2004 Investigator-Initiated Research Grant

Beta-amyloid is a protein fragment that may damage cell-to-cell communication and induce the loss of brain cells in Alzheimer’s disease. Beta-amyloid is clipped from its parent molecule in a two-stage process. The second cut is made by gamma-secretase, a team of at least four proteins.

One strategy to block the production of beta-amyloid is to inhibit gamma-secretase activity. A potential problem with this strategy is that gamma-secretase has other functions in the cell, including the processing of a protein called Notch, which is involved in essential cellular tasks.

Alain Israel, Ph.D., and colleagues are searching for additional proteins that might be directly involved in gamma-secretase activity or somehow regulate that activity. If one such protein’s function is limited primarily to beta-amyloid production, then it would be a good target for a new gamma-secretase inhibitor less likely to cause unwanted side effects.

The investigators will use a complex research method to match up a gene (which is a “blueprint” for a particular protein) with its corresponding protein’s function. Through a number of stages, they will genetically modify cells to create a nearly “clean slate” of gamma-secretase function and then reintroduce genes to determine which ones restore the missing functions.

This process may single out proteins involved in beta-amyloid production but not all gamma-secretase activity. The work could suggest ideal targets for developing safe and effective disease-modifying therapies.