In the past, there has been a great deal of focus on stopping the initial production of amyloid beta (A-beta) proteins that form plaque in the brains of patients with Alzheimer's disease. Now a research team led by investigators from Florida's Mayo Clinic campus have shown that drug-like compounds can be used to speed up the destruction of A-beta proteins. Specifically, they found that two chemicals - dubbed "Ia1" and "Ia2" - were able to speed up the activity of insulin-degrading enzyme (IDE), essentially helping "chew up" A-beta proteins produced in the brain.

"Historically, a lot of effort has been made at stopping initial production of A-beta in order to halt development of Alzheimer's disease, but we are interested in what happens to A-beta after it is produced," says Lead Researcher Malcolm Leissring, Ph.D., from Mayo's Department of Neuroscience. "This study describes the first examples of synthetic small-molecule activators of IDE, showing that activation of this important enzyme with drug-like compounds is achievable." And he adds, "If it is possible to generate drugs for human use that stimulate the activity of IDE, these agents might offer therapeutic benefit for treating and preventing Alzheimer's disease."

Dr. Leissring explains that while scientists understand that A-beta is produced when the larger amyloid precursor protein (APP) is cut into smaller pieces by beta-secretase and gamma-secretase enzymes, not much is known about what happens to A-beta after it is produced. What is known, he says, is that "A-beta proteins, especially those of a certain length, are found sticking to each other in clumps of plaque in the brains of patients with Alzheimer's disease." As a result, drug manufacturers have tried to inhibit beta-secretase and gamma-secretase from cutting APP into the smaller pieces. Their efforts have stemmed from the belief that plaques can't form if A-beta isn't produced. However, to date, this and other approaches have not yet resulted in clearly beneficial therapies. By focusing on what ultimately happens to A-beta produced normally, Dr. Leissring says that they have found that "more than 99 percent of all A-beta is destroyed immediately. The story that is emerging now is that the level of activity of A-beta degrading enzymes may play a significant role in the development of Alzheimer's disease. We are actively pursuing the next chapter," he says.

News Release: Researchers find agents that speed up destruction of proteins linked to Alzheimer's disease  www.newswise.com  April 21, 2009