The S100B Alarmin Is a Dual-Function Chaperone Suppressing Amyloid-β Oligomerization through Combined Zinc Chelation and Inhibition of Protein Aggregation.,ACS Chemical Neuroscience

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The S100B Alarmin Is a Dual-Function Chaperone Suppressing Amyloid-β Oligomerization through Combined Zinc Chelation and Inhibition of Protein Aggregation.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-07-24 , DOI: 10.1021/acschemneuro.0c00392
Joana S Cristóvão _{1,

2} , António J Figueira _{1,

2} , Ana P Carapeto _{1,

3} , Mário S Rodrigues _{1,

3} , Isabel Cardoso _{4,

5} , Cláudio M Gomes _{1,

2}

Affiliation

Amyloid beta (Aβ) aggregation and imbalance of metal ions are major hallmarks of Alzheimer’s disease (AD). Indeed, amyloid plaques of AD patients are enriched in zinc and Aβ42, and AD related-cognitive decline is dependent on extracellular zinc concentration. In vitro, zinc induces the formation of polymorphic Aβ42 oligomers that delay the formation of amyloid fibers at the expense of increased cellular toxicity. S100B is an inflammatory alarmin and one of the most abundant proteins in the brain and is upregulated in AD and associated with amyloid plaques, where it exerts extracellular functions. Recent findings have uncovered novel neuroprotective functions for S100B as a suppressor of Aβ aggregation and toxicity and in the regulation of zinc homeostasis in neurons. Here we combine biophysical and kinetic approaches to demonstrate that such S100B protective functions converge, making the protein a dual-function chaperone capable of suppressing the formation of toxic Aβ oligomers through both chelation of zinc and inhibition of protein aggregation. From detailed kinetic analysis of Aβ42 aggregation monitoring ThT fluorescence, we show that substoichiometric S100B prevents the formation of toxic off-pathway oligomers that are formed by monomeric Aβ42 in the presence of zinc. Indeed, S100B is effective when added during the lag and transition phases of Aβ42 aggregation, and its action under these circumstances results from its ability to buffer zinc, as it perfectly mimics the effect obtained with the chelating agent EDTA. Further, bioimaging analysis combining transmission electron microscopy and atomic force microscopy confirms that catalytic amounts of S100B partly revert the formation of toxic oligomers. Taken together these results indicate a new role for S100B as a dual chaperone whose distinct functions are interrelated and depend on the relative levels of zinc, S100B, and Aβ, which dynamically evolve during AD.

中文翻译：

S100B Alarmin 是一种双功能伴侣，通过结合锌螯合和抑制蛋白质聚集来抑制淀粉样蛋白-β 寡聚化。

β-淀粉样蛋白 (Aβ) 聚集和金属离子失衡是阿尔茨海默病 (AD) 的主要标志。事实上，AD 患者的淀粉样斑块富含锌和 Aβ42，AD 相关的认知衰退依赖于细胞外锌浓度。体外, 锌诱导多态性 Aβ42 寡聚体的形成，以增加细胞毒性为代价延迟淀粉样蛋白纤维的形成。S100B 是一种炎症性警报素，是大脑中最丰富的蛋白质之一，在 AD 中上调，并与淀粉样斑块相关，发挥细胞外功能。最近的研究结果揭示了 S100B 作为 Aβ 聚集和毒性抑制剂以及调节神经元锌稳态的新神经保护功能。在这里，我们结合生物物理和动力学方法来证明这种 S100B 保护功能会聚，使蛋白质成为一种双功能伴侣，能够通过螯合锌和抑制蛋白质聚集来抑制有毒 Aβ 寡聚体的形成。通过监测 ThT 荧光的 Aβ42 聚集的详细动力学分析，我们表明亚化学计量的 S100B 可防止在锌存在下由单体 Aβ42 形成的有毒异路低聚物的形成。事实上，在 Aβ42 聚集的滞后和过渡阶段添加 S100B 时，它是有效的，它在这些情况下的作用是由于它具有缓冲锌的能力，因为它完美地模拟了用螯合剂 EDTA 获得的效果。此外，结合透射电子显微镜和原子力显微镜的生物成像分析证实，催化量的 S100B 可部分逆转有毒低聚物的形成。综上所述，这些结果表明 S100B 作为双重伴侣具有新的作用，其不同的功能相互关联并取决于锌、S100B 和 Aβ 的相对水平，

更新日期：2020-09-02

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