As readers of this blog will recall, years of research have revealed that ß-amyloid is produced by the cleavage of a very large protein found throughout the body called amyloid precursor protein, or APP, by the enzyme gamma-secretase. An obvious ‘target’ for pharmaceutical intervention would be the development of gamma-secretase inhibitors: Blocking cleavage of APP by gamma-secretase to form amyloid-ß would prevent this abnormal accumulation in the brain, and prevent ß-amyloid from exerting its presumed toxic effects on the brain. However, there have been a recent series of failures in clinical trials involving gamma-secretase inhibition for mild to moderate AD.
The Nobel Prize winning neuroscientist Paul Greengard and his laboratory at The Rockefeller University published a paper in Nature last week describing the discovery of the “gamma-secretase activating protein” or GSAP *. The paper shows that GSAP interacts with both the enzyme gamma-secretase and amyloid precursor protein (APP). From their results, they hypothesize that this protein is specific for this cleavage, and will not affect any of the other essential activities of gamma-secretase. Indeed, they show that addition of excessive GSAP or lack of GSAP had no effect on the cleavage of notch (a protein whose cleavage may have negative health effects) by gamma-secretase, but addition of GSAP tremendously increased the cleavage of APP by gamma-secretase to form amyloid-ß.
Perhaps the most exciting finding of the paper is the discovery of the mechanism of action of imatinib, or Gleevec, an approved anti-cancer drug that previously had been observed to prevent amyloid-ß formation by an unknown mechanism. It turns out Gleevec blocks GSAP. Following the recent failure of Eli Lilly’s phase III drug that inhibited gamma secretase, and the ensuing round of questions that the failure spawned about the validity of the amyloid hypothesis, this is reassuring news. It gives clarity to some possible reasons why there have been such challenges with gamma-secretase inhibition. With the discovery of this new protein, it is suggested that we might be able to turn off the harmful activities of gamma-secretase while allowing its beneficial activities to continue.
This finding points to a potential refinement of current thinking. It is clear that gamma-secretase has multiple roles, some of which are essential and others which lead to overproduction of ß-amyloid. Several clinical trials are now ongoing based on injection of monoclonal antibodies against amyloid-ß, the abnormal protein building up in the brain, with the hopes that the antibody/amyloid–ß complex will be cleared by normal immune mechanisms. Perhaps combination therapy, inhibition of GSAP to prevent new amyloid-ß formation along with an antibody approach to clear existing plaques, is the best hope of slowing progression of the disease.
* He, G., Luo, W., Li, P., et al. Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease. Nature. 467: 95-98. 2010.
Michael Rafii, M.D., Ph.D
Associate Medical Director, ADCS
This post originally appeared in Alzheimer’s Insights, an ADCS Blog.