Novel Approach Targets Alzheimer's Development

'Chaperone' protein blocks clumping of beta-amyloid

FRIDAY, Oct. 29, 2004 (HealthDayNews) -- A new technique may someday be able to stop Alzheimer's disease before it starts.

Tapping into the "Trojan horse" strategy, scientists from Howard Hughes Medical Institute and Stanford University designed a small molecule that can recruit a larger molecule to stop beta-amyloid proteins from clumping together.

"This represents a new way to get at an old problem, and hopefully it can lead to a new class of drugs," said Dr. Gerald Crabtree, a professor of pathology and developmental biology at Stanford University and an investigator at Howard Hughes Medical Institute.

However, one of Crabtree's co-authors, Dr. Isabella Graef, cautioned that a lot of work still needs to be done before any potential human therapies could be developed.

Results of the study appear in the Oct. 29 issue of Science.

About 4 million Americans currently have Alzheimer's disease, according to the Alzheimer's Association. Alzheimer's disease begins as proteins called beta-amyloid start to stick together and accumulate around neurons in the brain, eventually causing the death of those neurons. As those neurons die off, cognitive symptoms, such as memory loss, begin.

Stopping this process before it begins is one of the main avenues of research in Alzheimer's disease, according to Dr. Sam Gandy, vice chairman of the Alzheimer's Association's Medical and Scientific Advisory Council.

"Amyloid is normally made by all cells in the body throughout life," said Gandy. "One of the great mysteries of Alzheimer's disease is why, after 50 or 60 years, it changes shape. For some undiscovered reason, the shape changes and clumps form."

One way to either prevent Alzheimer's or slow it down "is to inhibit the production or aggregation of amyloid-beta," said Graef, a senior research scientist at Stanford University.

The problem, she explained, is that when amyloid-beta clumps together, it is two large proteins interacting, and they cover a large area. Most drugs therapies are small molecules, which can't make much of a difference when put on such a large area.

"It's like two strips of Velcro. The whole surface area interacts and putting in a small molecule drug is like putting in a grain of salt to try to stop this interaction," Graef explained.

To effectively inhibit the amyloid-beta clumping, very large concentrations of drugs would be needed, but large doses of medications are often toxic. What's needed, she said, is a large molecule.

"Our idea was a very simple one: to increase the size of the drug with a trick. We made the drug bi-functional. One side binds to amyloid-beta, the other to a chaperone protein. This increases the bulk of the drugs, making it larger than amyloid-beta. Now, the grain of sand is dragging a tennis ball behind it, and can block the interaction between the two strips of Velcro," Graef said.

However, she added that this current drug is not suitable for clinical use because it doesn't cross the blood-brain barrier. From here, Graef said, she and her colleagues will try to design a therapy that can cross that key barrier and work on cells in the brain. Once they have success on cells, they will try the therapy in animal models. So, she noted, any potential human therapy is a long way away.

But she added that this idea of bi-functional drugs may also be useful in treating other diseases.

"We hope this whole rationale behind this drug might be applicable to other protein to protein interactions," such as in cancer or HIV, she said.

Of this study, Gandy said, "There's a new way to harness some of a cell's normal proteins to recruit them into the process. It's a new way to help the body use its own tools to fight the disease."

More information

To learn more about Alzheimer's disease, visit the Alzheimer's Association.

SOURCES: Isabella Graef, M.D., senior research scientist, Stanford University Medical School, Palo Alto, Calif.; Gerald Crabtree, professor, pathology and developmental biology, Stanford University, and investigator, Howard Hughes Medical Institute, Palo Alto, Calif.; Sam Gandy, M.D., Ph.D., vice chairman, Alzheimer's Association Medical and Scientific Advisory Council, Oct. 29, 2004, Science
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