Multiple lines of evidence indicate that amyloid beta (Aβ) peptide is responsible for the pathological devastation caused in Alzheimer's disease (AD). Aβ aggregation species predominantly contribute to multifaceted toxicity observed in neuronal cells including generation of reactive oxygen species (ROS), mitochondrial dysfunction, interfering with synaptic signaling, and activation of premature apoptosis. Herein, we report a natural product berberine-derived (Ber-D) multifunctional inhibitor to ameliorate in cellulo multifaceted toxicity of AD. The structural attributes of polyphenolic Ber-D have contributed to its efficient Cu chelation and arresting the redox cycle to prevent the generation of ROS and rescue biomacromolecules from oxidative damage. Ber-D inhibits metal-dependent and -independent Aβ aggregation, which is supported by in silico studies. Ber-D treatment averts mitochondrial dysfunction and corresponding neuronal toxicity contributing to premature apoptosis. These key multifunctional attributes make Ber-D a potential therapeutic candidate to ameliorate multifaceted Aβ toxicity in AD.

多项证据表明，β 淀粉样蛋白 (Aβ) 肽是造成阿尔茨海默病 (AD) 病理破坏的原因。 Aβ 聚集物质主要导致神经元细胞中观察到的多方面毒性，包括活性氧 (ROS) 的产生、线粒体功能障碍、干扰突触信号传导以及过早凋亡的激活。在此，我们报道了一种天然产物小檗碱衍生（Ber-D）多功能抑制剂，可改善 AD 的细胞多方面毒性。多酚 Ber-D 的结构特性有助于其有效的 Cu 螯合和阻止氧化还原循环，从而防止 ROS 的产生并拯救生物大分子免受氧化损伤。 Ber-D 抑制金属依赖性和非金属依赖性 Aβ 聚集，这一点得到了计算机研究的支持。 Ber-D 治疗可避免线粒体功能障碍和相应的导致过早凋亡的神经元毒性。这些关键的多功能属性使 Ber-D 成为改善 AD 多方面 Aβ 毒性的潜在治疗候选药物。