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Alzheimer's 'Cocktail' Shows Promise

In lab tests, enzyme combo outperformed individual ingredients, researchers say

WEDNESDAY, Jan. 6, 2010 (HealthDay News) -- Targeting two different enzymes simultaneously may hold promise for treating people with Alzheimer's disease, researchers report.

This "cocktail" strategy, described in the Jan. 6 issue of Science Translational Medicine, outperformed a one-enzyme-at-a-time treatment and also avoided the troublesome side effects seen with that strategy, Johns Hopkins scientists say.

"This does give an idea that moderate reduction of both of these [enzymes] in combination could have an effective response and get rid of all the side effects," said Ian Murray, an assistant professor of neuroscience and experimental therapeutics at Texas A&M Health Science Center College of Medicine in College Station.

So far the results have only been seen in mice, although clinical trials could be on the horizon.

Most experts believe that Alzheimer's is caused by the overproduction of amyloid beta protein or amyloid plaque in the brain.

Two enzymes, beta-secretase and gamma-secretase, produce amyloid plaque by cleaving or breaking down the parent protein, known as amyloid precursor protein (APP).

"They work hand in hand, one after the other and act like scissors, cutting up this [APP] protein into smaller bits and smaller bits called amyloid peptide, which we think is the cause of Alzheimer's disease when it's abnormally accumulated in the brain," explained study senior author Philip C. Wong, a professor of pathology and of neuroscience at Johns Hopkins University School of Medicine in Baltimore.

"They both are required for generation of amyloid beta peptide," he added.

Researchers and pharmaceutical companies hope to figure out how to inhibit these enzymes as a way to treat Alzheimer's.

But beta secretase and gamma secretase have other jobs, too, which likely would be affected by any attempt to reduce their activity.

"Initially we knocked out each one individually and showed that if you reduce the activity you do have good efficacy in terms of reducing amyloid burden, but it also led to other problems," Wong said.

In this trial, the researchers tried a new approach: reducing levels of both enzymes at the same time in genetically altered mice. That worked.

"The combination of reducing both enzymes simultaneously will give you a better outcome in terms of reducing the amyloid and attenuating the learning and memory behavior you see in these animal models," Wong said. "Moreover, we did not see any evidence of side effects."

Compounds to inhibit these genes are nearing possible use in clinical trials, the authors stated.

"It does hold promise for future studies in human subjects," Murray said. But, no actual drugs were used in the study, only genetic alterations to mimic the desired effect of a future drug, he added.

Another potential obstacle is amyloid beta's recently discovered role in synaptic function, or connections and communication between neurons.

"Too much or too little amyloid beta is detrimental, so it seems that you have to have a balance," Murray pointed out.

And, "it has been suggested that reduction of amyloid beta at late stages in the disease may not have any benefit, as the neurological damage has already occurred," he added. "However, clinical trials with amyloid beta vaccination suggest that reduction of amyloid beta halts cognitive decline in this disease [so] there is promise for such therapy."

More information

Visit the Alzheimer's Association for more on this condition.

SOURCES: Philip C. Wong, Ph.D., professor, pathology and neuroscience, Johns Hopkins University School of Medicine, Baltimore; Ian Murray, Ph.D., assistant professor, neuroscience and experimental therapeutics, Texas A&M Health Science Center College of Medicine, College Station; Jan. 6, 2010, Science Translational Medicine
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