Distinct Membrane Disruption Pathways Are Induced by 40-Residue β-Amyloid Peptides
Distinct Membrane Disruption Pathways Are Induced by 40-Residue β-Amyloid Peptides
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DOI：
10.1074/jbc.m116.720656
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发表时间：
2016-06-03
影响因子：
4.8
通讯作者：
Qiang, Wei
中科院分区：
文献类型：
--
作者：
Delgado, Dennis A.;Doherty, Katelynne;Qiang, Wei
β-淀粉样蛋白（Aβ）肽诱导的细胞膜破坏被认为是阿尔茨海默病的主要病理机制之一。另一方面，即使在磷脂脂质体等简化的模型系统中，多种可能途径的共存也阻碍了高分辨率水平的膜破坏过程的机制研究。因此，分离这些途径对于深入了解 Aβ 诱导的膜破坏过程至关重要。这项研究结合了多种生物物理技术，表明肽与脂质 (P:L) 摩尔比是在脂质体中存在 40 个残基 Aβ 肽的情况下调节主要膜破坏途径选择的重要因素。在特定条件下，三种不同的途径（膜内容物泄漏的纤维颤动、囊泡融合和通过暂时稳定的离子通道的脂质摄取）在模型脂质体系统中占据主导地位。这些单独的系统以 Aβ 肽的初始状态和 P:L 摩尔比为特征。我们的结果证明了生成具有均质膜破坏途径的简化 A β 膜模型系统的可能性，这将有利于未来的高分辨率机制研究。从根本上说，P:L 控制途径选择的可能性表明，A β 聚集和 A β 膜相互作用的驱动力在分子水平上可能是相似的。
Cellular membrane disruption induced by beta-amyloid (A beta) peptides has been considered one of the major pathological mechanisms for Alzheimer disease. Mechanistic studies of the membrane disruption process at a high-resolution level, on the other hand, are hindered by the co-existence of multiple possible pathways, even in simplified model systems such as the phospholipid liposome. Therefore, separation of these pathways is crucial to achieve an in-depth understanding of theA beta-induced membrane disruption process. This study, which utilized a combination of multiple biophysical techniques, shows that the peptide-to-lipid (P:L) molar ratio is an important factor that regulates the selection of dominant membrane disruption pathways in the presence of 40-residue A beta peptides in liposomes. Three distinct pathways (fibrillation with membrane content leakage, vesicle fusion, and lipid uptake through a temporarily stable ionic channel) become dominant in model liposome systems under specific conditions. These individual systems are characterized by both the initial states of A beta peptides and the P:L molar ratio. Our results demonstrated the possibility to generate simplified A beta-membrane model systems with a homogeneous membrane disruption pathway, which will benefit high-resolution mechanistic studies in the future. Fundamentally, the possibility of pathway selection controlled by P:L suggests that the driving forces for A beta aggregation and A beta-membrane interactions may be similar at the molecular level.