Peptide–Polyphenol (KLVFF/EGCG) Binary Modulators for Inhibiting Aggregation and Neurotoxicity of Amyloid-β Peptide,ACS Omega

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Peptide–Polyphenol (KLVFF/EGCG) Binary Modulators for Inhibiting Aggregation and Neurotoxicity of Amyloid-β Peptide
ACS Omega ( IF 3.7 ) Pub Date : 2019-02-26 00:00:00 , DOI: 10.1021/acsomega.8b02797
Qunxing Huang _{1,

2} , Qiong Zhao _{1,

3} , Jiaxi Peng ₁ , Yue Yu _{1,

2} , Chenxuan Wang _{1,

2} , Yimin Zou _{1,

2} , Yanlei Su ₃ , Ling Zhu _{1,

2} , Chen Wang _{1,

2} , Yanlian Yang _{1,

2}

Affiliation

Alzheimer’s disease (AD) is known as a typical neurodegenerative disease, and the pathogenic hallmark is the aggregation and deposition of amyloid-β peptide (Aβ) fibrils and plaque on neuronal cells resulting in cell dysfunction and cell death. One effective approach to preventing and curing AD lies in tuning Aβ aggregation and inhibiting the neurotoxicity by using molecular modulators. Peptide breakers and antioxidants are widely used inhibitors to modulate Aβ aggregation and neurotoxicity, although less efficiency of single modulators hinders the practical application of these molecules. An integration of different molecular modulators is expected to make use of multiple interactions and modulating sites and therefore synergistically improve the capacity of modulators in inhibiting Aβ aggregation. In this work, the concept of a binary peptide–polyphenol binary modulator (Aβ-segment KLVFF and (−)-epigallocatechin-3-gallate, KLVFF/EGCG) is proposed, and the synergistic effect of the KLVFF/EGCG modulator is demonstrated for efficient inhibition of Aβ aggregation and neurotoxicity. With the aid of thioflavin T fluorescence, circular dichroism spectroscopy, atomic force microscopy, and transmission electron microscopy, the inhibitory effect on Aβ42 fibrillation was determined. Further liquid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulations evidenced the affinity of the KLVFF/EGCG complex to the Aβ42 monomer. Furthermore, a tentative schematic mechanism is also proposed to illustrate the synergistic effect. Besides, the MTT assay and DCFH-DA (2′,7′-dichlorodihydrofluorescein diacetate) test were performed to explore the reduction of Aβ42-induced neurotoxicity by treating with the KLVFF/EGCG complex. The binary inhibitors showed remarkable reduction in Aβ42-induced ROS generation. This work could be beneficial for the designing of potential therapeutic binary modulators and shed light on AD prevention.

中文翻译：

肽多酚（KLVFF / EGCG）二元调节剂，可抑制淀粉样β肽的聚集和神经毒性

阿尔茨海默氏病（AD）是一种典型的神经退行性疾病，其致病标志是淀粉样β肽（Aβ）的原纤维和噬菌斑在神经元细胞上的聚集和沉积，从而导致细胞功能障碍和细胞死亡。预防和治愈AD的一种有效方法是通过使用分子调节剂来调节Aβ聚集并抑制神经毒性。肽破胶剂和抗氧化剂是广泛用于调节Aβ聚集和神经毒性的抑制剂，尽管单个调节剂的效率较低，阻碍了这些分子的实际应用。期望不同分子调节剂的整合利用多种相互作用和调节位点，因此协同提高调节剂抑制Aβ聚集的能力。在这项工作中，提出了二元肽-多酚二元调节剂（Aβ段KLVFF和（-）-epigallocatechin-3-gallate，KLVFF / EGCG）的概念，并证明了KLVFF / EGCG调节剂的协同作用可有效抑制Aβ聚集和神经毒性。借助于硫黄素T荧光，圆二色光谱，原子力显微镜和透射电子显微镜，确定了对Aβ42原纤化的抑制作用。进一步的液态核磁共振波谱和分子动力学模拟证明了KLVFF / EGCG复合物对Aβ42单体的亲和力。此外，还提出了一种示意性的原理机制来说明协同效应。此外，MTT分析和DCFH-DA（2' 进行了7'-二氯二氢荧光素二乙酸酯）试验，以探讨通过用KLVFF / EGCG复合物治疗减少Aβ42诱导的神经毒性。二元抑制剂显示出Aβ42诱导的ROS生成显着减少。这项工作可能有益于设计潜在的治疗性二进制调节剂，并有助于预防AD。

更新日期：2019-02-26

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