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 Investigation 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.