bcrp - publications

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1. J Alzheimers Dis. 2012 Mar 5. [Epub ahead of print]

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

Do TM, Noel-Hudson MS, Ribes S, Besengez C, Smirnova M, Cisternino S, Buyse M,
Calon F, Chimini G, Chacun H, Scherrmann JM, Farinotti R, Bourasset F.

Department of Clinical Pharmacy and Pharmacokinetics, Faculty of Pharmacy,
University of Paris-Sud, Châtenay-Malabry, France.

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.

PMID: 22391220 [PubMed - as supplied by publisher]