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Grape Expectations

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Noble Research Institute scientists join Mount Sinai in researching cure for Alzheimer's disease

A cross section of a brain scan (left) and a grape (right) may not seem to have anything in common, but researchers at Mount Sinai and the Noble Research Institute believe that chemicals in grape seed extract may be able to delay Alzheimer's disease.
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In 2007, Richard Dixon, D.Phil., took a phone call from a man who identified himself as Giulio Pasinetti, M.D., Ph.D., a professor in the psychiatry and neuro-science department at Mount Sinai School of Medicine in New York. Pasinetti told Dixon he wanted to collaborate with Noble Research Institute to find a treatment for Alzheimer's disease. Dixon drew the obvious conclusion: this man had dialed the wrong number. The Noble Research Institute is a research center, but for plants, not people.

Moments later, Dixon realized that Pasinetti had indeed come to the right place. The New York researcher had gathered early data in animals that suggested that some chemical ingredient of grape seeds might counteract the devastating mental erosion of Alzheimer's disease. But Pasinetti needed a laboratory that could analyze and supply the plant's individual chemical components. He needed the scientists at Noble.

Almost four years later, the Mount Sinai-Noble Research Institute collaboration is on the verge of planning its first human trials. If the human experiments play out as hoped - and it is still too early to know what will happen - Noble may play a role in combating a disease predicted to strike as many as 16 million Americans by 2050. The achievement would be personally gratifying for Dixon, who watched his mother suffer the unforgiving decline of Alzheimer's until her death. "Without that experience, I might have been less likely to get involved in this project," said Dixon, who serves as senior vice president and director of the Plant Biology Division.

As Dixon and others well know, Alzheimer's has no cure and no known cause apart from age. It occurs when the brain starts to produce abnormal proteins that accumulate in and around brain cells in misshapen twists and clumps. These protein deposits, called plaques and tangles, eventually cause nerve cells to malfunction and die.

Since the 1990s, studies have suggested that people who consume red wine have a lower risk of Alzheimer's disease. But what's the magic of merlot? Pasinetti's laboratory has found in experiments with mice that particular compounds in grapes, called polyphenols, may be responsible for the protection.

Polyphenols are naturally occurring molecules in many plants. One variety of polyphenol, called condensed tannins, appeared to be involved in protecting the brain. Grapes are known to contain these molecules in abundance, with a high concentration in the seeds and skins. (Probably, Dixon said, because tannins can protect the seeds and give the fruit a bitter taste to discourage herbivores.)

Noble scientists have specific expertise in the area of tannins. For almost a decade, Noble researchers have worked to develop an alfalfa that produces tannins in the plant's stems and leaves. For grazing animals, such a development would prevent the occurrence of a condition known as "pasture bloat" that commonly afflicts animals that graze protein-rich forages such as alfalfa.

But Noble's study of tannins may also benefit people. In 2008, Pasinetti described a study showing that mice with an Alzheimer's-like condition which consumed grape-derived polyphenols were able to improve on tests of cognitive function and memory. Many members of the scientific community were skeptical of the results, Pasinetti said, believing that polyphenol molecules were too bulky to pass through the wall of the intestine. Pasinetti wanted a closer look. "Nobody had tested the possibility that maybe a subfraction of the polyphenols was able to become bio-available and reach a sufficient concentration in the bloodstream," he said. That was about the time Pasinetti turned to Noble. He needed experts who could separate the complex makeup of grape seed into its individual parts, and the Noble Research Institute "is the top research group in the world in plant physiology."

On some counts, the skeptics were right. Many tannins are too large to make it into the bloodstream. But the molecules come in lots of different sizes. "There are literally hundreds of compounds in the grape seed," said Jack Blount, a researcher in Dixon's laboratory who is working on the project. "You want to find out which one or group is improving cognitive function. That's the complexity of this type of research." Noble researchers are like bakers in reverse, taking cake batter and trying to extract the flour.

The Noble scientists divided the grape seed tannins into three groups of different sizes. The process starts with a sample of concentrated grape seed being shipped to Noble's Ardmore, Okla., campus in large batches where it is broken apart with different kinds of solvents and columns, and the solution is then dried. If it sounds straightforward, it's not. This phase of the process alone takes months to get enough material for one feeding experiment.

In the end, once the Noble researchers have made a concentrated powder of the three groups of polyphenols, they pack the products in dry ice and ship them overnight to Pasinetti's laboratory.

There the Mount Sinai research team will sprinkle the compound into the mice's water.

In a series of experiments in mice, the researchers have been able to determine that only a handful of the smaller tannins can pass through the intestine. They are not completely identical to the molecules in the plant; these tannins become slightly modified as they pass through the gut wall and liver.

Nonetheless, they are found in the blood and, most significantly, in the brain. "That is the most remarkable thing - that a small fraction of the molecules can get into the brain," Pasinetti says. Since the compounds found in the brain are a modified version of those found in the plant, the Noble scientists must synthesize these new compounds in the lab for further studies.

The work has now narrowed down to one molecule that appears to be the most promising of the bunch.

Last year, Pasinetti and his team published the most tantalizing findings yet. Upon autopsy, the mice which had consumed one of the compounds synthesized at Noble were found to have less of the brain abnormalities that form the hallmarks of Alzheimer's.

Nonetheless, all the scientists involved in this research can list many promising experiments in the past that have failed to hold up in later tests. The compound may not work in people, or it may not work unless it has some modification or some companion molecule.

The studies in people will be the ultimate test. "I feel really good about where the research is going," Blount said. "But until you get the final results, you don't put on the party hat."