Yong Shen, M.D., Ph.D.
Sun Health Research Institute
Sun City, Arizona

2003 Investigator-Initiated Research Grant

Many experts believe that abnormal processing of amyloid precursor protein (APP) to produce the protein fragment beta-amyloid is the single most important pathological event in Alzheimer’s disease. Beta-amyloid is produced from APP by the action of two separate enzymes: beta-secretase, which makes the first cut, and gamma-secretase, which makes the second. Both enzymes have attracted strong interest as potential therapeutic targets because blocking the activity of either one would stop beta-amyloid production. Developing effective blocking strategies will require more detailed understanding of exactly how these enzymes function.

In previous work, this research team observed that levels of beta-secretase are elevated in Alzheimer brain tissue. In this project, the team aims to further explore the activity of beta-secretase, which is a protein, to learn at exactly what point the elevation occurs. One possibility is that excess amounts of the template for beta-secretase construction, called messenger RNA, are produced from the DNA that codes the beta-secretase “blueprint.” Another possibility is that normal amounts of the messenger RNA template are produced, but excess amounts of beta-secretase are generated when the messenger RNA template is “translated” into the actual protein. Understanding exactly where the excess beta-secretase production occurs may suggest attractive points of intervention to stop production of beta-amyloid.