A molecule that has long been an obstacle to cancer chemotherapy and drug treatments for brain disorders may soon become an ally in the fight against Alzheimer's disease, according to researchers at Washington University School of Medicine in St. Louis and the University of Rochester.
In studies in genetically modified mice, scientists found that the molecule, P-glycoprotein (Pgp), accelerates clearance from the brain of amyloid beta (A-beta) peptide, the primary component of the plaques that are the hallmark of Alzheimer's disease.
According to scientists, the new link is potent and intriguing enough to suggest several potential follow-up studies, including investigations of how pharmaceuticals might affect Alzheimer's risk by altering Pgp activity levels.
"We would never claim that Pgp activity is the single critical causative factor in Alzheimer's disease, just like there isn't any single cause of heart attacks, hypertension or cancer," says author David Holtzman, M.D., the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. "But our evidence suggests that it may be one of the more significant risk factors so far identified."
The Journal of Clinical Investigations will publish their results online on Oct. 20.
Scientists are already familiar with a variety of drugs that can promote and suppress Pgp activity. The new connection may, for example, explain a puzzling study that suggested the antibiotic rifampin could slow the decline of patients with mild to moderate Alzheimer's.
"That result didn't seem to be linked to the drug's antibiotic properties, and now we have a much more appealing explanation: rifampin is a known inducer of Pgp activity," says co-author David Piwnica-Worms, M.D., Ph.D., professor of molecular biology and pharmacology and of radiology at Washington University. "Researchers will likely be evaluating this drug and other known Pgp promoters as potential ways to reduce risk."
Several drugs regularly prescribed over extended periods of time are also known to suppress Pgp activity. These drugs include some calcium channel blockers, immune suppression drugs and anti-depressants. Such compounds may need to be reevaluated for potential effects on long-term risk of Alzheimer's disease.
Scientists emphasized that the pharmaceuticals that suppress Pgp have confirmed medical benefits, while their potential to increase Alzheimer's risk is still tentative and unconfirmed. They strongly urged against any thought of stopping a prescription on the basis of their study alone.
"The decision to begin or stop a pharmaceutical treatment must always be based on an assessment of benefits and risks," says Holtzman. "We identified the possibility of an increase in risk, but detailed human studies are necessary before that risk can even be confirmed, let alone weighed against the benefits conferred by these drugs."
When German scientists published in vitro evidence in 2000 that Pgp might transport A-beta, the labs of Holtzman and Piwnica-Worms independently read the findings. Pgp is one of several molecular transporters that form the blood-brain barrier, a layer of cells that strictly limits the ability of many types of molecules —including many pharmaceuticals — to enter the brain via the circulatory system.
At the time, Holtzman and other Alzheimer's researchers had been seeing evidence that something might be helping A-beta get out of the brain after it was produced there.
"Everything that's in the spaces between the cells of the brain can get out passively, but the A-beta peptide appeared to be getting out of the brain at a high speed that was consistent with it being helped out of the brain by other mechanisms," he explains.
Meanwhile, Piwnica-Worms' lab had spent more than a decade studying Pgp's role in resistance to chemotherapy.
"When tumor cells make Pgp, they can use it to pump cancer chemotherapy agents out of themselves and increase their chances of surviving the chemotherapy," explains Piwnica-Worms.
John R. Cirrito, a student in Holtzman's lab, contacted Piwnica-Worms about the potential overlap, and the two labs combined their expertise to study whether Pgp transports A-beta out of the brain. In one test, Cirrito, the lead author of the paper, crossbred genetically engineered mouse models used in each lab. The first mouse model, used by Piwnica-Worms' group, lacks the gene that makes Pgp. The second, used by Holtzman's group, has an inserted human gene, APP, that makes it develop a condition similar to Alzheimer's disease.
Once he had established a line of mice that lacked Pgp but had the APP gene, Cirrito compared them to a control group that was born at the same time but only had the APP gene. When they were older, the mice who lacked Pgp had approximately three times as much A-beta buildup in their brains as the APP mice.
"This shows that if Pgp is not working properly over the course of months, it can actually impact the pathology of Alzheimer's disease," Holtzman says.
Working with scientists in the laboratory of Berislav Zlokovic, MD, PhD, professor of neurosurgery at the University of Rochester, researchers injected A-beta labeled with a radioactive tag directly into the mouse brains. After 30 minutes, mice lacking Pgp had cleared less of the labeled A-beta from their brains.
In another test, Cirrito sampled the cerebral fluid at various points in mouse brains. He showed that when the mice were given a drug that inhibits Pgp activity, A-beta levels increased.
Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, Jiang H, Prior JL, Sagare A, Bales KR, Paul SM, Zlokovic BV, Piwnica-Worms D, Holtzman DM. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-b deposition in an Alzheimer's disease mouse model. Journal of Clinical Investigation, online publication, Oct. 20, 2005.
Funding from the National Institute on Aging, the National Cancer Institute and the U.S. Department of Energy supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
© 2005 Washington University School of Medicine
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