Amyloid beta (Aβ) aggregation is the key trait responsible for the pathological devastation caused by Alzheimer’s disease (AD). Among the various pathways of multifaceted toxicity exhibited by Aβ aggregates in neuronal cells, generation of reactive oxygen species (ROS) by Aβ-Cu^II complex and mitochondrial damage are prominent. Aβ interferes with mitochondrial transport channels, causing mitochondrial dysfunction. Herein, we present nontoxic hybrid multifunctional modulators (HMMs, TGR86–88) developed by integrating the structural and functional features of the metal chelating aggregation modulator, clioquinol (Clq), and the antioxidant epigallocatechin gallate (EGCG). Detailed biophysical and docking studies show that TGR86 interacts with Aβ and efficiently modulates both metal-dependent and metal-independent Aβ aggregation. TGR86 complexes with Cu^II, arrests its redox cycle, and thereby prevents the generation of ROS. The antioxidant nature of the HMMs effectively prevents DNA damage and protein oxidation. TGR86 rescued PC12 cells from Aβ-induced neurotoxicity by preventing the generation of ROS and foiling the interaction of toxic Aβ species with mitochondria, thereby averting its damage. These key attributes make TGR86 a potential candidate to develop therapeutics for the multifactorial Aβ toxicity in Alzheimer’s disease.

中文翻译：

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混合多功能调节剂抑制多方面的Aβ毒性并防止线粒体损伤

淀粉样β（Aβ）聚集是导致阿尔茨海默氏病（AD）引起病理破坏的关键性状。在由神经元细胞中Aβ聚集体显示出多方面的毒性的各种途径，活性氧类别（ROS）的Aβ-Cu系^II复杂的和线粒体损害是突出的。Aβ干扰线粒体运输通道，导致线粒体功能障碍。在这里，我们介绍了通过整合金属螯合聚集调节剂，氯喹诺醇（Clq）和抗氧化剂表没食子儿茶素没食子酸酯（EGCG）的结构和功能特性而开发的无毒混合多功能调节剂（HMM，TGR86-88）。详细的生物物理和对接研究表明，TGR86与Aβ相互作用，并有效调节金属依赖性和非金属依赖性Aβ聚集。TGR86与Cu ^II的配合物，阻止其氧化还原循环，从而防止ROS的产生。HMM的抗氧化性质可有效防止DNA损伤和蛋白质氧化。TGR86通过阻止ROS的产生并阻止有毒Aβ物种与线粒体的相互作用，从而避免了其损害，从而使PC12细胞免于Aβ诱导的神经毒性。这些关键特性使TGR86成为开发阿尔茨海默氏病多因素Aβ毒性治疗剂的潜在候选者。