Effects of Hyperglycemia on Neuronal Activity, Cerebral Metabolism, and Amyloid-beta Levels

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 DESCRIPTION (provided by applicant): The goal of this K01 Mentored Career Development Award is to facilitate the transition of the individual to the role of an independent investigator y providing training and mentorship in the areas of glucose metabolism, Alzheimer's disease (AD), and type-2-diabetes (T2DM). Under the mentorship of Dr. David Holtzman, and in collaboration with Drs. Joseph Culver, Tamara Hershey, and Colin Nichols, the candidate will investigate the role of hyperglycemia on neuronal activity and functional connectivity as a function of age and pathology. Additionally, the candidate will receive extensive didactic and methodological training in the areas of small animal neuroimaging, KATP channel physiology, and AD-related research to help accomplish the goals set forth in the research application. Recent studies suggest that individuals with diabetes or those with elevated blood glucose levels have an increased risk for developing dementia or dementia due to AD; however, the mechanisms linking aberrant glucose metabolism, T2DM, and AD remain poorly understood. Our preliminary data suggests that acute increases in blood glucose levels have the ability to modulate amyloid-β (Aβ) levels in the brain, providing one explanation for the link between T2DM and AD. Yet it is unclear how age or pathology impacts the relationship between blood glucose levels, brain function, and Aβ metabolism. Moreover, our work suggests cerebral glucose metabolism is coupled with cellular excitability, neuronal activity, and Aβ metabolism via ATP-sensitive, inward rectifying potassium (KATP) channels; however, investigating whether chronic activation of KATP channels and increased cellular excitability is responsible for increased Aβ deposition warrants further study. To test the hypothesis that hyperglycemia regulates Aβ levels by KATP channel modulation and that this relationship is altered as a function of age and pathology, we will examine the following Aims: 1) Investigate the effects of hyperglycemia on neuronal activity, synaptic plasticity, and functional connectivity metabolism in a healthy brain as a function of normal aging. 2) Determine the effects of hyperglycemia on neuronal activity, network connectivity, and Aβ metabolism as a function of AD pathology using a genetic model of human APP overexpression. 3) Through the loss of KATP channel activity, we will uncouple glucose sensitivity from hyperexcitability in a mouse model of human APP overexpression and determine their effects on Aβ metabolism and neuronal activity.