β-Amyloid (1-40) Peptide Interactions with Supported Phospholipid Membranes: A Single-Molecule Study
β-Amyloid (1-40) Peptide Interactions with Supported Phospholipid Membranes: A Single-Molecule Study
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DOI：
10.1016/j.bpj.2012.08.051
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发表时间：
2012-10-03
影响因子：
3.4
通讯作者：
Gafni, Ari
中科院分区：
文献类型：
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作者：
Ding, Hao;Schauerte, Joseph A.;Gafni, Ari
最近的证据支持这样的假设：β-淀粉样肽在其聚集过程早期形成的寡聚体具有神经毒性，并且可能是阿尔茨海默病的特征。尽管这种神经毒性的机制尚不清楚，但据信这些寡聚物与神经元膜的相互作用参与其中。识别神经毒性物质具有挑战性，因为 β-淀粉样肽在非常低的生理浓度 (nM) 下形成寡聚物，并且这些寡聚物具有高度异质性和亚稳定性。在这里，我们报告使用单分子成像技术来研究 β-淀粉样蛋白 (1-40) 肽和支持的合成模型阴离子脂质膜之间的相互作用。对膜上 β-淀粉样蛋白种类的演变进行了长达数天的监测，结果表明 β-淀粉样蛋白 (1-40) 肽最初与脂质膜紧密、均匀地结合，随后在膜中形成寡聚物。在这些低浓度下，小寡聚物形成过程中早期的行为可以根据 H.W. Huang 提出的两亲性肽与膜之间相互作用的双态模型进行定性解释。然而，膜中低聚物形成的速率及其大小高度依赖于水溶液中β-淀粉样蛋白（1-40）肽的浓度，这表明低聚物形成有两种不同的途径，这导致膜中的物种截然不同，并且随着浓度的增加而偏离两种状态模型。
Recent evidence supports the hypothesis that the oligomers formed by the beta-amyloid peptide early in its aggregation process are neurotoxic and may feature in Alzheimer's disease. Although the mechanism underlying this neurotoxicity remains unclear, interactions of these oligomers with neuronal membranes are believed to be involved. Identifying the neurotoxic species is challenging because beta-amyloid peptides form oligomers at very low physiological concentrations (nM), and these oligomers are highly heterogeneous and metastable. Here, we report the use of single-molecule imaging techniques to study the interactions between beta-amyloid (1-40) peptides and supported synthetic model anionic lipid membranes. The evolution of the beta-amyloid species on the membranes was monitored for up to several days, and the results indicate an initial tight, uniform, binding of beta-amyloid (1-40) peptides to the lipid membranes, followed by oligomer formation in the membrane. At these low concentrations, the behavior at early times during the formation of small oligomers is interpreted qualitatively in terms of the two-state model proposed by H. W. Huang for the interaction between amphipathic peptides and membranes. However, the rate of oligomer formation in the membrane and their size are highly dependent on the concentrations of beta-amyloid (1-40) peptides in aqueous solution, suggesting two different pathways of oligomer formation, which lead to drastically different species in the membrane and a departure from the two-state model as the concentration increases.