beta-Amyloid efflux mediated by p-glycoprotein

F C Lam; R Liu; P Lu; A B Shapiro; J M Renoir; F J Sharom; P B Reiner

doi:10.1046/j.1471-4159.2001.00113.x

beta-Amyloid efflux mediated by p-glycoprotein

J Neurochem. 2001 Feb;76(4):1121-8. doi: 10.1046/j.1471-4159.2001.00113.x.

Authors

F C Lam¹, R Liu, P Lu, A B Shapiro, J M Renoir, F J Sharom, P B Reiner

Affiliation

¹ Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, Canada.

PMID: 11181832
DOI: 10.1046/j.1471-4159.2001.00113.x

Abstract

A large body of evidence suggests that an increase in the brain beta-amyloid (Abeta) burden contributes to the etiology of Alzheimer's disease (AD). Much is now known about the intracellular processes regulating the production of Abeta, 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 Abeta efflux pump. Pharmacological blockade of p-gp rapidly decrease extracellular levels of Abeta secretion. In vitro binding studies showed that addition of synthetic human Abeta1-40 and Abeta1-42 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 Abeta 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 Abeta detachment from cellular membranes, and represents an obvious route towards identification of such a mechanism in the brain.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
Adenosine Triphosphate / metabolism
Alzheimer Disease / metabolism
Amyloid beta-Peptides / genetics
Amyloid beta-Peptides / metabolism*
Amyloid beta-Protein Precursor / genetics
Amyloid beta-Protein Precursor / metabolism*
Anilino Naphthalenesulfonates
Animals
Binding, Competitive / drug effects
Cell Line
Cell Membrane / metabolism
Cricetinae
Humans
Kidney / cytology
Kidney / drug effects
Kidney / metabolism*
Mifepristone / analogs & derivatives
Mifepristone / pharmacology
Mutation
Peptide Fragments / genetics
Peptide Fragments / metabolism*
Secretory Vesicles / metabolism
Transfection

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Anilino Naphthalenesulfonates
Peptide Fragments
RU49953
amyloid beta-protein (1-40)
amyloid beta-protein (1-42)
Mifepristone
2-(4'-maleimidylanilino)naphthalene-6-sulfonic acid
Adenosine Triphosphate