Kochi Akiko, Lee Hyuck Jin, Vithanarachchi Sashiprabha M, Padmini Vediappen, Allen Matthew J, Lim Mi Hee
Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 689- 798, Korea.
Curr Alzheimer Res. 2015;12(5):415-23. doi: 10.2174/1567205012666150504150125.
When Alzheimer's disease (AD) progresses, several pathological features arise including accumulation of misfolded protein aggregates [e.g., amyloid-β (Aβ) plaques], metal ion dyshomeostasis, and oxidative stress. These characteristics are recently suggested to be interconnected through a potential factor, metal-associated Aβ (metal-Aβ) species. The role of metal-Aβ species in AD pathogenesis remains unclear, however. To elucidate the contribution of metal-Aβ species to AD pathology, as well as to develop small molecules as chemical tools and/or theranostic (therapeutic and diagnostic) agents for this disease, curcumin (Cur), a natural product from turmeric, and its derivatives have been studied towards both metal-free and metal-induced Aβ aggregation. Although Cur has indicated anti-amyloidogenic activities and antioxidant properties, its biological use has been hindered due to low solubility and stability in physiologically relevant conditions. Herein, we report the reactivity of Cur and its derivatives (Gd-Cur, a potential multimodal Aβ imaging agent; Cur-S, a water soluble derivative of Cur that has substitution at the phenolic hydroxyls) with metal-free Aβ and metal-Aβ species. Our results and observations indicate that Gd-Cur could modulate Cu(II)-triggered Aβ aggregation more noticeably over metal-free or Zn(II)-induced analogues; however, Cur-S was not observed to noticeably modulate Aβ aggregation with and without metal ions. Overall, our studies present information that could aid in optimizing the molecular scaffold of Cur for the development of chemical tools or theranostics for metal-Aβ species.
当阿尔茨海默病（AD）进展时，会出现几种病理特征，包括错误折叠的蛋白质聚集体（如β-淀粉样蛋白（Aβ）斑块）的积累、金属离子稳态失衡和氧化应激。最近有人提出，这些特征通过一个潜在因素——金属相关Aβ（金属-Aβ）物种相互关联。然而，金属-Aβ物种在AD发病机制中的作用仍不清楚。为了阐明金属-Aβ物种对AD病理的贡献，并开发小分子作为该疾病的化学工具和/或治疗诊断剂，姜黄素（Cur），一种来自姜黄的天然产物，及其衍生物已针对无金属和金属诱导的Aβ聚集进行了研究。尽管Cur已显示出抗淀粉样蛋白生成活性和抗氧化特性，但其在生理相关条件下的低溶解度和稳定性阻碍了其生物学应用。在此，我们报告了Cur及其衍生物（Gd-Cur，一种潜在的多模态Aβ成像剂；Cur-S，Cur的一种水溶性衍生物，在酚羟基处有取代）与无金属Aβ和金属-Aβ物种的反应性。我们的结果和观察表明，与无金属或锌（II）诱导的类似物相比，Gd-Cur能更显著地调节铜（II）触发的Aβ聚集；然而，未观察到Cur-S在有无金属离子的情况下对Aβ聚集有明显调节作用。总体而言，我们的研究提供了有助于优化Cur分子支架以开发针对金属-Aβ物种的化学工具或治疗诊断剂的信息。
