β-sheet structured β-amyloid(1-40) perturbs phosphatidylcholine model membranes
β-sheet structured β-amyloid(1-40) perturbs phosphatidylcholine model membranes
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DOI：
10.1016/j.jmb.2007.02.063
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发表时间：
2007-05-11
影响因子：
5.6
通讯作者：
Watts, Anthony
中科院分区：
文献类型：
--
作者：
de Planque, Maurits R. R.;Raussens, Vincent;Watts, Anthony
细胞内钙稳态的破坏在阿尔茨海默病的病理学中起着核心作用，该病的特征还在于淀粉样β肽Aβ40和Aβ42的积累。这些两亲性肽可能与神经元膜相关并影响其屏障功能，导致钙稳态的丧失。通过将无蛋白模型膜（囊泡或平面双层）暴露于可溶性 Aβ，已对该建议进行了广泛研究。主要非结构化的 Aβ 已被证明会经历膜诱导的构象变化，变为主要的 β 结构或螺旋结构，这取决于模型膜的组成等因素。 A 的结合使脂质双层可渗透离子，但存在争议，这是否是由于 A 肽离散跨膜离子通道的形成，还是由于脂质头基相关的 A 对双层完整性的非特异性扰动。在这里，我们尝试将 A β 掺入两性离子双层（最简单的模型膜系统）的疏水核心中，方法是通过 A β 肽和 A 肽混合膜的水合来制备蛋白脂质体。磷脂酰胆碱 (PC) 脂质。尽管使用的溶剂混合物中Aβ40和Aβ42几乎完全是螺旋状的，但Aβ类似物在所得囊泡分散体中是β结构的。当含有 Aβ 40 的囊泡融合成两性离子平面双层时，观察到 Aβ 的典型不规则“单通道样”电导。最大电导随着额外的囊泡融合而增加，同时仍然表现出类似单通道的行为。由 A beta 40/PC 囊泡形成的支撑双层没有表现出任何通道状拓扑特征，但双层会随着时间的推移而不稳定。 β 40 主要以β-片层形式存在于由相同囊泡形成的支撑多层中。综合观察结果表明，小两亲性 A beta 40 组装体的表面缔合对两性离子双层具有非特异性扰动。 (c) 2007 Elsevier Ltd. 保留所有权利。
The disruption of intracellular calcium homeostasis plays a central role in the pathology of Alzheimer's disease, which is also characterized by accumulation of the amyloid-beta peptides A beta 40 and A beta 42. These amphipathic peptides may become associated with neuronal membranes and affect their barrier function, resulting in the loss of calcium homeostasis. This suggestion has been extensively investigated by exposing protein-free model membranes, either vesicles or planar bilayers, to soluble A beta. Primarily unstructured A beta has been shown to undergo a membrane-induced conformational change to either primarily beta-structure or helical structure, depending, among other factors, on the model membrane composition. Association of A renders lipid bilayers permeable to ions but there is dispute whether this is due to the formation of discrete transmembrane ion channels of A peptides, or to a non-specific perturbation of bilayer integrity by lipid head group-associated A. Here, we have attempted incorporation of A beta in the hydrophobic core of zwitterionic bilayers, the most simple model membrane system, by preparing proteoliposomes by hydration of a mixed film of A beta peptides and phosphatidylcholine (PC) lipids. Despite the use of a solvent mixture in which A beta 40 and A beta 42 are almost entirely helical, the A beta analogs were beta-structured in the resulting vesicle dispersions. When A beta 40-containing, vesicles were fused into a zwitterionic planar bilayer, the typical irregular "single channel-like" conductance of A beta was observed. The maximum conductance increased with additional vesicle fusion, while still exhibiting single channel-like behavior. Supported bilayers formed from A beta 40/PC vesicles did not exhibit any channel-like topological features, but the bilayer destabilized in time. A beta 40 was present primarily as beta-sheets in supported multilayers formed from the same vesicles. The combined observations argue for a non-specific perturbation of zwitterionic bilayers by surface association of small amphipathic A beta 40 assemblies. (c) 2007 Elsevier Ltd. All rights reserved.