Effects of aging and gender on gamma-secretase

Progress Updates

More than 90% of all Alzheimer's disease (AD) cases happen spontaneously and are of unknown origin (often called sporadic). Aging and gender are common risk factors for the development of AD. The study of rare forms of autosomal-dominant early onset Familial Alzheimer’s Disease (FAD) helps to discover the underlying molecular mechanisms of AD. FAD mutations have been linked to three genes: APP, presenilin 1 (PS1) and presenilin 2 (PS2). Growing evidence suggests that these FAD mutations affect gamma-secretase and the production of toxic beta-amyloid peptides. Dr. Yueming Li’s team will investigate whether risk factors and genetic mutations exhibit a similar effect on gamma-secretase protein.

How aging and gender influence the structure and function of the gamma-secretase protein has been elusive due to its characteristics of embedding in cell membranes, its chemistry, and a lack of high resolution structure of the bundle of proteins that associate with the gamma-secretase complex. Dr. Li’s team has developed a method called "photophore walking" to investigate how the shape of the active site of gamma-secretase is changed by aging and gender. They first validated this practical approach by investigating the effect of PS1 protein mutations on the structure and function of gamma-secretase in mice with early-onset Alzheimer’s disease. They have shown that both aging (from 4- to 32-month old mice) and gender have an effect on gamma-secretase activity and specificity, which is reminiscent of FAD gene mutations. These studies provide a model system for the study of the effect of aging and gender on the structure and function of gamma-secretase and offer a molecular basis of sporadic AD pathogenesis as well as facilitate the development of effective AD therapies.