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

作者：Do Tuan Minh; Noel Hudson Marie Sophie; Ribes Sandy; Besengez Capucine; Smirnova Maria; Cisternino Salvatore; Buyse Marion; Calon Frederic; Chimini Giovanna; Chacun Helene; Scherrmann Jean Michel; Farinotti Robert; Bourasset Fanchon^*

来源：Journal of Alzheimer's Disease, 2012, 30(1): 155-166.

DOI：10.3233/JAD-2012-112189

• Abca1
• Abcb1
• Abcg4
• Abcg2
• Alzheimer%26apos
• s disease
• amyloid-beta
• blood-brain barrier
• in situ brain perfusion
• mouse

The accumulation of amyloid-beta peptide (A beta) in the brain is a critical hallmark of Alzheimer%26apos;s disease. This high cerebral A beta concentration may be partly caused by impaired clearance of A beta 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 A beta across the BBB. We hypothesized that other ABC proteins, such as members of the G subfamily, are also involved in the BBB clearance of A beta. We therefore investigated the roles of ABCG2 (BCRP) and ABCG4 in the efflux of [H-3]A beta(1-40) from HEK293 cells stably transfected with human ABCG2 or mouse abcg4. We showed that ABCG2 and Abcg4 mediate the cellular efflux of [H-3]A beta(1-40). In addition, probucol fully inhibited the efflux of [H-3]A beta(1-40) 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 (Cl-up, mu l/g/s) of [H-3]A beta(1-40) 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 A beta at the mouse BBB. Perfusing the brains of Abcb1/Abcg2- and Abca1-deficient mice with [H-3]A beta(1-40) plus probucol significantly increased the Cl-up of A beta. This suggests that a probucol-sensitive transporter that is different from Abca1, Abcb1, and Abcg2 is involved in the brain efflux of A beta. We suggest that this probucol-sensitive transporter is Abcg4. We conclude that Abcg4 acts in concert with Abcg2 to efflux A beta from the brain across the BBB.

• 出版日期2012