Protein 'Pump' May Aid in Alzheimer's Prevention

In study with mice, it removed dangerous plaques from the brain

THURSDAY, Oct. 20, 2005 (HealthDay News) -- A protein well known to scientists appears to clear the brain of amyloid beta, the main component of the plaques that are found in Alzheimer's patients, according to a new study with mice.

The protein, P-glycoprotein (Pgp), has long been known to obstruct chemotherapy drugs and other drugs used in treating brain disorders. But, by creating drugs that alter the natural levels of Pgp, it may be possible to prevent and treat Alzheimer's disease, the researchers suggest.

"We found a new way of getting amyloid out of the brain," said lead author John Cirrito, a postdoctorate research fellow at Washington University School of Medicine in St. Louis. "Now there are avenues we can explore to try to find a treatment. Anything you can do to prevent amyloid beta from being produced or helping get it cleared is good."

The study findings appear Oct. 20 in the online edition of the Journal of Clinical Investigation.

Pgp is one of several molecular transporters that form the blood-brain barrier, a layer of cells that limits the ability of many types of molecules -- including many drugs -- to enter the brain through the circulatory system, Cirrito said. "In the blood-brain barrier, it normally acts to keep molecules out of the brain," he explained, adding the protein actually pumps molecules out of brain cells.

Earlier research had hinted that Pgp could also transport amyloid beta molecules out of the brain, Cirrito said. "We basically show that if we inject amyloid beta into the brains of mice, Pgp can pump amyloid beta out of the brain," he said.

The researchers also found that when specially bred mice were given a Pgp inhibitor, amyloid beta levels significantly increased in just a few hours. Also, mice bred not to produce Pgp had higher levels of amyloid beta, compared with mice that were able to make the protein, the researchers said.

Cirrito believes these findings might be used one day to both treat and prevent Alzheimer's disease. "If you could enhance Pgp activity, perhaps you could get amyloid beta out of the brain and not let it build up," he said.

"There are drugs that are used to inhibit Pgp in cancer therapy to help chemotherapy drugs get into tumor cells," Cirrito said. "These inhibitors could make Alzheimer's worse," he noted. There are also common drugs such as statins that inhibit Pgp activity, Cirrito said. And there are compounds, such as St. John's wort, that enhance Pgp activity, he noted.

One expert thinks these findings add to the understanding of how amyloid beta plaque could be removed from the brain.

"This is an exciting paper, and it dovetails well with existing knowledge about the biology of Pgp," said Dr. Sam Gandy, chairman of the Medical and Scientific Advisory Council of the Alzheimer's Association, and director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia.

There have been fewer studies about how amyloid beta can be removed from the brain than studies examining how it is generated, Grandy said. "But now we can add Pgp to the growing list of molecules that control amyloid beta catabolism," he said.

Grandy thinks this discovery might lead to new treatments for Alzheimer's. Some dietary substances or medications may block Pgp and increase the risk for Alzheimer's disease, while others may enhance the protein, he said.

"It might be possible to develop Pgp modulators that accelerate clearance of amyloid beta in a beneficial way," Gandy said.

More information

To learn more, visit the Alzheimer's Association.

SOURCES: John Cirrito, Ph.D., postdoctorate research fellow, Washington University School of Medicine, St. Louis; Sam Gandy, M.D., Ph.D., chairman, Medical and Scientific Advisory Council, Alzheimer's Association, and director, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia; Oct. 20, 2005, online edition, Journal of Clinical Investigation
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