Journal
JOURNAL OF NEUROCHEMISTRY
Volume 76, Issue 4, Pages 1121-1128Publisher
WILEY
DOI: 10.1046/j.1471-4159.2001.00113.x
Keywords
ABC transporter; Alzheimer's disease; beta-amyloid; MDR1; membrane; p-glycoprotein
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A large body of evidence suggests that an increase in the brain beta -amyloid (A beta) burden contributes to the etiology of Alzheimer's disease (AD). Much is now known about the intracellular processes regulating the production of A beta, however, less is known regarding its secretion from cells. We now report that p-glycoprotein (p-gp), an ATP-binding cassette (ABC) transporter, is an A beta efflux pump, Pharmacological blockade of p-gp rapidly decrease extracellular levels of A beta secretion. In vitro binding studies showed that addition of synthetic human A beta1-40 and A beta1-42 peptides to hamster mdr1-enriched vesicles labeled with the fluorophore MIANS resulted in saturable quenching, suggesting that both peptides interact directly with the transporter. Finally, we were able to directly measure transport of A beta peptides across the plasma membranes of p-gp enriched vesicles, and showed that this phenomenon was both ATP- and p-gp-dependent. Taken together, our study suggests a novel mechanism of A beta detachment from cellular membranes, and represents an obvious route towards identification of such a mechanism in the brain.
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