gSAP: A Key Protein in Plaque Formation

By: www.ALZinfo.org

Dr. Gen He and Dr. Paul Greengard of the Fisher Center for Alzheimer’s Research laboratory have discovered a protein that stimulates the production of beta-amyloid, the toxic protein that is linked to the development of plaques in the brain that are typically associated with Alzheimer’s disease. This important discovery has the potential to guide the development of highly effective and safe drugs that could treat the underlying cause of Alzheimer’s, and thus stop or slow the disease’s progression.

Their findings were published in the September 2, 2010 edition of the journal Nature.

Dr. He and Dr. Greengard have identified gamma secretase activating protein (gSAP), and showed that it stimulates an enzyme called gamma secretase that is responsible for producing beta-amyloid. The researchers also discovered that the anti-cancer drug, Gleevec, binds to gSAP, preventing it from activating gamma secretase. Fisher Center researchers had previously discovered that Gleevec lowers levels of beta-amyloid in the brain by blocking the activity of gamma secretase, but they did not know how Gleevec did this or whether it was affecting gamma secretase directly or indirectly, through another protein. “I was researching the mechanism of Gleevec’s effect of lowering amyloid,” says Dr. He. “My preliminary results indicated that Gleevec works by indirectly inhibiting gamma secretase. Therefore, I started to search for a specific protein that is targeted by Gleevec and regulates gamma secretase activity. This is how gSAP was found.”

Dr. Paul Greengard

Just as importantly, the process of inhibiting gSAP did not prove toxic to nerve cells or other body cells, a factor that has plagued many other experimental treatments that inhibit beta-amyloid. This discovery therefore opens a new door for research into highly specific anti-amyloid drugs that do not harm the body. That’s what Dr. He and his team are engaged in now. “We are working on selecting more potent drug-like compounds that selectively target gSAP and reduce plaques in experimental animal models; hopefully this will provide new treatments for Alzheimer’s,” Dr. He says.

“Millions of people suffer from Alzheimer’s disease, and treatment options are limited,” says Dr. Paul Greengard, Nobel Laureate and director of the Fisher Center for Alzheimer’s Research laboratory at The Rockefeller University. “Existing drugs may mask symptoms for a time but do nothing to stop the relentless downward progression of Alzheimer’s. What is needed are safe and effective medications that will halt the cause of the underlying disease. It is our hope that this gamma secretase activating protein will greatly add to the creation of safe and effective Alzheimer’s treatments.”

Kent Karosen, President and CEO of the Fisher Center for Alzheimer’s Research Foundation says, “We are so proud of the scientists we support, and would like to
specifically congratulate Drs. He and Greengard for discovering this important protein. Their latest research is a potential paradigm shift in how scientists and doctors around the world will attack Alzheimer’s.”

For more information, visit Dr. Greengard’s profile.

Source: www.ALZinfo.org. Preserving Your Memory: The Magazine of Health and Hope; Fall 2010.