beta-Amyloid efflux mediated by p-glycoprotein.
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.
Lam
F C
FC
Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, Canada.
Liu
R
R
Lu
P
P
Shapiro
A B
AB
Renoir
J M
JM
Sharom
F J
FJ
Reiner
P B
PB
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000817:Anilino Naphthalenesulfonates; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015735:Mifepristone / Q000031:analogs & derivatives / Q000494:pharmacology; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000817:Anilino Naphthalenesulfonates; D010446:Peptide Fragments; C422205:RU49953; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D015735:Mifepristone; C021310:2-(4'-maleimidylanilino)naphthalene-6-sulfonic acid; D000255:Adenosine Triphosphate