Alzheimer's disease affects four million people in the US, a number that is expected to triple in the next fifty years. Understanding the basic mechanisms that lead to AD is essential for the development of effective treatments. The goal of this research is to determine the consequences of X11 alpha interaction with APP on its trafficking and processing. We hypothesize that X11 alpha binding to the carboxy terminus of APP reduces Abeta secretion by blocking APP endocytosis and gamma secretase mediated cleavage and that lin2 binding to the amino terminal domain of X11 alpha will abrogate this effect on APP in transfected cells. We will determine if X11 alpha alters Abeta production by impairing endocytosis of APP. Using single missense mutations in the YENPTY internalization sequence of APP, we will examine whether endocytosis can be dissected away from X11 alpha mediated effects on APP processing. Second we will determine if X11 alpha interaction with APP inhibits presenilin1/gamma-secretase mediated increases in Abeta 42 generation. Third, we will determine if binding of lin2/CASK to the amino terminus of X11 alpha will block the ability of X11 alpha to interact with APP and alter its processing.
