Web Exclusives:PawPlus

June 5, 2002:

MoBio major
Scott Vafai '02 discovers link between diet and Alzheimer's

You could say Scott Vafai '02 made the most of the academic opportunities at Princeton. Since freshman year he's conducted research in Jeffry Stock's molecular biology lab, published two papers in scientific journals, and with his senior thesis contributed a theory that explains one contributing factor of Alzheimer's. What he discovered —a biological link between high homocysteine in the blood and Alzheimer's — could lead to new drugs for the treatment of the disease. "It's the best thesis I have encountered in 20 years of teaching at Princeton," says Stock, his adviser. Not bad for a 22-year-old.

Vafai and his adviser didn't start out studying Alzheimer's disease, but instead they were interested in a multicomponent enzyme called PP2A (protein phosphatase 2A) that regulates proteins in cells. PP2A's major role in the cell is to remove phosphate groups that have been added to other proteins. His lab found that the addition of a methyl group to PP2A — methylation — controls the binding of subunits to PP2A that steer it to remove phosphates from certain proteins in the cell.

"We characterized this methylation system," says Vafai. "There's an enzyme that drives the forward reaction. There's an enzyme that drives the reverse reaction. Both enzymes were discovered here at Princeton," says Vafai, who cowrote a paper on PP2A methylation that was published his junior year.

Later, Vafai was drawn into Alzheimer's because of the central role PP2A plays in the disease. Other scientists had already established that within the brain cells of people with Alzheimer's, tangles form. The primary component of the tangles is tau protein with phosphate groups added to them. Tau is responsible for binding microtubules in the neurons, and when too many phosphate groups are added to tau, it falls off and disrupts the structure in the neuron. A lot of scientists, says Vafai, have been trying to figure out why PP2A isn't removing the phosphate groups from tau.

"We've already characterized the system by which PP2A is regulated, so we're in a really interesting position to try to understand why PP2A activity is decreased in this Alzheimer's situation," says Vafai. He was working on that problem when a study by researchers at Boston University and Tufts University published in the New England Journal of Medicine last February showed that people with high homocysteine (an amino acid normally found in blood) have a greater risk of developing Alzheimer's.

Homocysteine can rise when people eat lots of animal proteins and few fruits or leafy vegetables. Fruits and vegetables, which provide B vitamins and folic acid, can lower homocysteine levels as they help convert homocysteine to other amino acids that aren't harmful.

Combing the scientific literature, Vafai used his earlier paper and many others to build a series of links showing how high levels of homocysteine could promote the formation of protein tangles in brain cells. Vafai was the lead author on a paper describing his hypothesis, published one week before his thesis was due. Vafai and Stock believe that high homocysteine levels lead to the inhibition of PP2A methylation, which in turn decreases PP2A's ability to remove the phosphate groups from tau, resulting in tau's falling off the neuron's microtubules and disrupting the neuron's structure.

His study suggests the possibility that people could decrease the chance of developing Alzheimer's if they eat a diet rich in folic acid and B vitamins. His work "also has strong implications for the development of drugs to treat Alzheimer's disease," says Vafai. "If what we're saying is true, it will be very important for understanding Alzheimer's disease." To test his hypothesis, Vafai conducted an experiment using mice and expects results in a few months.

Vafai has been working in labs since he was a high-school student in Edison, New Jersey. Next year, he'll start pursuing an M.D./Ph.D. at Harvard. "I've really fallen in love with this idea of taking medical phenomenon and using knowledge of molecular biology to try to understand vexing problems," says Scott. "As a physician-scientist, you're in a powerful position to see that research is applied quickly to clinical care and to the making of new pharmaceuticals."

By K.F.G.