Glucose Metabolism, Synaptic Plasticity, and Oxidative Stress in Alzheimer's Disease

Our aims, which integrate with all members of the PPG using differentiated human cortical neurons (Project 2) or an AD mouse model (TG19959, Projects, 3 and 4) are targeted at developing strategies to maintain the short term, beneficial effects of glucose deprivation on learning and memory while interdicting the ability of this enzyme to trigger oxidative death and increased AD production over the long term. In our last aim, we will use a novel reporter of the redox regulated transcription factor, Nrf-2 expressed in astrocytes as a strategy to identify when redox dyshomeostasis occurs in the TG19959 model of AD. We will also use this reporter to develop, with Project 4, a safer and more effective approach using an FDA approved Nrf-2 activator in combination with an FDA approved antioxidant which we predict will nullify oxidative stress while maintaining adaptive plasticity associated gene expression. Together these studies will evaluate novel targets and therapies for optimizing the adaptive effects of reducing glucose into neurons on learning and memory while minimizing deleterious consequences related to oxidative stress and bioenergetic dysfunction.