2004 New Investigator Research Grant

Beta-amyloid is a protein fragment that may be a key factor in damaging cells in Alzheimer’s disease. Beta-amyloid is clipped from its parent molecule in two stages. The first cut is made by a protein called beta-secretase, and the second by a cluster of proteins called gamma-secretase.

Previous research suggests that tiny compartments inside the cells, called endosomes and lysosomes, may be the actual “manufacturing sites” of beta-amyloid. The possible role of endosomes and lysosomes has not been thoroughly characterized, however, primarily because they are difficult to study in isolation from other cellular elements.

Stephen Pasternak, M.D., C.M., Ph.D., and colleagues are adopting new technologies to investigate these cellular elements. In preliminary work with lysosomes from rat liver cells, the researchers found all the necessary biochemical machinery for beta-amyloid production. They also found evidence that other proteins may reside in these compartments and contribute to the process.

In this study, the investigators will examine endosomes and lysosomes extracted from cultured human brain cells, as well as from brain cells of normal mice and genetically altered mice that develop an Alzheimer-like disorder. They will assess beta-secretase and gamma-secretase activity in these compartments, determine the amount of beta-amyloid produced, and search for other resident proteins that may be involved in the process. The outcome of this work may clarify details of beta-amyloid production and suggest new targets for drug development.