Cu²⁺ plays a key role in the pathogenesis of Alzheimer's disease (AD). The dysregulation of Cu²⁺ can cause neuronal damage and aggravate development of AD. Moreover, a series of 4-substituted sampangine derivatives have been investigated as inhibitors of acetylcholinesterase and β-amyloid (Aβ) aggregation for the treatment of AD in our previous studies. In the present study, we reported that one of these derivatives SD-1 was able to modulate Cu²⁺-mediated multiple pathological elements in AD. The high selectivity of SD-1 for Cu²⁺ over other biologically relevant metal ions was demonstrated by ITC. Western blotting analysis, light-scattering study, DCF-DA assay and paralysis experiment indicated that SD-1 suppressed the formation of Cu²⁺-Aβ species, alleviated the Cu²⁺-Aβ species induced neurotoxicity and inhibited the production of ROS catalyzed by Cu²⁺-Aβ species in SH-SY5Y cells over-expressing the Swedish mutant form of human APP (APPsw SH-SY5Y) and Aβ42 transgenic C elegans (CL2020). Furthermore, SD-1 inhibited the expressions of NO, iNOS, TNF-α, IL-1β and IL-6 induced by Cu²⁺ in BV2 microglial cells. Collectively, these findings provided valuable insights into the design and development of potent metal-chelating agents for AD treatment.

Cu ²⁺在阿尔茨海默病 (AD) 的发病机制中起关键作用。Cu ²⁺的失调可引起神经元损伤并加重AD的发展。此外，在我们之前的研究中，已经研究了一系列 4-取代的桑葚衍生物作为乙酰胆碱酯酶和 β-淀粉样蛋白 (Aβ) 聚集的抑制剂，用于治疗 AD。在本研究中，我们报道了这些衍生物之一SD-1能够调节AD 中Cu ²⁺介导的多种病理成分。SD-1对 Cu ²⁺的高选择性ITC 证明了比其他生物相关的金属离子。Western印迹分析、光散射研究、DCF-DA测定和麻痹实验表明，SD-1抑制了Cu ²⁺ -Aβ物种的形成，减轻了Cu ²⁺ -Aβ物种诱导的神经毒性并抑制了由过表达瑞典突变形式的人类 APP (APPsw SH-SY5Y) 和 Aβ42 转基因秀丽隐杆线虫(CL2020) 的SH-SY5Y 细胞中的Cu ²⁺ -Aβ 物种。此外，SD-1抑制Cu ²⁺诱导的NO、iNOS、TNF-α、IL-1β和IL-6的表达在 BV2 小胶质细胞中。总的来说，这些发现为设计和开发用于 AD 治疗的强效金属螯合剂提供了宝贵的见解。