ABCG2- and ABCG4-Mediated Efflux of Amyloid-β Peptide 1-40 at the Mouse Blood-Brain Barrier

Article type: Research Article

Authors: Do, Tuan Minh^a | Noel-Hudson, Marie-Sophie^a | Ribes, Sandy^a | Besengez, Capucine^b | Smirnova, Maria^b | Cisternino, Salvatore^b | Buyse, Marion^a | Calon, Frédéric^c | Chimini, Giovanna^d | Chacun, Hélène^e | Scherrmann, Jean-Michel^b | Farinotti, Robert^a | Bourasset, Fanchon^b

Affiliations: [a] Department of Clinical Pharmacy and Pharmacokinetics, Faculty of Pharmacy, University of Paris-Sud, Châtenay-Malabry, France | [b] Department of Pharmacokinetics, INSERM U705, CNRS UMR 8206, Faculty of Pharmacy, Université Paris Descartes, Université Paris Diderot, Sorbonne Paris Cité, Paris, France | [c] Faculty of Pharmacy, Laval University, QC, Canada | [d] Centre d'Immunologie de Marseille-Luminy, INSERM-CNRS-Université de La Méditerranée, Marseille, France | [e] Laboratory of Biopharmacy and Pharmaceutical Technology, CNRS UMR 8612, Faculty of Pharmacy, University of Paris-Sud, Châtenay-Malabry, France

Correspondence: [*] Correspondence to: Fanchon Bourasset, PharmD, PhD, Department of Pharmacokinetics, INSERM U705, CNRS UMR 8206, Faculty of Pharmacy, University Paris Descartes, 4 avenue de l'Observatoire 75006, Paris, France. Tel.: +33 1 53 73 96 31; Fax: +33 1 40 51 75 60; E-mail: [email protected].

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.

Keywords: Abca1, Abcb1, Abcg4, Abcg2, Alzheimer's disease, amyloid-β, blood-brain barrier, in situ brain perfusion, mouse

DOI: 10.3233/JAD-2012-112189

Journal: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 155-166, 2012