From The Quarterly, Fall 2010

Dr. Paul Greengard, member of the NARSAD Scientific Council, 2000 Nobel Prize winner, and NARSAD Lieber Prize winner, discovered a new protein that when blocked, can slow or prevent the development of the telltale plaque that builds up in the brains of people with Alzheimer’s. The neuroscience research community buzzed with excitement in early September when the team, led by Dr. Greengard, published results of a new study with these findings. Dr. Greengard’s Alzheimer’s research is part of an explosion

of studies into causes and treatments of the disease.



It has long been known that sheet-like beta amyloid proteins form plaques in the brain. The theory being worked on for treatment of Alzheimer’s has been to reduce beta amyloid protein levels in the brain. This, it is hypothesized, could slow the development of the plaques, thus slowing onset of the disease or even halting or preventing it in the first place.



Dr. Greengard showed in 2003 that the widely used anti-cancer drug Gleevec (imatinib) could be used to inhibit beta amyloid formation. However, any drug interfering with the process must not disrupt other essential functions in the process — its anti-plaque action needs to be highly localized and plaque-specific.



In the newly published work, Dr. Greengard and colleagues at Rockefeller University have discovered that there is an enabling protein they call GSAP, or gamma secretase activating protein, which plays a precursor role in the plaques-generating action of beta amyloid proteins. Gamma secretase belongs to a family of proteins called proteases that chop proteins into smaller molecules. But often proteases are not very specific. They can attack many different proteins. If this protein can be successfully targeted, it is believed that it will be an ideal beta amyloid inhibitor, highly specific in its effect by reducing or stopping the development of amyloid plaques without disrupting other essential brain functions. Greengard’s study shows that by knocking out the gene that produces GSAP, beta amyloid levels and plaque development in mice that model human Alzheimer’s can be reduced.



New work will now focus on developing an inhibitor of GSAP — and the search is already under-way, Dr. Greengard is happy to acknowledge.