Expression and function of Abcg4 in the mouse blood-brain barrier: role in restricting the brain entry of amyloid-β peptide.
Expression and function of Abcg4 in the mouse blood-brain barrier: role in restricting the brain entry of amyloid-β peptide.
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DOI：
10.1038/s41598-017-13750-0
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发表时间：
2017-10-17
影响因子：
4.6
通讯作者：
Bourasset F
中科院分区：
文献类型：
--
作者：
Dodacki A;Wortman M;Saubaméa B;Chasseigneaux S;Nicolic S;Prince N;Lochus M;Raveu AL;Declèves X;Scherrmann JM;Patel SB;Bourasset F
ABCG4是一种atp结合盒跨膜蛋白，在体外已被证明参与去氨甾醇和淀粉样蛋白β肽（Aβ）的细胞外排。ABCG4在脑内高表达，但其在血脑屏障（BBB）水平的定位和功能尚不清楚。我们通过qRT-PCR和共聚焦成像证实Abcg4在小鼠脑毛细血管内皮细胞中表达。Abcg4二聚体的模型研究表明，去氨甾醇在假定的甾醇结合位点表现出热力学上有利的结合，这比胆固醇更有利。此外，无偏对接也显示Aβ在该位点结合。利用一种新的Abcg4缺陷小鼠模型，我们发现Abcg4能够在血脑屏障水平上输出a β和去氨甾醇，这些过程可以被probucol和l -甲状腺素抑制。我们的实验还表明，去氨甾醇可以抑制Aβ的输出，这可能是由于两者都结合在Abcg4上的甾醇结合位点上。我们首次发现Abcg4可能在体内在血脑屏障处发挥输出a β的作用，这一过程可以被其假定的天然配体，去氨甾醇（可能还有胆固醇）拮抗。
ABCG4 is an ATP-binding cassette transmembrane protein which has been shown, in vitro, to participate in the cellular efflux of desmosterol and amyloid-β peptide (Aβ). ABCG4 is highly expressed in the brain, but its localization and function at the blood-brain barrier (BBB) level remain unknown. We demonstrate by qRT-PCR and confocal imaging that mouse Abcg4 is expressed in the brain capillary endothelial cells. Modelling studies of the Abcg4 dimer suggested that desmosterol showed thermodynamically favorable binding at the putative sterol-binding site, and this was greater than for cholesterol. Additionally, unbiased docking also showed Aβ binding at this site. Using a novel Abcg4-deficient mouse model, we show that Abcg4 was able to export Aβ and desmosterol at the BBB level and these processes could be inhibited by probucol and L-thyroxine. Our assay also showed that desmosterol antagonized the export of Aβ, presumably as both bind at the sterol-binding site on Abcg4. We show for the first time that Abcg4 may function in vivo to export Aβ at the BBB, in a process that can be antagonized by its putative natural ligand, desmosterol (and possibly cholesterol).
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影响因子：
4
作者：
Canepa, Elisa;Borghi, Roberta;Ricciarelli, Roberta
通讯作者：
Ricciarelli, Roberta
影响因子：
7.4
作者：
Graham, Annette
通讯作者：
Graham, Annette
影响因子：
4
作者：
Do, Tuan Minh;Noel-Hudson, Marie-Sophie;Bourasset, Fanchon
通讯作者：
Bourasset, Fanchon
影响因子：
6.4
作者：
Eisele, Yvonne S.
通讯作者：
Eisele, Yvonne S.
DOI：
10.1006/bbrc.2001.5756
发表时间：
2001-10-26
影响因子：
3.1
作者：
Engel, T;Lorkowski, S;Assmann, G
通讯作者：
Assmann, G