ABCG2- and ABCG4-Mediated Efflux of Amyloid-β Peptide (1-40) at the Mouse Blood-Brain Barrier
ABCG2- and ABCG4-Mediated Efflux of Amyloid-β Peptide (1-40) at the Mouse Blood-Brain Barrier
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DOI：
10.3233/jad-2012-112189
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发表时间：
2012-01-01
影响因子：
4
通讯作者：
Bourasset, Fanchon
中科院分区：
文献类型：
--
作者：
Do, Tuan Minh;Noel-Hudson, Marie-Sophie;Bourasset, Fanchon
淀粉样β肽（A β）在大脑中的积累是阿尔茨海默病的一个重要标志。这种高脑A β浓度可能部分由A β穿过血脑屏障（BBB）的清除受损引起。低密度脂蛋白受体相关蛋白-1（LRP-1）和ATP结合盒（ABC）蛋白ABCB 1（P-糖蛋白）参与A β穿过BBB的流出。我们假设其他ABC蛋白，如G亚家族成员，也参与A β的BBB清除。因此，我们研究了ABCG 2（BCRP）和ABCG 4在稳定转染人ABCG 2或小鼠abcg 4的HEK 293细胞中[H-3]A β（1-40）外排中的作用。我们发现ABCG 2和Abcg 4介导[H-3]A β（1-40）的细胞外排。此外，普罗布考完全抑制[H-3]A β（1-40）从HEK 293-abcg 4细胞的流出。使用原位脑灌注技术，我们发现GF 120918（Abcb 1和Abcg 2的双重抑制剂）强烈增强Abcb 1缺陷小鼠脑对[H-3]A β（1-40）的摄取（Cl-up，μ l/g/s），但不增强Abcb 1/Abcg 2缺陷小鼠脑的摄取，这表明Abcg 2参与了小鼠BBB的A β转运。用[H-3]A β（1-40）加普罗布考灌注Abcb 1/Abcg 2和Abca 1缺陷小鼠的大脑，显著增加了A β的Cl-up。这表明与Abca 1，Abcb 1和Abcg 2不同的普罗布考敏感转运蛋白参与了A β的脑外排。我们认为这种普罗布考敏感的转运蛋白是Abcg 4。我们的结论是，Abcg 4与Abcg 2协同作用，将A β从大脑中流出穿过BBB。
The accumulation of amyloid-beta peptide (A beta) in the brain is a critical hallmark of Alzheimer'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.