Alzheimer's Protein: What's Normal?

Scientists try to figure out how healthy nerve protein behaves

WEDNESDAY, Dec. 5, 2001 (HealthDayNews) -- A protein that acts like a warehouse supervisor, ordering worker molecules to move other proteins around inside nerve cells, may be the key to understanding Alzheimer's disease, suggests a new study.

When this supervisor substance -- amyloid precursor protein (APP) -- breaks down, beta-amyloid proteins are created, and their buildup in the brain is linked to the disease's severe mental decline.

Scientists have known that beta-amyloids arise from APP's breakdown, but how APP functions normally has been a mystery. Now, a team of California researchers has found that APP normally plays a role in cell transport, helping to send protein-filled capsules from one portion of a neuron to another. The finding appears in the Dec. 6 issue of Nature.

Roughly 4 million Americans have Alzheimer's disease, and experts predict that number will rise to between 10 million and 14 million by 2050.

Early signs, which often are overlooked, include mild forgetfulness of names or recent events, eventually progressing to forgetting how to perform simple tasks such as speaking or eating. People with Alzheimer's often become anxious or aggressive, frequently wander off and eventually require round-the-clock care. Progression of the disease varies, ranging from five years to more than 20. There is no known cure, and death occurs, on average, eight years after the onset of symptoms.

Senior investigator Lawrence S. B. Goldstein and his research team focused on APP's normal job.

"Neurons are very large cells, and they need to move things [chemicals, etc.] from the places where they make them, which is the cell body, to the tips of long, thin tubes," says Goldstein. The tubes are called axons, and they extend whip-like from the main nerve cell body. They are called axons if they transmit electrical signals away from the cell body and dendrites if they receive incoming signals.

"Those thin tubes … are simultaneously a wire through which electrical signals are passed, but also a pipe through which needed materials, chemicals and other signals are moved around," he says.

Molecules called kinesins play a key role in this transport process, which also relies on microtubules that act like roadways within the cells. Goldstein's research suggests that one of APP's normal functions is to link the kinesins to certain packages that must be moved around the cells. These packages contain the proteins beta-secretase and presenilin-1.

However, Goldstein says his findings about APP's function don't provide all the answers.

"If you're an automobile mechanic, and your car has a broken piston, you need to know something about how pistons work normally in order to understand why a broken piston leads to engine failure," says Goldstein.

While he says neurodegenerative diseases are more complicated, it's not clear whether the normal functions of any of these proteins are related to what happens in the disease process.

Goldstein says several of his colleagues wonder whether knowing the normal function of APP will be useful in understanding the disease. Using the car analogy again, Goldstein says, "If you've got an engine, and you throw a screwdriver into a functioning engine, it fails -- but, of course, it's not related to the normal function of the screwdriver."

While mutations in the APP protein can lead to nerve abnormalities like those seen in Alzheimer's, those characteristics don't provide a clear view of what goes wrong in the earliest stage of the disease, he says.

Philip Wong, associate professor of pathology at the Johns Hopkins University School of Medicine, in Baltimore, says, "The key finding is that they could identify this APP involvement."

Wong says, "This report demonstrates a potential function for the amyloid precursor protein," though "how it relates to Alzheimer's disease is less clear in this paper."

"It will open up a variety of investigations that I'm sure, down the road, will prove fruitful for our understanding … This is a step closer to finding either novel therapeutics or understanding of the normal function of the protein," says Wong. However, he says any practical applications for treatment are still years away.

What To Do: For more information on Alzheimer's disease, check the Alzheimer's Association, the Alzheimer's Disease Education and Referral Center or the National Institute of Neurological Disorders and Stroke.

SOURCES: Interviews with Lawrence S. B. Goldstein, Ph.D., Howard Hughes Medical Investigator, professor, department of cellular and molecular medicine, University of California San Diego School of Medicine; Philip Wong, Ph.D., associate professor, department of pathology, Johns Hopkins University School of Medicine, Baltimore, Md.; Dec. 6, 2001, Nature
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