2004 Investigator-Initiated Research Grant

Beta-amyloid, a protein fragment that is a key suspect in Alzheimer’s disease, is clipped from the amyloid precursor protein (APP). This processing of APP is not a specific feature of Alzheimer’s and may be necessary for normal APP function. A better understanding of the role of APP processing in brain cell function may help solve some mysteries about cell dysfunction and cell death in Alzheimer’s disease.

APP is a transmembrane protein, which means it resides both inside and outside the cell. Beta-amyloid and another portion are left outside the cell when APP is chopped up. The part left inside the cell is the focus of investigations by Tomasso Russo, M.D., and colleagues.

The researchers have studied how another protein called Fe65 is anchored to the inside portion of APP. Other evidence shows that Fe65 has a role in regulating gene transcription inside a cell’s nucleus. Transcription is the process by which a copy of a gene is made and then sent as a “blueprint” to a cell’s protein-making compartments outside the nucleus.

The investigators have hypothesized that APP cleavage is a kind of “send-off” for Fe65 to make its way to the nucleus. Therefore, the events that regulate APP cleavage may indirectly influence how Fe65 activates or silences certain genes. In the current study, the research team will carry out a series of experiments with cells to identify genes regulated by APP-Fe65 interaction and to analyze the possible role of these genes in Alzheimer-related cellular dysfunction. The outcome of this work may help explain complex disease processes and suggest new directions in drug development.