摘要
伴随阿尔茨海默氏病(AD)的发展, 出现包括错误折叠蛋白聚合物的积累(如:β-淀粉样蛋白斑块)、金属离子稳态失衡和氧化应激等在内的一些病理特征性改变。最新研究表明这些特征是通过一个潜在因素相互关联的,即金属与β-淀粉样蛋白(金属− Aβ)的联合物种。然而,金属-Aβ复合物在AD发病机制中的作用尚不清楚。为了阐明金属-Aβ联合物种在阿尔茨海默氏病病理改变中的作用,并开发小分子化学试剂和/或探索诊治(治疗和诊断)该病的新途径,来自于姜黄的天然产品姜黄素及其衍生物已广泛应用于对无金属和金属诱导的β-淀粉样蛋白聚合物的研究中。尽管研究表明姜黄素具有抗淀粉样蛋白活性和抗氧化特性,但其生物学效用受限于低溶解度和生理状态下的稳定性。在此,我们报告了姜黄素的反应性及其无金属-Aβ与金属-Aβ复合物的衍生物(Gd-Cur,一种潜在的多模式β-淀粉样蛋白显像剂;Cur-S,一种水溶性的取代了酚羟基的姜黄素衍生物)。我们的观察和研究结果表明Gd-Cur对铜(II)诱导的β-淀粉样蛋白聚合物的调节效果明显优于对无金属或锌(II)诱导的类似物;然而,没有发现Cur-S能显著调节有和没有金属离子诱导的β-淀粉样蛋白聚合物。总的说来,我们的研究信息能帮助优化姜黄素的分子结构以发展化学试剂或开发金属−Aβ联合物种以提高诊疗技术。
关键词: 阿尔茨海默氏病;β-淀粉样蛋白;金属-Aβ联合物种;β-淀粉样蛋白聚合调控;水溶性姜黄素衍生物;化学试剂
Current Alzheimer Research
Title:Inhibitory Activity of Curcumin Derivatives Towards Metal-Free and Metal-Induced Amyloid-β Aggregation
Volume: 12 Issue: 5
Author(s): Akiko Kochi, Hyuck Jin Lee, Sashiprabha M. Vithanarachchi, Vediappen Padmini, Matthew J. Allen and Mi Hee Lim
Affiliation:
关键词: 阿尔茨海默氏病;β-淀粉样蛋白;金属-Aβ联合物种;β-淀粉样蛋白聚合调控;水溶性姜黄素衍生物;化学试剂
摘要: 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.
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Cite this article as:
Akiko Kochi, Hyuck Jin Lee, Sashiprabha M. Vithanarachchi, Vediappen Padmini, Matthew J. Allen and Mi Hee Lim , Inhibitory Activity of Curcumin Derivatives Towards Metal-Free and Metal-Induced Amyloid-β Aggregation, Current Alzheimer Research 2015; 12 (5) . https://dx.doi.org/10.2174/1567205012666150504150125
DOI https://dx.doi.org/10.2174/1567205012666150504150125 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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