Journal of Federation of American Societies for Experimental Biology
March 7, 2011
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Fisher Scientists Discover New Ways to Rid Cells of Alzheimer Protein
Identifying a cure for Alzheimer’s disease remains a major challenge. Few drugs are currently approved by the U.S. Food and Drug Administration to treat Alzheimer’s patients. Unfortunately none of these drugs halt progression of the disease and their impact on cognitive defects is minimal. On top of that, current strategies to reduce beta-amyloid, plaque forming proteins found in the brain of Alzheimer’s patients, are associated with severe side effects. This limitation was highlighted recently by the failures of various clinical trials.
Two current discoveries by researchers at the Fisher Center for Alzheimer’s Research laboratory under the direction of Nobel laureate Dr. Paul Greengard have now made it possible to prevent accumulation of beta-amyloid in nerve cells and in the brain. One involves inhibiting the formation of beta-amyloid. The second discovery involves stimulating the breakdown of beta-amyloid. According to Dr. Greengard, “the combination of inhibition of formation and acceleration of breakdown of beta-amyloid represents a new and powerful strategy for treating Alzheimer’s disease.”
In the first project, Dr. Greengard and researchers in his laboratory identified gamma-secretase activating protein (gSAP), and showed that it stimulates an enzyme called gamma-secretase that is responsible for producing beta-amyloid. This discovery was published in the September 2 issue of the journal Nature. The process of inhibiting gSAP did not prove toxic to the cells in models of Alzheimer’s disease, 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.
In the more recent study, published in the March 7, 2011 issue of the Journal of Federation of American Societies for Experimental Biology (FASEB), they succeeded in accelerating the breakdown of beta-amyloid. They discovered that a process called autophagy reduces the buildup of beta-amyloid in isolated cells and might be utilized to eliminate the buildup of beta-amyloid in the brains of Alzheimer’s patients. Autophagy is a process cells use to “clean out” the debris from their interiors, including unwanted materials such as the protein aggregates that are hallmarks of Alzheimer’s disease. The scientists discovered that a compound called SMER28 lowers the level of beta-amyloid found in nerve cells. This occurs because SMER28 stimulates autophagy, which then rids the cell of beta-amyloid.
“Our work demonstrates that small molecules can be developed as therapies, by activating autophagy, to prevent Alzheimer’s disease,” says Marc Flajolet, a research assistant professor in Greengard’s lab. “By increasing our understanding of autophagy, it may be possible to stimulate it, pharmacologically or naturally, to improve the quality of life for aging people.”