Interactions of amyloid-β peptides on lipid bilayer studied by single molecule imaging and tracking
Interactions of amyloid-β peptides on lipid bilayer studied by single molecule imaging and tracking
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DOI：
10.1016/j.bbamem.2018.03.017
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发表时间：
2018-09-01
影响因子：
3.4
通讯作者：
Gafni, Ari
中科院分区：
文献类型：
--
作者：
Chang, Chun-Chieh;Edwald, Elin;Gafni, Ari
淀粉样β肽（A β 40和A β 42）在与阿尔茨海默病（AD）相关的突触功能障碍和神经元损失中具有显著特征。这被认为是由于A β和细胞表面受体之间的相互作用影响细胞信号传导，或由于膜中钙渗透通道的形成破坏钙稳态。在这两种机制中，细胞膜是A β相互作用的主要细胞结构。人体体液中的β浓度非常低（pM-nM），使得对体内形成的寡聚体的大小、组成、细胞结合位点和作用机制的研究非常具有挑战性。因此，大多数研究都使用了在微摩尔肽浓度下制备的A β寡聚体，其中A β形成具有容易观察到的细胞毒性的寡聚体种类。当在实验中使用nM浓度的肽时，未观察到这种毒性，这突出了使用生理学相关肽浓度对于具有生物学意义的结果的重要性。在本文中，单分子显微镜被用来监测A β寡聚体的形成和扩散的支持脂质双层纳摩尔肽浓度。A β单体是溶液中的主要物质，与膜紧密结合，并且是高度移动的，而三聚体和更高级的寡聚体在很大程度上是不移动的。AO二聚体以移动的和非移动的状态的混合存在。A β 40在膜上的低聚物生长比淀粉样蛋白生成性更强的A β 42更快，但对于1：1的A β 40：A β 42混合物，低聚物生长在很大程度上受到抑制。这些A β 40-A β 42相互作用的潜在机制可能是阿尔茨海默病病理学的特征。
The amyloid-beta peptides (A beta 40 and A beta 42) feature prominently in the synaptic dysfunction and neuronal loss associated with Alzheimer's disease (AD). This has been proposed to be due either to interactions between A beta and cell surface receptors affecting cell signaling, or to the formation of calcium-permeable channels in the membrane that disrupt calcium homeostasis. In both mechanisms the cell membrane is the primary cellular structure with which A beta interacts. A beta concentrations in human bodily fluids are very low (pM-nM) rendering studies of the size, composition, cellular binding sites and mechanism of action of the oligomers formed in vivo very challenging. Most studies, therefore, have utilized A beta oligomers prepared at micromolar peptide concentrations, where A beta forms oligomeric species which possess easily observable cell toxicity. Such toxicity has not been observed when nM concentrations of peptide are used in the experiment highlighting the importance of employing physiologically relevant peptide concentrations for the results to be of biological significance. In this paper singlemolecule microscopy was used to monitor A beta oligomer formation and diffusion on a supported lipid bilayer at nanomolar peptide concentrations. A beta monomers, the dominant species in solution, tightly associate with the membrane and are highly mobile whereas trimers and higherorder oligomers are largely immobile. AO dimers exist in a mixture of mobile and immobile states. Oligomer growth on the membrane is more rapid for A beta 40 than for the more amyloidogenic A beta 42 but is largely inhibited for a 1:1 A beta 40:A beta 42 mixture. The mechanism underlying these A beta 40-A beta 42 interactions may feature in Alzheimer's pathology.