Lipid membrane templates the ordering and induces the fibrillogenesis of Alzheimer's disease amyloid-β peptide
Lipid membrane templates the ordering and induces the fibrillogenesis of Alzheimer's disease amyloid-β peptide
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DOI：
10.1002/prot.21887
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发表时间：
2008-07-01
影响因子：
2.9
通讯作者：
Lee, Ka Yee C.
中科院分区：
文献类型：
--
作者：
Chi, Eva Y.;Ege, Canay;Lee, Ka Yee C.
脂质膜已被证明介导阿尔茨海默病（AD）淀粉样蛋白- p （A β）肽的纤维形成和毒性。A β 40和磷脂头基团之间的静电相互作用被发现可以控制单体A β与脂质单分子层的结合和插入，其中A β与带电脂质的相互作用比两性离子脂质强。为了阐明A - β膜关联的分子尺度结构细节，我们在本研究中使用互补的x射线和中子散射技术（掠射x射线衍射、x射线反射率和中子反射率）原位研究了A - β与脂质单分子层的关联，脂质单分子层由阴离子脂质1,2-二棕榈酰基-甘油酸-3-[磷酸rac-（1-甘油）]（DPPG）、两性离子脂质1,2-二棕榈酰基-甘油酸-3-磷脂（DPPC）、或在空气缓冲界面处的阳离子脂质1,2-二对二酰基3-三甲基丙烷铵（DPTAP）。我们发现阴离子脂质DPPG独特地诱导了A β在膜表面的晶体排序，与原纤维中的β片结构非常相似，揭示了DPPG对A β的有趣的模板排序效应。此外，将A β与含有阴离子脂质1-棕榈酰-2-油酰- asn -甘油-3-[磷酸-（1-甘油）]（POPG）的脂质囊泡一起培养，诱导淀粉样蛋白原纤维的形成，证实了A β在膜表面的模板化排序促进了原纤维的形成。这项研究提供了一个详细的分子尺度表征早期结构波动和组装事件，可能触发体内a β的错误折叠和聚集。我们的研究结果提示，A β对阴离子脂质的吸附可能是体内模板聚集的机制，并驱动AD的发病机制，阴离子脂质可能因细胞损伤而暴露在外膜小叶上。
The lipid membrane has been shown to mediate the fibrillogenesis and toxicity of Alzheimer's disease (AD) amyloid-P (A beta) peptide. Electrostatic interactions between A beta 40 and the phospholipid headgroup have been found to control the association and insertion of monomeric A beta into lipid monolayers, where A beta exhibited enhanced interactions with charged lipids compared with zwitterionic lipids. To elucidate the molecular-scale structural details of A beta-membrane association, we have used complementary X-ray and neutron scattering techniques (grazing-incidence X-ray diffraction, Xray reflectivity, and neutron reflectivity) in this study to investigate in situ the association of A beta with lipid monolayers composed of either the anionic lipid 1,2-dipalmitoylsn-glycero-3-[phospho-rac-(1-glycerol)] (DPPG), the zwitterionic lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), or the cationic lipid 1,2-dipaimitoyl 3-trimethylammonium propane (DPTAP) at the air-buffer interface. We found that the anionic lipid DPPG uniquely induced crystalline ordering of A beta at the membrane surface that closely mimicked the beta-sheet structure in fibrils, revealing an intriguing templated ordering effect of DPPG on A beta. Furthermore, incubating A beta with lipid vesicles containing the anionic lipid 1-palmitoyl-2-oleoyl-sn-glycero-3-[phosphorac-(1-glycerol)] (POPG) induced the formation of amyloid fibrils, confirming that the templated ordering of A beta at the membrane surface seeded fibril formation. This study provides a detailed molecular-scale characterization of the early structural fluctuation and assembly events that may trigger the misfolding and aggregation of A beta in vivo. Our results implicate that the adsorption of A beta to anionic lipids, which could become exposed to the outer membrane leaflet by cell injury, may serve as an in vivo mechanism of templated-aggregation and drive the pathogenesis of AD.