Alzheimer's Research Target May Be a Dead End

By E.J. Mundell
HealthDay Reporter
Sunday, January 27, 2008; 3:00 PM

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SUNDAY, Jan. 27 (HealthDay News) -- A once-promising pathway for research into preventing and treating Alzheimer's disease may have been derailed by a surprise chemical finding, researchers report.

Scientists in laboratories around the world have been investigating drug candidates called amyloid inhibitors, which many experts believed could keep proteins such as amyloid-beta from sticking together in brain tissue.

This type of "sticky" protein plaque build-up is a hallmark of Alzheimer's disease. It also characterizes brain illnesses such as Huntington's disease and "mad cow" disease.

But the new study, published Jan. 27 in the journal Nature Chemical Biology, may sound an unexpected death knell for amyloid inhibitor research.

In the study, a team of chemists at the University of California, San Francisco, found that these candidate drugs form large, unwieldy clumps themselves, rendering them useless as targeted therapy against amyloid in the brain.

High-tech research in the lab is revealing that typical amyloid inhibitors "seem to act not in the way people expect them to and want them to," explained study senior author Brian Shoichet, professor of pharmaceutical chemistry at UCSF.

Once these drugs aggregate into clumps, "they no longer have the right pharmacology, they won't cross the [brain's] membrane barriers, and they inhibit everything -- any protein will bind with them," he said.

In other words, the drugs lose their ability to migrate to the brain to fight amyloid plaque. They also give up their targeted specificity against amyloid, Shoichet said. "They end up inhibiting everything -- any protein that sees them will be sequestered by them," he said. This molecular clumping process is largely inevitable, Shoichet added.

His advice to neuroscientists investigating these agents as potential Alzheimer's therapies: "They should stop."

Another expert agreed.

David Lynn is a Howard Hughes Institute investigator and professor of biological chemistry at Emory University in Atlanta. "I think that Brian's paper argues that [scientists] have been missing the boat here," he said. "It's not clear that you are ever going to get the concentrations that you need of these agents at the right site to be able to have any therapeutic intervention."