Aluminum, copper, iron and zinc differentially alter amyloid-Aβ1-42 aggregation and toxicity
Aluminum, copper, iron and zinc differentially alter amyloid-Aβ1-42 aggregation and toxicity
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DOI：
10.1016/j.biocel.2011.02.009
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发表时间：
2011-06-01
影响因子：
4
通讯作者：
Zatta, Paolo
中科院分区：
文献类型：
--
作者：
Bolognin, Silvia;Messori, Luigi;Zatta, Paolo
淀粉样蛋白β（1-42）（A β）被认为在阿尔茨海默病（AD）的发病机制中起关键作用。特别是，它与生物相关的金属离子的相互作用可能会导致形成高度神经毒性的复合物。在这里，我们描述了A β与几种生物金属（即铜，锌，铁）和非生理铝反应后形成的物质，以评估不同的金属离子是否能够不同地驱动A β聚集。通过许多生物物理技术，包括电喷雾电离质谱法，动态光散射，荧光，透射电子显微镜和通过使用构象敏感性抗体（DC，α APF），确定所得A β-金属络合物和相应聚集体的性质。金属结合到A β被证明赋予高度不同的化学性质所产生的复合物，因此，他们的整体聚集行为被深深地修改。铝（III）和铁（III）离子被发现诱导特殊的聚集特性，最终导致形成环状原纤维和纤维状低聚物。值得注意的是，只有A β-铝的特征在于存在相关百分比的平均半径略小于30 nm的聚集体。与此相反，锌（II）和铜（II）离子完全防止形成可溶性的水溶性聚集体。在神经母细胞瘤细胞培养物中研究了各种A β-金属络合物的生物学效应：A β-铝原来是唯一能够触发淀粉样蛋白前体和tau 181蛋白过度产生的物质。我们的研究结果指出，铝可以有效地与A β相互作用，形成“结构化”的聚集体，具有独特的生物物理特性，这与高神经毒性有关。(C)2011爱思唯尔有限公司版权所有。
Amyloid-beta(1-42) (A beta) is believed to play a crucial role in the ethiopathogenesis of Alzheimer's Disease (AD). In particular, its interactions with biologically relevant metal ions may lead to the formation of highly neurotoxic complexes. Here we describe the species that are formed upon reacting A beta with several biometals, namely copper, zinc, iron, and with non-physiological aluminum to assess whether different metal ions are able to differently drive A beta aggregation. The nature of the resulting A beta-metal complexes and of the respective aggregates was ascertained through a number of biophysical techniques, including electrospray ionization mass spectrometry, dynamic light scattering, fluorescence, transmission electron microscopy and by the use of conformation-sensitive antibodies (DC, alpha APF). Metal binding to A beta is shown to confer highly different chemical properties to the resulting complexes; accordingly, their overall aggregation behaviour was deeply modified. Both aluminum(III) and iron(III) ions were found to induce peculiar aggregation properties, ultimately leading to the formation of annular protofibrils and of fibrillar oligomers. Notably, only A beta-aluminum was characterized by the presence of a relevant percentage of aggregates with a mean radius slightly smaller than 30 nm. In contrast, both zinc(II) and copper(II) ions completely prevented the formation of soluble fibrillary aggregates. The biological effects of the various A beta-metal complexes were studied in neuroblastoma cell cultures: A beta-aluminum turned out to be the only species capable of triggering amyloid precursor and tau181 protein overproduction. Our results point out that Al can effectively interact with A beta, forming "structured" aggregates with peculiar biophysical properties which are associated with a high neurotoxicity. (C) 2011 Elsevier Ltd. All rights reserved.