Project DetailsThe long term objective of the study is to investigate the effect of aging and gender on the function of gamma-secretase, a complex of proteins involved in the generation of toxic amyloid beta. Aberrant gamma-secretase activity is associated with Alzheimer's disease (AD). The vast majority of AD is sporadic in nature and has no known genetic basis. Aging and gender are common risk factors for the development of AD. How aging and gender affect gamma-secretase is poorly understood. The objective of the study is to uncover the mechanism of aging and gender in the regulation of gamma-secretase activity and specificity. Therefore, we will investigate the relationship between aging and gamma-secretase. The first aim will examine the effect of aging and gender on the dynamics of gamma-secretase complexes using an integrated approach of enzymology and chemical biology. The second aim will determine the effect of aging and gender on changes of the active site within the gamma-secretase complex using a multiple photo-affinity probe" approach. The proposed studies will provide insights into the role of altered gamma-secretase activity during aging and in the development of sporadic AD and in neurodegeneration. These studies will provide a foundation for investigating the mechanism of human aging and gender in the most common forms of AD and facilitate the development of effective AD therapies."