2004 Zenith Fellows Award

The beta-amyloid protein fragment may be a key factor in damaging cell-to-cell communication and causing the loss of brain cells in Alzheimer’s disease. Beta-amyloid is clipped from its parent molecule in a two-step process. The second step is done by a complex of proteins called gamma-secretase.

Gamma-secretase belongs to a relatively small class of protein-clipping “machines” that do their jobs within the cell membrane, rather than inside or outside the cell. Much research is devoted to understanding what proteins make up this complex, how they work together to produce beta-amyloid and what other cellular activity occurs as a result of gamma-secretase clipping.

Yeuming Li, Ph.D., and colleagues developed an experimental system that has enabled them to remove gamma-secretase from its normal cellular environment. This process has enhanced their ability to conduct biochemical analysis of the complex. In the current study, they will be examining in detail how gamma-secretase functions: how does it recognize its target, what is the role of each protein in the complex, what is the “step-by-step” process carried out by gamma-secretase? The answers to these questions may direct the development of drug therapies that specifically inhibit gamma-secretase activity associated with Alzheimer’s disease.