Association Among the Secretases: Model of APP Cleavage
MentorDennis J. C Selkoe, M.D. Brigham and Women's Hospital
The goal of this proposal is to validate and confirm a functional complex of alpha (and also beta)-secretase with gamma-secretase. The hypothesis is that alpha- and gamma-secretase associate together in a larger complex that is able to accept full-length substrates and process them rapidly and sequentially. I will rigorously and meticulously characterize this complex both structurally and functionally.
A number of related secretase proteins cut the amyloid precursor protein (APP) at different locations to create many smaller pieces. One of these smaller pieces is the toxic beta-amyloid peptide, which plays an important role in the development of Alzheimer's disease. Because of this, the secretases have become ideal targets for the treatment of Alzheimer's disease; however, more needs to be known about the secretases and how they work before scientists can create new treatments for Alzheimer's disease. The current theory is that the various secretases work in isolation to cut the APP protein and produce the beta-amyloid peptide. Dr. Allen Chen and collaborators propose that the action of the secretases are more interconnected and suggest that a number of secretases physically associate with each other to rapidly and sequentially cut APP. These researchers will test whether alpha- and beta-secretase associate with gamma-secretase and determine whether they work together to process APP. These studies could establish a new biological model of APP processing and may help to guide the development of safer and more effective treatments for Alzheimer's disease.