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Molecular Clues Found for Alzheimer's

Brain-cell killers may be treatment targets

THURSDAY, May 24, 2001 (HealthDayNews) -- Digging away at the mechanisms of Alzheimer's disease and other conditions that affect mental function, two teams of researchers have identified molecules that contribute to the death of brain cells and might be targets for preventive treatment.

In Japan, researchers at the RIKEN Brain Science Institute studied neprilysin, an enzyme that breaks down the amyloid-beta deposits that build up in the brains of Alzheimer's patients, killing nerve cells. Increasing the activity of that enzyme could prevent the destruction, and studies of the gene for the enzyme could provide an early warning signal for persons at high risk, the researchers say.

Scientists at Stanford University in California say they have found clumps of protein that help destroy brain cells in people with Alzheimer's and other conditions that attack the brain. "Those protein aggregates could provide people with targets for treatment," says study leader Ron R. Kopito, professor of biological sciences.

Both studies, reported in the May 25 issue of Science, are "examples of the level of sophistication of modern biological investigations," says Bill Thies, vice president for medical and scientific affairs of the Alzheimer's Association.

"They are looking at very basic mechanisms, and I think it will be those basic mechanisms that will lead to the definitive treatment, but they are a long way from clinical relevance," Thies says.

The Japanese work is one of a number of studies of the cell-killing amyloid beta deposits, including enzymes called secretases that promote formation of the deposits and other enzymes that break them down. Normally, the enzymes are in balance, but "subtle alterations in this balance over a long period of time are likely to influence not only the pathological progression but also the incidence of the disease," the Japanese researchers write.

Working with mice, the Japanese scientists identified neprilysin as the key enzyme in the breakdown of beta-amyloid deposits and six molecules that help in that breakdown process. A deficiency of neprilysin was linked to the death of brain cells, the researchers say. The genetics are complex, but the neprilysin gene is "a potential target in the search for genetic risk factors," they say.

The Stanford study solves what the researchers describe as a longstanding conundrum: whether the protein clumps in the brains of patients with dementias, such as Alzheimer's disease, are a cause or an effect of the disease process.

Their work focused on the molecular system by which the body gets rid of abnormal, toxic proteins. Working with cells grown in laboratory cultures, they found that a collection of abnormal proteins produces molecules that prevents this disposal system from working properly.

Kopito says the result is not focused specifically on Alzheimer's disease, but could be applicable to any condition that causes the death of nerve cells. "Our studies can provide a plausible hypothesis for understanding how they die. This is very basic science we are doing," he says.

Thies says there are many barriers to ultimate medical use of the findings. For one thing, any medication aimed at correcting these molecular faults would have to pass the protective blood-brain barrier, a major challenge. But it is work of this sort "that leads us in the direction of ultimate control," he says.

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Don't expect an immediate payoff. Thies draws an analogy with the basic research on the angiotensin system that controls blood pressure. The "very fundamental" studies that outlined the details of that system took many years, but they ultimately helped produce a major class of drugs, the angiotensin-converting enzyme inhibitors that now are widely used to prevent heart attacks and stroke, he says.

An overview of basic research on Alzheimer's disease is available from the Alzheimer's Association.

If you're interested in clinical trials for the disease, visit Veritas Medicine.

Read other HealthScout articles about Alzheimer's disease.

SOURCES: Interviews with Ron R. Kopito, Ph.D., professor of biological science, Stanford University, Palo Alto, Calif., and Bill Thies, Ph.D., vice president for medical and scientific Affairs, Alzheimer's Association, Chicago; May 25, 2001, Science
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