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Key Alzheimer's Protein May Help and Hurt

New piece of disease's puzzle found

THURSDAY, July 5, 2001 (HealthDayNews) -- Researchers have taken another step toward solving the molecular riddle of Alzheimer's disease, learning what happens to the "other end" of the protein that plays a key role in causing the brain-robbing condition.

That molecule is the amyloid precursor protein (APP), which sits in the membrane of neurons -- nerve cells -- in the brain. And scientists have discovered that it can wear a white hat as well as a black one.

Previous work has shown that APP is split into smaller pieces by a series of enzymes. The last split, called gamma cleavage, produces the beta-amyloid fragment that forms plaques, the deposits that are associated with the deterioration of brain function.

The function of the other part of APP has been unknown. Now Drs. Xinwei Cao and Thomas C. Sudhof of the University of Texas Southwestern Medical Center in Dallas report that it plays an important role in a basic cell process called gene transcription, the translation of genetic information into proteins.

"As a neuroscientist, I am fascinated by the fact that this protein is useful," says Sudhof, professor of molecular genetics at UT-Southwestern. "It is located in the cell membrane and is cut into pieces in order to send a signal to the cell nucleus, and I find this to be amazing."

Knowing that the splitting of APP is a normal process, one that is essential to cell function, can help understand how and why Alzheimer's disease occurs, he says.

"One way to think about it is that it may be overproduction of beta-amyloid," Sudhof says. "One possible cause is that over a long period of time, too much beta-amyloid is produced. This might be the result of up and down regulation of the pathway, so understanding the pathway is important."

A report in the July 6 issue of the journal Science gives a detailed sequence of events involving the role of the APP fragment in the transcription process. That role is similar to one played by another protein, called notch, which also sits in the cell membrane and is cleaved by a related enzyme.

Once the APP fragment comes into existence, it travels to the cell nucleus, where genetic material is stored in the form of DNA, binds to two other proteins and takes part in the translation of information from DNA into molecules of RNA, which then manufacture proteins.

It isn't clear yet exactly how the entire process fits into how Alzheimer's disease is caused. One possibility is that some of the experimental drugs being tested to prevent Alzheimer's disease might have unexpected side effects, since they could interfere with the production of the useful APP fragment.

"We don't know if they are bad or good, but we have to pay attention to this," Sudhof says.

The Texas work "is an important finding, but it should not raise alarms about the work being done to treat Alzheimer's disease," says Zaven Khachaturian, former director of Alzheimer's disease research at the National Institute on Aging and now senior medical and scientific consultant to the Alzheimer's Association.

The importance is that the work "fills a significant gap in our knowledge" about APP, Khachaturian says. But any speculation about possible side effects "might be a bit premature," he says, in part because all their work has been done with cells grown in laboratory dishes.

What To Do

While this sort of basic research goes on, it is important for older people to be aware of the warning signs of Alzheimer's disease, with a thought toward joining one of the trials of experimental treatments.

For information about the disease and what is being done against it, go to the Alzheimer's Association or the Alzheimer Society of Canada.

Learn about clinical trials for Alzheimer's from Veritas Medicine.

SOURCES: Interviews with Thomas C. Sudhof, M.D., profssor of molecular genetics, University of Texas Southwestern Medical Center, Dallas; and Zaven Khachaturian, Ph.D, senior medical and scientific consultant, Alzheimer's Association, Bethesda, Md.; July 6, 2001 Science
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