Protease inhibitor could help prevent alzheimer's

April 10, 2000

Principle similar to AIDS treatment

Researchers have succeeded for the first time in designing a chemical that -- in test tube studies -- can stop the chain reaction that leads to Alzheimer's disease, a finding reported in the current (April 12) print edition of the Journal of the American Chemical Society, published by the American Chemical Society, the world's largest scientific society.

Chemist Jordan Tang, Ph.D., has created a highly potent protease inhibitor for a human brain enzyme called memapsin 2. This could be a step forward in finding a drug for treating the now-incurable disease, he said. Although the inhibitor has yet to be made into a drug or tested outside the laboratory, the discovery holds great promise, according to the researcher. In principle it is similar to a treatment currently used successfully to combat the AIDS virus, Tang continued.

The work differs from other Alzheimer's research because it prevents the beginnings of the disease rather than treating the symptoms or coping with the damaged cells.

"I think (memapsin 2) is one of the most promising targets for Alzheimer's disease to come along that can be translated into treatments," said Tang, head of the protein studies program at the Oklahoma Medical Research Foundation. "We have accumulated a lot of knowledge on the proteases like memapsin 2. We thought it should be possible to design very potent inhibitors using this knowledge. Now we know it works."

Alzheimer's is a genetic defect that causes a loss of brain function, primarily among elderly people. There are an estimated 4 million diagnosed cases in the United States, according to the National Institute of Aging. Approximately 10 percent of the U.S. population have inherited genetic mutations that may lead to the disease, according to the Alzheimer's Disease Education and Referral Center.

Among reported cases of Alzheimer's, the remaining 90 percent are "sporadic," meaning they have no familial connection. All Alzheimer's cases, however, have a common basis: the accumulation of a chemical that kills brain cells and leads to dementia.

In theory, memapsin 2 will stop the production of the killer chemical, known as beta-amyloid, thus stopping the progression of Alzheimer's disease. It essentially cuts the larger protein known as amyloid precursor protein (APP) in half and prevents it from affecting other brain cells.

"The production of (beta-amyloid) to cause Alzheimer's disease is a mistake in the cell," Tang said. "If we can prevent the cell from making this mistake, then we can stop the progression and maybe even the onset of Alzheimer's disease."

Tang and his research team initially discovered memapsin 2 as a possible new human protease while searching the human genome sequence database. They eventually connected its function to Alzheimer's, though they originally were looking at a protease found in human immunodeficiency virus (the virus that leads to AIDS). Their research experience with similar compounds and the HIV inhibitor contributed to the design of memapsin 2, Tang said.

The next step in the research, according to Tang, is to shrink the chemical compound into a size usable for drug treatments. Such a step should be feasible, he said, but will likely take five years or more. Only after continuing studies in the laboratory can animal and human testing begin.

"If the ultimate inhibitor drug has low side effects, it should permit these people to live the rest of their lives normally," Tang said.
A nonprofit organization with a membership of 161,000 chemists and chemical engineers, the American Chemical Society ( publishes scientific journals and databases, convenes major research conferences, and provides educational, science policy and career programs in chemistry. Its main offices are in Washington, D.C., and Columbus, Ohio.

American Chemical Society

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