New mechanism explains Alzheimer’s damage

Harvard Medical School researchers say they have found a "completely new" mechanism for explaining how Alzheimer's disease damages the brain. They say a chemical reaction, involving proteins that accumulate in Alzheimer's patients' brains, produces a bleaching agent that is toxic to cells there. The scientists think the discovery could provide a unique target for new drugs to treat Alzheimer's, which causes dementia in at least four million Americans.

The findings will be in the June 15 print edition of the peer-reviewed journal Biochemistry, which is published by the American Chemical Society (ACS), the world's largest scientific society. The paper was published on the ACS Web May 27.

Currently incurable, Alzheimer's disease is the fourth leading cause of death in Western countries. Those over 85 years of age, the fastest growing portion of the U.S. population, have a 50-50 chance of developing the disease. Upon autopsy, patients' brains are typically found to be riddled with deposits of amyloid protein plaques.

Though the amyloid plaques have long been an obvious suspect as a cause of the disease pathology, exactly how they might do it has been a mystery. "We have found that the amyloid protein…binds copper and iron and produces hydrogen peroxide (H2O2) out of oxygen when doing so. Yes, bleach," says co-author Ashley I. Bush, M.D., Ph.D., who directs the Laboratory for Oxidation Biology in Massachusetts General Hospital's Psychiatry Department, a part of Harvard Medical School.

While H2O2 has previously been detected in laboratory cell cultures exposed to synthetic amyloid, researchers thought that some reaction within dying cells produced the substance. The new study is the first indication that a substantial portion of the H2O2 is being made by the plaques themselves, adding that "previously it was not shown that amyloid could produce any new chemicals."

Bush says that copper and iron, abundant in the brain, are known to be enriched in amyloid deposits. So he expects levels of hydrogen peroxide, which can easily travel from where it is produced in the plaques, to be high in other parts of patients' brains. "This is important since H2O2 can cause brain damage, and will be a source of oxidative stress in the brain," according to Bush.

Could this be the sole cause of Alzheimer's disease? Bush's answer: "The possibility that it's the most important of the chemical events to occur is difficult to judge right now, however it's the kind of chemical event that can't be ignored. Having this protein be able to produce this obviously toxic chemical out of oxygen is a property that's clearly got direct potential to harm the brain." Conclusive answers will have to wait for results of ongoing animal studies.

In the laboratory, the researchers showed that hydrogen peroxide production could be inhibited by chemicals that reacted with the copper or iron binding to the amyloid. Many well-known drugs, such as aspirin and some antibiotics, similarly target metals on the active site of a specific protein. "If we could make drugs that specifically shut down the ability of amyloid to produce H2O2 from oxygen, then we might have a new therapeutic approach to Alzheimer's disease," says Bush.

Source: American Chemical Society Press Release: June 8, 1999

Contact: Julie Malveaux, j_malveaux@acs.org, 202-872-6042

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