Molecular Basis of PIB in the AD Brain: Inducing the AD Phenotype in Neuronal Culture and TgAPP/PS1

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, currently affecting more than five million people in the U.S.A. The vast majority of AD cases are sporadic, with no clear etiology. An unexplained connection exists between risk for Alzheimer's disease (AD), vascular dementia and the occurence of type 2 Diabetes Mellitus (T2DM), a metabolic disease tightly linked to obesity. This proposal considers a novel possibility: that the connection may be through the development of resistance to the adipokine leptin. Leptin is an ad i pocyte-de rived peptide hormone that regulates satiety and hunger via signaling through the leptin receptor, which is expressed throughout the brain. The progressive fibrillization and deposition of the amyloid-P peptide (AP) is widely believed to be the primary causal factor in the development of AD, and leptin negatively regulates AP production. However, T2DM and obese patients have high levels of leptin, yet still have elevated AP levels. The key may lie in the fact that these individuals are leptin resistant, and insensitive to the high levels of leptin released from their adipocytes. Our hypothesis is that it is this leptin resistance that is the biological basis of the connection between T2DM and AD. To test this hypothesis, we will first cross a mouse model of obesity related diabetes and leptin resistance with a unique mouse model of AP pathology that does not overexpress disease related proteins or use artificial promoter systems. We hypothesize that leptin resistance will accelerate the development of AP pathology in the brain, in spite of high levels of circulating leptin. We will use an innovative technique to demonstrate the specificity of this effect, by selectively reversing leptin resistance in the brain. Using this technique, we will be able to specifically separate the effects of leptin signaling on the development of AD-like pathology from the complex problems associated with systemic metabolic disease. In other words, these mice will have combined features of both diabetes and Alzheimer's Diease, but will be either able to signal through brain leptin receptors or not. If we then compare how AD related pathology develops in different groups of these mice, we will be able to definitively determine if leptin is the factor that connects AD to diabetes. We believe that we have identified the specific biological process through which leptin influences the development of AD-like pathology, the activity of the y-secretase enzyme complex. In the second part of this project, we will test this hypothesis by comparing intact and dysfunctional leptin signaling in primary neurons isolated from this same mouse model. In this way, we will determine the downstream mechanism through which leptin signaling breaks down and ultimately causes some diabetics to develop AD. Major strengths of this proposal are the use of an animal model with unique features, and our innovative ability to selectively repair the leptin pathway in the brains of these animals. This novel approach gives us an unparalleled opportunity to explore how diabetes is connected to AD, a puzzle that has resisted all prior attempts at resolution, and will lay the foundation for the development of novel therapeutics.