The overarching hypothesis in this proposal is that brain glucose metabolism outside of oxidative phosphorylation (which we refer to as glycolysis) plays an important role in brain function in health and disease. Our interest in glycolysis arose from several observations made by us leading up to this proposal. Glycolysis accounts for 12 to15% of glucose metabolized by the adult human brain. A large fraction of this glycolysis occurs in a network of brain areas dubbed the brain's default mode network (DMN). The DMN consists of areas in medial and lateral parietal cortices, dorsal and ventral medial prefrontal cortex and the medial temporal cortices. It is noteworthy because it is more active in the resting state, is central to the functional organization of the brain, has the highest rate of glycolysis o any group of brain areas and is uniquely vulnerable to Alzheimer's disease. Because diabetes has emerged as a significant risk factor for Alzheimer's disease caused us to consider these two diseases together in terms of how glucose metabolism might not only serve to define a specific network of areas in the brain but also increase the vulnerability of these areas to Alzheimer's disease. In the experiments proposed, we ask how brain glycolysis and resting-state functional connectivity are regulated by age, sleep and systemic alterations in glucose homeostasis and insulin sensitivity. We specifically hypothesize that chronic hyperglycemia and insulin resistance as well as sleep deprivation increase glycolysis and A? release in brain areas, such as the DMN, that are heavily reliant on glycolysis, leading to increased A? deposition and accelerating the pathogenesis of AD. Project 1 and 2 will explore how brain glycolysis and functional connectivity in the DMN are regulated by systemic alterations in glucose homeostasis and insulin sensitivity in populations at risk for AD (older individuals and people with T2DM), and experiments in Project 3 will enable ideas tested in Projects 1 and 2 to be taken from the systems neuroscience level to the cellular and molecular level.
This work will provide critically needed mechanistic links between glycolysis (glucose use outside of oxidative phosphorylation), diabetes (a risk factor for Alzheimer's disease - AD) and the brain's default mode network (DMN), a network uniquely dependent on glycolysis and a primary target of AD.
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