Misbehaving Protein May Provide Clue to Alzheimer’s Drug

Scientists have glimpsed proteins turning into the distinctive clumps of Alzheimer’s disease, an action that takes a millisecond or less, providing researchers with clues on drugs to target the ailment.

This stage when amyloid beta clumps begin to form may be a crucial place to target preventive medicines, said Michele Vedruscolo, the study author and a biophysicist at the University of Cambridge in the U.K. Today’s finding, published in the journal Science, could lead to “a statin for neurodegenerative disease,” he said.

Cholesterol-lowering statins like Pfizer Inc.’s Lipitor work to prevent heart attacks, which damage heart muscle in ways that can’t be repaired, Vedruscolo said. Similarly, in Alzheimer’s disease, a drug targeted at preventing the characteristic abnormal proteins of the disease may ward off brain cell death and resulting memory loss.

“It’s fair to say prevention is the key,” Vedruscolo said in a telephone interview. “After the disease has already exhibited symptoms, it’s far, far more difficult to intervene.”

He is working with Elan Corp. to develop drugs that may shepherd the protein past the vulnerable state described in the paper, preventing the formation of beta amyloid clumps that have been associated with Alzheimer’s disease since Alois Alzheimer first described them in 1906. Many researchers theorize that the disease is caused by these plaques.

Once the beta amyloid clumps form, they encourage other clumps in a vicious cycle, so it’s crucial to prevent the disease, Vedruscolo said.

Nuclear Imaging Tools

Researchers used nuclear magnetic resonance imaging and computer modeling to see how proteins assemble themselves. Many of the intermediate states of folding last a millisecond or less, said Lewis Kay, a study author and a biophysical chemist at the University of Toronto in Canada.

Proteins are made of amino acids, like beads on a string, Kay said. Before folding, or assembling themselves into patterns, there are just beads. In order to make sure proteins assemble properly, some chaperoning molecules exist in the body to help the process. Unfortunately, as people age, the chemical chaperones get less good at their jobs, Kay said.

“If I can bind a drug to the vulnerable regions, I can protect it,” Kay said. “I can chaperone the protein on in the folding process.”

Amyloid protein may also play an important role in Parkinson’s disease, according to the paper. This finding may lead to new therapies there as well.

‘Game Changer’

“This is potentially a game changer for drug discovery,” said Dale Schenk, chief scientific officer for Elan, in an e-mail. “We look forward in the future to applying the principles described in this work to other proteins.”

Global dementia cases are expected to double within the next 20 years to as many as 65.7 million people, the World Health Organization said April 11. More than 5 million Americans have Alzheimer’s, which is the most-common type of dementia, according to the Alzheimer’s Association.

Vedruscolo is working with Elan as part of the Dublin-based company’s collaboration with the University of Cambridge. Today’s research was funded by the National Science and Engineering Research Council of Canada and the Canadian Institutes of Health Research.