigations suggest that neuronal resistance to Aβ toxicity is partly mediated by a Warburg Effect-like metabolism, in which cells exhibit elevated glycolytic activity and lactate production, while limiting mitochondrial respiration. Elevated lactate dehydrogenase A (LDHA) activity, which catalyzes lactate production from pyruvate, has been demonstrated to counter Aβ-induced oxidative stress and neurotoxicity, however the role of LDHB, which catalyzes the reverse reaction, has not been determined in this regard. This study utilized Aβ-sensitive and resistant PC12 cell lines, derived from a tumour of the rat adrenal medulla, and sought to determine the effect of altered LDHB protein levels on mitochondrial membrane potential, mitochondrial ROS levels, and cell viability following treatment with Aβ. Elevated levels of LDHB were detected in Aβ- resistant PC12 cells, compared to sensitive cells. Attenuation of LDHB expression using shRNA-mediated silencing resulted in increased mitochondrial membrane potential, ROS levels, and neurotoxicity in Aβ-resistant PC12 cells. Additionally, the effect of monocarboxylate (pyruvate and lactate) transport inhibition on PC12 cell viability, was investigated. In contrast to Aβ-sensitive PC12 cells, resistant cells were tolerant of monocarboxylate transporter inhibition while all cell lines were intolerant of mitochondrial pyruvate transporter inhibition. These findings indicate that LDHB may regulate mitochondrial respiration and sensitivity to Aβ in PC12 cells.
Tam, Tyler, "The role of lactate dehydrogenase B in aerobic glycolysis-mediated resistance to AB toxicity" (2014). Electronic Thesis and Dissertation Repository. 2218.