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Effects of Altered Glucose Utilization on AB Levels and Functional Connectivity

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Alzheimer's disease (AD) is the most common form of dementia, affecting approximately 30 million people worldwide. Accumulation of the amyloid-? (A?) peptide in the brain is hypothesized to be a key instigator in the pathogenesis of Alzheimer's disease (AD). Approximately 10-15 years prior to cognitive decline, aggregation of normally soluble monomeric A? accumulates into toxic forms, most notably amyloid plaques, within specific brain regions in the AD brain. Recent studies identified characteristics common to these AD prone regions including high neuronal activity, high functional connectivity, and high glucose utilization (relative to oxygen consumption). Interestingly, one of the first changes observed in the AD brain prior to or concurrent with clinical symptoms is aberrant glucose uptake. Furthermore, recent epidemiological studies suggest that patients with diabetes, a metabolic disorder characterized by chronic hyperglycemia, have a 2-4 increased risk for developing AD. Taken together, these observations implicate alterations in glucose metabolism in the disease progression of AD. Preliminary data suggests that a systemic increase in blood glucose levels results in a significant increase in A? production within the brain's interstitial fuid (ISF). Therefore, the goal of this proposal is to properly understand the relationship between aberrant glucose metabolism, neuronal activity, and functional connectivity as it relates to A? production and deposition in a mouse model of AD. By combining glucose clamps, to alter systemic blood glucose levels, with in vivo microdialysis, to ascertain the effects of systemic glucose modulation on the brain's neurochemistry, a direct understanding of how changes in blood glucose levels affect A? production and deposition, both acutely and chronically, can be achieved. Similarly, by monitoring neuronal activity via EEG recordings and functional connectivity via functional connectivity optical instrinsic signaling imaging (fcOIS), a better understanding of how increases in blood glucose levels and ISF A? affect these variables will be attained. Lastly, this proposal also seeks to identify the underlying mechanisms that cause alterations in blood glucose levels to result in increased A? levels. Thus, this proposal will help elucidate the role of glucose metabolism in AD pathogenesis as well as the link between AD and diabetes.
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