A new target for Alzheimer's emerges: Exciting discovery generates a new path for treatments

A search of ClinicalTrials.gov reveals 712 ongoing clinical trials to treat Alzheimers disease with drugs. 346 of them are in Phase 2 or Phase 3 clinical trials, meaning they have advanced past the initial safety testing in people, and are now in trials to examine their effect on memory and cognitive thinking in Alzheimer’s patients. This adds up to billions and billions of dollars now being spend each year on the tiny hope that one of these drugs may be able to slow down the irreversible dementia that characterizes this horrific disease. A clear and consistent component of this disease is the abnormal accumulation of amyloid-β protein in the brain. The excessive accumulation of this abnormal protein interferes with normal neuronal transmission and precipitates brain neuronal cell death leading to dementia and ultimately death. Decades of research have revealed that amyloid-β is produced by the cleavage of a very large protein found throughout the body called amyloid precursor protein, or APP, by an enzyme called gamma secretase. An obvious ‘target’ for pharmaceutical intervention would be the development of gamma secretase inhibitors: No more cleavage of APP by gamma secretase to form amyloid-β would prevent this abnormal accumulation in the brain. This is a relatively easy goal for a pharmaceutical company. They are experts at developing small molecule inhibitors of enzymes that can be made into pills and taken every day to stop the cleavage of proteins into pathologic products. Aspirin, or acetylsalicylic acid, for example, is an inhibitor of cylooxygenase, the enzyme that causes the formation of prostaglandins that cause pain, inflammation and fever. But cyclooxygenase is also responsible for some important activities that should not be inhibited, including protection of the gastric mucosa, so constant inhibition of cylooxygenase results in side effects including gastric ulcers. Similarly, gamma-secretase in important in cleavage of notch proteins, which are imperative for normal cell-cell communication, immune system (T cell) formation and other physiologic functions which should not be altered by gamma-secretase inhibitors. Despite this understanding, the unmet medical need for treatments of Alzheimer’s disease has led pharmaceutical companies to develop gamma-secretase inhibitors. The latest, extremely disappointing news in the fight against Alzheimer’s is that last month Lilly terminated it’s Phase 3 gamma-secretase inhibitor trial because the signs of Alzheimer’s disease in the treated patients actually progressed more quickly than the placebo treated patients. What a disappointment! And what a way to underline how little we know about the interaction of the various pathways in the brain. It is possible that the drug by Lilly affected another protein (a so called “off target effect”) or it inhibited an essential function of gamma-secretase unrelated to the cleavage of APP to amyloid-β.

So on to the new discovery which may make it unnecessary to directly inhibit gamma-secretase. 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 (1). The paper described some careful work to show that GSAP interacts with both the enzyme gamma-secretase and it’s substrate APP. So, 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 by gamma-secretase, but addition of GSAP tremendously increased the cleavage of APP by gamma-secretase to form amyloid-β. Most of the results are in in vitro systems meaning they only involve cells in tissue culture plates, but they did use a mouse model of Alzheimer’s disease and genetically alter the mice to have a greatly reduced production of GSAP. Examination of the brains of these mice demonstrated markedly less amyloid-β plaques leading one to speculate that inhibition of GSAP activity, or reduction of the levels of protein, would prevent further formation of amyloid plaques in Alzheimer’s patients.

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-β formation by an unknown mechanism. Gleevec is a small molecule tyrosine kinase inhibitor that blocks the abnormally constitutively active tyrosine kinase, Bcr-Abl found in some leukemias thereby causing apoptosis of the leukemia cell. The observed, but not understood, in vitro inhibition of amyloid-β formation by Gleevec was discovered by Dr. Greengard’s laboratory to be due to a specific interaction of Gleevec with GSAP, preventing GSAP’s interaction with both the enzyme gamma-secretase and it’s substrate APP. It does not affect the other activities of gamma-secretase, namely cleavage of notch. Unfortunately, Gleevec does not cross the blood brain barrier and so cannot be used as a therapeutic for Alzheimer’s disease. By rational drug design, it should be quite possible to take Gleevec as a starting compound and alter it’s composition to enable it to cross the blood brain barrier. An increase in specificity will also be achievable, as Gleevec was designed in the late 1990’s when much less was known about tyrosine kinases and their inhibitors.

The disappointing trial results by Lilly’s gamma-secretase inhibitor has clearly put a pallor on this method of intervention in Alzheimer’s disease progression. Several other interventional trials are now ongoing based on injection of monoclonal antibodies against amyloid-β, the abnormal protein building up in the brain, with the hopes that the antibody/amyloid–β complex will be cleared by normal immune mechanisms. Meanwhile desperation has spurred trials of therapeutics with unclear mechanisms which may increase cognitive function for a certain length of time including the anti-histimine Dimebon (Pfizer), the anti-inflammatory Tarenflurbil (Myriad), the smoking cessation treatment Varenicline (Pfizer) and the neurotransmitter modulator ST101 (Sonexa Therapeutics). Now, with this new understanding of the activation of gamma-secretase by GSAP, there will undoubtedly be a push in the pharmaceutical industry to modify small molecules to develop inhibitors of GSAP that will have access to the brain. Perhaps inhibition of GSAP to prevent new amyloid-β formation in combination with an antibody approach to clear existing plaques is the best hope of slowing progression and perhaps someday even improving existing cognitive function in patients with signs of Alzheimer’s disease.

1. 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.