Nanoprobing of the effect of Cu(2+) cations on misfolding, interaction and aggregation of amyloid β peptide.
Nanoprobing of the effect of Cu(2+) cations on misfolding, interaction and aggregation of amyloid β peptide.
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DOI：
10.1007/s11481-012-9416-6
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发表时间：
2013-03
影响因子：
6.2
通讯作者：
Lyubchenko, Yuri L.
中科院分区：
文献类型：
--
作者：
Lv, Zhengjian;Condron, Margaret M.;Teplow, David B.;Lyubchenko, Yuri L.
关键词：
淀粉样β蛋白（Aβ）的错误折叠和聚集是阿尔茨海默病的标志。这两个过程都取决于环境条件，包括二价阳离子的存在，如Cu2+。Cu2+阳离子调控Aβ聚集的早期阶段，但Cu2+调控的分子机制尚不清楚。在这项研究中，我们应用单分子AFM力谱来阐明Cu2+阳离子在肽间相互作用中的作用。通过将两个相互作用的a β42分子中的一个固定在云母表面，并将对应的分子拴在尖端上，我们能够在pH 7.4、6.8、6.0、5.0和4.0的情况下探测Cu2+阳离子存在和不存在时的肽间相互作用。结果表明，在pH 7.4 ~ pH 5.0范围内，Cu2+阳离子的存在改变了a - β相互作用的模式。在这些条件下，Cu2+阳离子诱导Aβ42肽结构改变，导致二聚体内n端相互作用。Cu2+阳离子也能稳定二聚体。在pH 4.0下，Cu2+阳离子对a - β - a - β相互作用没有影响，表明肽质子化改变了肽-阳离子相互作用。利用原子力显微镜（AFM）形貌图像研究了Cu2+阳离子对Aβ聚集后期的影响。结果表明，pH值为7.4和5.0时，亚化学计量Cu2+阳离子加速了原纤维的形成，而pH值为4.0时，Cu2+阳离子对原纤维的形成没有影响。综合AFM力谱和成像分析表明，Cu2+离子促进了Aβ聚集的初始阶段和延伸阶段，但蛋白质质子化减弱了Cu2+的作用。
Misfolding and aggregation of the amyloid β-protein (Aβ) are hallmarks of Alzheimer’s disease. Both processes are dependent on the environmental conditions, including the presence of divalent cations, such as Cu2+. Cu2+ cations regulate early stages of Aβ aggregation, but the molecular mechanism of Cu2+ regulation is unknown. In this study we applied single molecule AFM force spectroscopy to elucidate the role of Cu2+ cations on interpeptide interactions. By immobilizing one of two interacting Aβ42 molecules on a mica surface and tethering the counterpart molecule onto the tip, we were able to probe the interpeptide interactions in the presence and absence of Cu2+ cations at pH 7.4, 6.8, 6.0, 5.0, and 4.0. The results show that the presence of Cu2+ cations change the pattern of Aβ interactions for pH values between pH 7.4 and pH 5.0. Under these conditions, Cu2+ cations induce Aβ42 peptide structural changes resulting in N–termini interactions within the dimers. Cu2+ cations also stabilize the dimers. No effects of Cu2+ cations on Aβ–Aβ interactions were observed at pH 4.0, suggesting that peptide protonation changes the peptide-cation interaction. The effect of Cu2+ cations on later stages of Aβ aggregation was studied by AFM topographic images. The results demonstrate that substoichiometric Cu2+ cations accelerate the formation of fibrils at pH 7.4 and 5.0, whereas no effect of Cu2+ cations was observed at pH 4.0. Taken together, the combined AFM force spectroscopy and imaging analyses demonstrate that Cu2+ cations promote both the initial and the elongation stages of Aβ aggregation, but protein protonation diminishes the effect of Cu2+.
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