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2007 Grant - Wiley
APP Binding-Partner Modulation of Gamma-Secretase-Mediated Proteolysis
Jesse Wiley, Ph.D.
University of Washington
2007 New Investigator Research Grant
The beta-amyloid protein fragment, a key suspect in Alzheimer's disease, is cut from the much larger amyloid precursor protein (APP). APP is a transmembrane protein, which means portions of it exist both inside and outside a cell. The portion of APP that resides inside a brain cell binds to a number of other proteins. These protein partners compete with one another for a small group of overlapping APP regions with which to bind. Previous research suggests that beta-amyloid production might be dependent on the binding of certain protein partners with APP.
Jesse Wiley, Ph.D., and colleagues propose to study how these APP-binding proteins affect APP cleavage, especially the cleavage that produces beta-amyloid. Using mice genetically engineered to produce an Alzheimer-like pathology, the research team will test the effects of overexpressing or eliminating various protein partners of APP. Dr. Wiley's group hopes to isolate the specific protein or proteins that stimulate the production of beta-amyloid. They also hope to identify protein-induced APP cleavage that may prevent amyloid production.
The results of this study could shed new light on how APP-binding proteins either promote or inhibit the progression of Alzheimer's disease. Such results could suggest new strategies for disease-modifying therapies.