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.
According to the Alzheimer's Association, 1 in 8 Americans over the age of 65 has Alzheimer's disease (AD), nearly 1 in 2 has AD by the age of 85, and AD accounts for an estimated $183 billion in health care costs in 2011 to Americans. Similarly, diabetes is metabolic disorder that affects approximately 346 million people worldwide with an estimated 3.4 million dying from diabetes in 2004 alone. Given that patients suffering from diabetes have a 2-4 fold increased risk for developing AD, additional research is necessary to increase our understanding of the mechanistic link between diabetes and AD. Therefore, the goal of our research is to determine how changes in glucose metabolism affect neuronal activity, amyloid-beta (A?) production, plaque formation, and functional connectivity in a mouse model of AD.
| Macauley, Shannon L (2016) Combination Therapies for Lysosomal Storage Diseases: A Complex Answer to a Simple Problem. Pediatr Endocrinol Rev 13 Suppl 1:639-48 |
| Harris, Richard A; Tindale, Lauren; Lone, Asad et al. (2016) Aerobic Glycolysis in the Frontal Cortex Correlates with Memory Performance in Wild-Type Mice But Not the APP/PS1 Mouse Model of Cerebral Amyloidosis. J Neurosci 36:1871-8 |
| Stanley, Molly; Macauley, Shannon L; Caesar, Emily E et al. (2016) The Effects of Peripheral and Central High Insulin on Brain Insulin Signaling and Amyloid-? in Young and Old APP/PS1 Mice. J Neurosci 36:11704-11715 |
| Stanley, Molly; Macauley, Shannon L; Holtzman, David M (2016) Changes in insulin and insulin signaling in Alzheimer's disease: cause or consequence? J Exp Med 213:1375-85 |
| Macauley, Shannon L; Stanley, Molly; Caesar, Emily E et al. (2015) Hyperglycemia modulates extracellular amyloid-? concentrations and neuronal activity in vivo. J Clin Invest 125:2463-7 |
