2004 New Investigator Research Grant

Beta-amyloid, a tiny protein fragment and key suspect in Alzheimer’s disease, is clipped from a molecule called amyloid precursor protein (APP). A large effort in Alzheimer research aims to understand normal functions of APP and disease-related functions other than that of beta-amyloid.

APP is a transmembrane protein, which means portions of it exist both inside and outside a cell. Beta-amyloid is clipped from APP at one site outside the cell and at another site within the membrane surrounding the cell. Veronica Galvan, Ph.D., and colleagues are investigating what happens to the piece of APP inside the cell. In previous studies they observed that enzymes clip off a tiny portion that may play an important role in certain molecular events inside nerve cells.

The researchers have studied genetically altered mice that have the human APP gene and that develop an Alzheimer-like brain disease. The investigators tweaked the gene slightly, so that the clipping of APP within the cell does not occur. They found that in the absence of this clipping, the mice still develop beta-amyloid accumulations, but the brains do not shrink and the cell-to-cell communication network does not appear to break down.

In the current work, the researchers are extending the study with mice to determine whether the lack of intracellular clipping of APP translates into normal memory and learning skills or into Alzheimer-like deficits. The outcome may help researchers clarify the role of both APP and beta-amyloid in Alzheimer’s disease, understand the cause of memory and learning deficits, and identify new therapeutic strategies.