Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Biology

Supervisor(s)

Robert Cumming

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by amyloid plaques that are comprised of aggregated amyloid-beta peptides. These toxic proteins promote mitochondrial dysfunction and neuronal cell death. A shift in metabolism away from oxidative phosphorylation and toward aerobic glycolysis, with the concomitant production of lactate, affords neurons a survival advantage against amyloid-beta toxicity. Recent evidence now suggests that aerobic glycolysis in the brain plays a critical role in supporting synaptic plasticity, learning, and memory. However, the role of aerobic glycolysis and lactate metabolism in AD-mediated cognitive decline is unknown. My objective was to test the hypotheses that aerobic glycolysis is upregulated in neurons to mediate amyloid-beta resistance and promote memory processes in vivo using the APP/PS1 mouse model of AD. Cerebral lactate levels within the frontal cortex of control mice were found to decline with age, whereas lactate levels remained unaltered in APP/PS1 mice. An age-dependent decline in levels of key aerobic glycolysis enzymes and an increase in lactate transporter expression were detected in control mice. Increased expression of lactate-producing enzymes correlated with improved memory performance in control mice, yet the opposite effect was detected in APP/PS1 mice. To determine if aerobic glycolysis plays a role in mediating spatial memory processes, mice were injected with dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase. Dichloroacetate caused a reduction in conversion of pyruvate to lactate in the brain and a decline in phosphorylation of pyruvate dehydrogenase, the target of dichloroacetate, yet there was no significant effect on memory. In agreement with previous observations, a correlation analysis of cortical extracts revealed that increased phosphorylation of pyruvate dehydrogenase correlated with better spatial memory in control mice. These observations indicate that production of lactate, via aerobic glycolysis, is beneficial for memory function during normal aging, yet is not explicitly required for spatial memory tasks. In addition, elevated lactate levels in APP/PS1 mice indicate perturbed lactate processing, a factor that may contribute to memory impairment in AD. Collectively, this research demonstrates several novel observations that will lead to a better understanding of cerebral lactate metabolism in the AD brain and aid in the development of metabolic strategies to treat this devastating disease.


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