Monday, January 28, 2008

Alzheimers Research Target May Be a Dead End

(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."
On the level of basic chemistry, attacking Alzheimer's and other protein-clumping diseases by preventing amyloid from concentrating has "always been a long shot," Lynn said. That's because amyloid proteins are incredibly "sticky," chemically speaking.

"To find things that will competitively stick and stop them from assembling is theoretically hard to imagine," Lynn said. It was thought that individual molecules of amyloid inhibitors might do so, but the new finding -- that the molecules inevitably bind together in a more impractical mass -- renders them therapeutically useless.

But other avenues of Alzheimer's research remain promising, Lynn said.

"There are certainly other strategies that have potential," he noted, including antibody-focused strategies aimed at eliminating plaques, or treatments focused on easing the downstream effects of amyloid buildup.

Both scientists stressed that it's still not certain whether protein plaques even cause Alzheimer's and other brain diseases, or whether they are merely byproducts of the disease process. "That's really another open area of research," Shoichet said.

"The problem with these diseases is that it is such a moving target," Lynn said. "And so, different people are looking at different things."

More information
There's much more on Alzheimer's disease at the Alzheimer's Association.

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