Tabersonine Inhibits Amyloid Fibril Formation and Cytotoxicity of A尾(1鈥?2)

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• 作者：Tianhan Kai ; Lin Zhang ; Xiaoying Wang ; Aihua Jing ; Bingqing Zhao ; Xiang Yu ; Jie Zheng ; Feimeng Zhou
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：June 17, 2015
• 年：2015
• 卷：6
• 期：6
• 页码：879-888
• 全文大小：547K
• ISSN：1948-7193

文摘

The misfolding and aggregation of amyloid beta (A尾) peptides into amyloid fibrils are key events in the amyloid cascade hypothesis for the etiology of Alzheimer鈥檚 disease (AD). Using thioflavin-T (ThT) fluorescence assay, atomic force microscopy, circular dichroism, size exclusion chromatography, surface plasmon resonance (SPR), and cytotoxicity tests, we demonstrate that tabersonine, an ingredient extracted from the bean of Voacanga africana, disrupts A尾(1鈥?2) aggregation and ameliorates A尾 aggregate-induced cytotoxicity. A small amount of tabersonine (e.g., 10 渭M) can effectively inhibit the formation of A尾(1鈥?2) (e.g., 80 渭M) fibrils or convert mature fibrils into largely innocuous amorphous aggregates. SPR results indicate that tabersonine binds to A尾(1鈥?2) oligomers in a dose-dependent way. Molecular dynamics (MD) simulations further confirm that tabersonine can bind to oligomers such as the pentamer of A尾(1鈥?2). Tabersonine preferentially interact with the 尾-sheet grooves of A尾(1鈥?2) containing aromatic and hydrophobic residues. The various binding sites and modes explain the diverse inhibitory effects of tabersonine on A尾 aggregation. Given that tabersonine is a natural product and a precursor for vincristine used in cancer chemotherapy, the biocompatibility and small size essential for permeating the blood鈥揵rain barrier make it a potential therapeutic drug candidate for treating AD.