Edward H. Koo, M.D.
University of California at San Diego
La Jolla, California

2003 Investigator-Initiated Research Grant

Beta-amyloid, the protein fragment that is the prime suspect in Alzheimer’s disease, is clipped off a longer protein called amyloid precursor protein (APP) that extends through a cell’s outer membrane like a clove stuck through the skin of an orange. Beta-amyloid fragments remain outside the cell, where they aggregate into the plaques that are a hallmark Alzheimer pathology. Researchers have only recently begun to investigate the portion of APP that remains inside the cell and whether it also plays a role in Alzheimer’s disease. This other protein fragment, termed the APP intracellular domain (AICD), appears to travel from the outer membrane toward the center of the cell. Many researchers believe that the AICD may play a key role in “activating” certain genes so the cell begins producing the proteins whose blueprint they encode. But it is not yet known which genes the AICD might activate or whether the proteins they produce might contribute to Alzheimer pathology.

Edward H. Koo, MD, and his colleagues are teaming up with the company Genpathway, Inc., to identify the genes and proteins that interact with AICD. In some cases, this will involve following up on previously identified suspects. In other cases, Koo and his team will use a variety of molecular biology techniques, along with Genpathway’s proprietary technology, to identify new genes and proteins that interact with AICD. Identifying the most promising gene-protein pathways in this pilot project will open the door to future studies examining the role that AICD might play in Alzheimer’s disease. Understanding these pathways may reveal previously unidentified molecular sequences that may offer promising new therapeutic targets.