Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Biology

Supervisor

Dr. Robert Cumming

Abstract

Alzheimer’s disease (AD) is characterized by deposition of the amyloid beta (Ab) peptide in the brain, an event which frequently but not universally correlates with nerve cell death. Although most nerve cells die in response to Ab, small populations of cells are able to survive by becoming resistant to Ab toxicity. Understanding the mechanisms by which cells become resistant to Ab may reveal novel treatments for AD. Interestingly, nerve cell lines selected for resistance against Ab exhibit increased glucose uptake and glycolytic flux. Here I show that these metabolic changes are mediated through an upregulation of pyruvate dehydrogenase kinase 1 (PDK1) and increased lactate dehydrogenase A (LDHA) activity. These metabolic alterations in Ab resistant nerve cells are reminiscent of the Warburg effect, also known as aerobic glycolysis, a common anti-apoptotic mechanism elicited by cancer cells. Similar to cancer cells, Ab-resistant nerve cells exhibit reduced mitochondrial reactive oxygen species (ROS) production. Inhibiting PDK1 or LDHA expression or activity re-sensitized resistant cells to Ab toxicity. In contrast, overexpression of either PDK1 or LDHA in sensitive cells conferred resistance to Ab and other neurotoxins. Importantly, cells overexpressing either PDK1 or LDHA displayed repressed mitochondrial oxygen consumption with a concomitant decrease in mitochondrial ROS levels. Furthermore, these cells maintained cellular adenosine triphosphate (ATP) pools when exposed to Ab, whereas sensitive cells became depleted of ATP. Immunoblot analysis revealed a decrease in PDK1 and LDHA levels in mouse primary cortical neurons treated with Aβ and in cortical tissue extracts from 12-month-old AD transgenic (APPswe/PS1dE9) mice. A similar decrease in PDK1 expression was observed in post-mortem brain extracts from AD patients. Treatment of cultured nerve cell lines and primary cortical neurons with CNB-001 and J147, novel neurotrophic drugs that prevent cognitive decline in AD mice, restored PDK1 and LDHA expression following Ab treatment. Moreover, PDK1 expression was maintained in AD mice fed CNB-001. Collectively, these findings suggest that the Warburg effect plays a central role in mediating neuronal resistance to Αβ by decreasing mitochondrial activity and subsequent ROS production. Loss of this protective effect may render elderly individuals susceptible to AD.


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