2004 Zenith Fellows Award

A prime suspect in Alzheimer’s disease is beta-amyloid, a tiny protein fragment that tends to clump together in the brain. Some form of beta-amyloid accumulation may have a toxic effect that causes the breakdown of cell-to-cell communication and the loss of cells.

Beta-amyloid is clipped from its parent molecule in a two-stage process. The second cut is made by a cluster of proteins called gamma-secretase. One potential therapeutic strategy for slowing or stopping disease processes in Alzheimer’s disease is to block the activity of gamma-secretase.

Philip Wong, Ph.D., and his colleagues have designed a set of studies with mice to determine to what extent beta-amyloid production can be slowed or stopped and to what extent the brain can repair itself and restore damaged cells to normal activity. The mice, which are genetically engineered to carry two human Alzheimer-causing genes, serve as models of Alzheimer’s disease processes.

In a series of tests, the investigators will inhibit the activity of the gamma-secretase complex by targeting one of its proteins at a time. Using a specially designed genetic “switch,” they will shut off production of a protein and assess the subsequent outcome in beta-amyloid production, as well as the repair of damaged cells and communication networks in the brain. The findings may provide a clearer picture of the biological outcomes of gamma-secretase inhibition and enhance the development of safe and effective anti-amyloid treatments.