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

2004 Investigator-Initiated Research Grant

A tiny protein fragment called beta-amyloid is a key suspect in Alzheimer’s disease. It is clipped from a parent molecule called the amyloid precursor protein (APP). Scientists have learned much about how beta-amyloid is produced and forms abnormal structures in the brain, but there is no definitive explanation for how it may contribute to a breakdown in cell-to-cell communication and cell death.

APP is a transmembrane protein; part of it resides inside the cell and part of it outside. Beta-amyloid is clipped from the part on the outside. A growing body of evidence suggests that the inside portion may have multiple normal functions, such as transporting molecular cargo or passing along messages inside the cell. It may also play some role in Alzheimer’s disease.

Edward Koo, M.D., and colleagues are investigating how APP may participate in a series of events that trigger a cell to self-destruct. Using cell cultures, the investigators have observed that APP molecules form pairs, that beta-amyloid appears to accelerate these pairings, and that these phenomena are associated with a susceptibility to cell death. In this study the researchers will test their hypothesis about how these APP partners interact with other molecules inside the cell to induce cell dysfunction and death.

Clarification about APP’s possible role in Alzheimer pathology may help answer long-standing, fundamental questions about the disease and suggest new therapeutic strategies.