Project DetailsType II diabetes and insulin resistance are strong risk factors for developing Alzheimer's disease (AD). However, the underlying mechanism is not clear. Our laboratory studies a lipid receptor called LRP1 that plays critical roles in clearing toxic amyloid peptides that build up in AD brains. We have recently found that LRP1 regulates insulin signaling, thereby providing a potential link between AD and diabetes. We intend to study the molecular mechanisms that govern the reciprocal regulation of LRP1 and insulin signaling. Once our study is complete, we predict that we will not only solve the molecular puzzle of AD and diabetes but will also identify novel targets for AD diagnosis and therapy. Our work should also pave the way for future studies aimed at further defining the risk of AD in diabetes patients and address how we can treat patients with diabetes to reduce their risk of developing AD. We will use both cellular and animal models to study how modulation of LRP1 or insulin signaling affects AD pathogenesis. In Aim 1, we will study the molecular mechanism by which lipid receptor LRP1 regulates insulin signaling. In Aim 2, we will examine how LRP1 and insulin signaling affect the metabolism and toxicity of Alzheimer's amyloid beta peptide. Our research will uniquely address how type II diabetes links to AD and help to identify novel targets for AD prevention and therapy. Our experience, expertise and state-of-the-art technology used in this research should ensure the success of our project. These innovative concepts and methodologies place us in a unique position to carry out this exciting project.