title: ABCG2- and ABCG4-mediated efflux of amyloid-β peptide 1-40 at the mouse blood-brain barrier.
abstract: The accumulation of amyloid-β peptide (Aβ) in the brain is a critical hallmark of Alzheimer's disease. This high cerebral Aβ concentration may be partly caused by impaired clearance of Aβ across the blood-brain barrier (BBB). The low-density lipoprotein receptor-related protein-1 (LRP-1) and the ATP-binding cassette (ABC) protein ABCB1 (P-glycoprotein) are involved in the efflux of Aβ across the BBB. We hypothesized that other ABC proteins, such as members of the G subfamily, are also involved in the BBB clearance of Aβ. We therefore investigated the roles of ABCG2 (BCRP) and ABCG4 in the efflux of [3H] Aβ1-40 from HEK293 cells stably transfected with human ABCG2 or mouse abcg4. We showed that ABCG2 and Abcg4 mediate the cellular efflux of [3H] Aβ1-40. In addition, probucol fully inhibited the efflux of [3H] Aβ1-40 from HEK293-abcg4 cells. Using the in situ brain perfusion technique, we showed that GF120918 (dual inhibitor of Abcb1 and Abcg2) strongly enhanced the uptake (Clup, μl/g/s) of [3H] Aβ1-40 by the brains of Abcb1-deficient mice, but not by the brains of Abcb1/Abcg2-deficient mice, suggesting that Abcg2 is involved in the transport of Aβ at the mouse BBB. Perfusing the brains of Abcb1/Abcg2- and Abca1-deficient mice with [3H] Aβ1-40 plus probucol significantly increased the Clup of Aβ. This suggests that a probucol-sensitive transporter that is different from Abca1, Abcb1, and Abcg2 is involved in the brain efflux of Aβ. We suggest that this probucol-sensitive transporter is Abcg4. We conclude that Abcg4 acts in concert with Abcg2 to efflux Aβ from the brain across the BBB.
authors.affiliation: Department of Clinical Pharmacy and Pharmacokinetics, Faculty of Pharmacy, University of Paris-Sud, Châtenay-Malabry, France.
authors.forename: Tuan Minh
authors.initials: TM
authors.lastname: Do
authors.forename: Marie-Sophie
authors.initials: MS
authors.lastname: Noel-Hudson
authors.forename: Sandy
authors.initials: S
authors.lastname: Ribes
authors.forename: Capucine
authors.initials: C
authors.lastname: Besengez
authors.forename: Maria
authors.initials: M
authors.lastname: Smirnova
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cisternino
authors.forename: Marion
authors.initials: M
authors.lastname: Buyse
authors.forename: Frédéric
authors.initials: F
authors.lastname: Calon
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chimini
authors.forename: Hélène
authors.initials: H
authors.lastname: Chacun
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.forename: Fanchon
authors.initials: F
authors.lastname: Bourasset
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070996:ATP Binding Cassette Transporter, Subfamily G; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002247:Carbon Isotopes / Q000378:metabolism; D002461:Cell Line, Transformed; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D010477:Perfusion; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014316:Tritium / Q000378:metabolism
chemical_list: C577836:ABCA1 protein, human; C116614:ABCG2 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070996:ATP Binding Cassette Transporter, Subfamily G; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; C486685:Abcg4 protein, mouse; D000166:Acridines; D016229:Amyloid beta-Peptides; D002247:Carbon Isotopes; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D044005:Tetrahydroisoquinolines; C078592:amyloid beta-protein (1-40); D014316:Tritium; D005947:Glucose; C083501:Elacridar