Treatment For Alzheimer's Disease

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Alzheimer's disease usually begins after age 60, and the risk increases with age. According to the National Institute on Aging, about 5 percent of men and women ages 65-74 have Alzheimer's disease, and nearly half of those 85 and older may have the disease. The National Institute on Aging estimates that as many as 4.5 million Americans suffer from Alzheimer's disease, which leads to dementia by affecting parts of the brain that control thought, memory and language.

A molecule designed by a Purdue University researcher could lead to the first drug treatment for Alzheimer's disease. The new molecule prevents the first step in a chain of events that leads to amyloid plaque formation in the brain.

Jordan Tang, head of the Protein Studies Research Program at the Oklahoma Medical Research Foundation, is one of the discoverers of the critical enzyme and target for intervention. Tang discovered a key enzyme called memapsin 2, or beta-secretase, that is involved in the development of Alzheimer's disease. The action of this enzyme on a special protein, called the amyloid precursor protein, leads to the formation of plaques in the brain. The development of an inhibitor compound targeting memapsin 2 could block this reaction, thus preventing the disease. Utilizing Tang's information about the enzyme, Ghosh, the Purdue professor who designed the first memapsin 2 inhibitor. As a therapeutic target, memapsin 2 has an additional advantage because it belongs to a class of enzymes called aspartyl proteases.

Ghosh's team achieved a breakthrough in Alzheimer's disease research when they were the first to use a method called X-ray crystallography to map the structure of Ghosh's designed inhibitor bound to the enzyme. This revealed information necessary to move the research forward and develop molecules that could be used in drugs.

Research into memapsin 2 faced a setback when memapsin 1, an enzyme very similar in structure, was discovered. Unlike memapsin 2, memapsin1 is involved in many important biological processes and its inhibition would cause serious adverse side effects, Ghosh said. "Unfortunately, all of our early designed compounds that were potent against memapsin 2 also inhibited memapsin 1," he said. "Selective inhibition of memapsin 2, or building selectivity, became very important. The scientific community was faced with a formidable challenge." "According to our studies, inhibition of memapsin 2 does not cause toxic side effects," Tang said.

Ghosh and Tang founded the biopharmaceutical company Zapaq, located in Oklahoma City, which now has merged with CoMentis. San Francisco-based CoMentis has used the research results of Ghosh and Tang to begin to develop pharmaceuticals. A drug from the memapsin 2 inhibitor could go into the first phase of clinical trials this year and begin the lengthy trial process necessary before the FDA approves a drug to be available on the market.

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