Sci. Aging Knowl. Environ., 26 October 2005
Pumping-protein failure might spur Alzheimer's disease
It's a familiar-sounding scenario: Pumps that are the last defense against a rising tide falter, leading to a toxic buildup. It happened in New Orleans, compounding the damage from Hurricane Katrina, and it might also occur in Alzheimer's disease (AD). A new study suggests that disabling a protein that shuttles molecules out of the brain promotes the accumulation of noxious AD-associated plaques. Drugs that accelerate pumping might protect against the illness, the results suggest.
Not just any molecule can enter the brain; the blood-brain barrier controls access to the delicate organ. Transporter proteins in capillaries are part of this protective system, returning to the bloodstream unwanted compounds that manage to slip across. These pumps also eighty-six some molecules manufactured in the brain, such as the protein amyloid, which piles up in AD and spawns plaques (see "Detangling Alzheimer's Disease"). Researchers speculate that the failure to remove enough amyloid promotes AD, and they've identified a transporter, LRP1, that ejects the sticky protein. However, neuroscientists suspect that other -amyloid pumps exist. One candidate is Pgp, which kicks out a range of molecules, from antidepressants to chemotherapy drugs. Test-tube studies suggest that Pgp also transfers amyloid. Neuroscientist John Cirrito of Washington University School of Medicine in St. Louis, Missouri, tested whether the transporter performed the same function in neurons.
The researchers injected amyloid into the brains of mice that lack Pgp. Control rodents eliminated 31% of the amyloid through the blood-brain barrier, but the altered mice cleared only 14%. The team then measured -amyloid quantities in the brains of mice engineered to amass the protein. The amounts climbed 30% in mice dosed with a Pgp-blocker but remained unchanged in untreated animals. To determine whether shackling Pgp boosts the number of plaques, the researchers crossed mice that lack the pumping protein with animals that fashion excess amyloid. When the mice were a year old--about middle age--the team scrutinized their brains for plaques. The hybrid rodents carried more of the clumps than did mice able to produce Pgp. Overall, the work indicates that Pgp helps control -amyloid quantities within the brain and that augmenting the protein's activity might decrease vulnerability to AD, Cirrito says. Multiple drugs adjust Pgp pumping: Morphine and cyclosporine crank up Pgp's operations, and statins dampen them. Some of these compounds might shift the risk of AD (although, if anything, statins appear to decrease rather than increase that risk). Furthermore, some people inherit a sluggish version of Pgp, and they could be more susceptible to AD.
The study musters "more evidence that AD is a disease of the blood-brain barrier," says neuroscientist William Banks of Saint Louis University in Missouri. However, he notes that LRP1 output fell in some of the engineered rodents. He wants to see stronger evidence that this decline is not responsible for the rise in amyloid quantities. Future work might clarify whether turning up the pumps can stop the flood of amyloid.
October 26, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150