September 27, 2003
The laboratories of the Fisher Center for Alzheimer's Research at The Rockefeller University in New York City report that a novel cancer drug hailed in recent years for its ability to halt a deadly form of leukemia and stomach cancer may offer new hope for those afflicted with the mind-robbing ravages of Alzheimer's disease. The new study, carried out by researchers at the Fisher Center, will be published in the September 29 issue of the Proceedings of the National Academy of Sciences.
The drug, called Gleevec, was shown to lower production of a toxic substance called beta-amyloid that is thought to underlie the development of Alzheimer's disease. Beta-amyloid builds up in the brains of those with the disease, forming sticky patches called plaque and killing off healthy cells. In recent years, scientists and pharmaceutical companies have been searching avidly for medicines that will stem the production of this poison in the hopes of offering new ways to treat, prevent and potentially even reverse the brain ailment.
Paul Greengard, Ph.D., 2000 Nobel Laureate in Physiology or Medicine and Director of the Fisher Center for Alzheimer's Research at The Rockefeller University, along with other members of his laboratory at the Fisher Center previously have unraveled the roles of various cellular factors that affect beta-amyloid production. They were also the first to show that estrogen and testosterone have beta-amyloid lowering effects on cells.
"We are very excited by this discovery, because it provides a novel approach to the development of new therapies for Alzheimer's disease," says Dr. Greengard, one of the study's authors. "It reveals a previously unknown mechanism by which the toxic substance beta-amyloid is controlled, and opens up a new area of research for developing drugs for the treatment of Alzheimer's."
Currently available Alzheimer's drugs do not target beta-amyloid and offer only modest benefits, at best, for those in the early stages of mental decline. Finding a drug that safely and effectively diminishes the damaging effects of this brain toxin would be a major advance against a disease that affects five million Americans today. Unless a cure is found, Alzheimer's is expected to strike up to three times that many in the coming decades as the baby boomers age.
In the current study, researchers at the Fisher Center and at Memorial Sloan-Kettering Cancer Center demonstrated that Gleevec and a similar compound called inhibitor 2 dramatically diminished the production of beta-amyloid in rat brain cell cultures and in cells containing defective genes that lead to an inherited form of Alzheimer's at an early age.
They also showed that both compounds lowered levels of beta-amyloid that accumulate in the brains of live adult guinea pigs that produce beta-amyloid chemically identical to that made by people. Gleevec was dripped into their brains using a special pump attached to the spinal canal. More testing needs to be done to determine if the drug or related medicines are safe and potentially effective when delivered to the human brain.
Researchers have been trying for years to develop effective treatments against Alzheimer's disease by preventing the brain damage caused by the toxic beta-amyloid. Gleevec, which has shown stunning success against a growing variety of cancers, offers a whole new means to explore this promising therapeutic approach.
A Multi-Step Scientific Process
Scientists at the Fisher Center and other research institutes had previously shown that the brain toxin beta-amyloid is produced when a large protein called APP, or amyloid precursor protein, is chopped into smaller pieces by scissor-like proteins called beta-secretase and gamma-secretase. Drug researchers have been searching for compounds that inhibit these secretases, because blocking their activity would halt production of beta-amyloid.
Several gamma-secretase blockers, for example, have undergone early testing as potential Alzheimer's drugs. Unfortunately, while they block gamma-secretase, they also appear to block another protein called Notch-1 that is essential for proper functioning of the nervous and immune systems.
Gleevec also blocks the activities of gamma-secretase but, as Fisher Center researchers have now shown, it does not inhibit Notch-1. Therefore, Gleevec or related compounds hold great promise as a potentially safer Alzheimer's treatment. Indeed, in cancer patients, Gleevec has been remarkably free of serious side effects.
Quickening Pace of Alzheimer's Research
"One of the reasons Gleevec differs from other gamma-secretase inhibitors is that it probably does not inhibit gamma-secretase directly," says William Netzer, Ph.D., lead author of the current study. "Rather, it seems to affect another protein or proteins that regulate gamma-secretase."
Dr. Greengard and other Fisher Center scientists had previously shown that a substance called ATP, which fuels the energy requiring processes in all living cells, was essential for cells to make beta-amyloid. Gleevec is thought to compete with ATP for binding to proteins that regulate beta-amyloid production, thereby blocking the production of beta-amyloid in the brain.
The amazing thing about Gleevec, according to Dr. Netzer, is that the drug does not affect most of the hundreds of uses cells have for ATP throughout the body. Although we don't yet know all of the targets of Gleevec, it does bind to ATP targets that play a role in certain kinds of cancer and, it now turns out, Alzheimer's disease as well.
"It is somewhat surprising that the way Gleevec binds to prevent certain cancers is similar to the way it affects Alzheimer's disease," says Dr. Greengard. "We don't yet know exactly what the target is."
Gleevec itself will likely not be clinically useful as an Alzheimer's treatment, in part because in pill form it does not effectively penetrate the brain, where its benefits are needed. It might be possible to chemically change Gleevec or a related drug, so that it does penetrate the brain. Also, by unraveling the novel ways in which Gleevec targets beta-amyloid, it should be possible to develop medicines that safely enter the brain and have similar or better beta-amyloid lowering effects.
"The next step will be to determine the exact details by which Gleevec produces this beneficial effect," says Dr. Greengard.
Gleevec, which goes by the generic names imatinib mesylate, took years before its use as a cancer treatment was secured. Scientists are hopeful that, with continuing advances in drug research and testing, they can engineer related compounds even faster. Still, it will likely be years before a drug is proven safe and effective in people.
Even so, researchers are one exciting step closer to finding a much-needed cure for Alzheimer's disease.
By Toby Bilanow, Medical Writer, for www.ALZinfo.org. The Alzheimer’s Information Site. Reviewed by scientists at the Fisher Center for Research on Alzheimer's Disease at The Rockefeller University.