Tanshinones Inhibit Amyloid Aggregation by Amyloid-尾 Peptide, Disaggregate Amyloid Fibrils, and Protect Cultured Cells
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- 作者：Qiuming Wang ; Xiang Yu ; Kunal Patal ; Rundong Hu ; Steven Chuang ; Ge Zhang ; Jie Zheng
- 刊名：ACS Chemical Neuroscience
- 出版年：2013
- 出版时间：June 19, 2013
- 年：2013
- 卷：4
- 期：6
- 页码：1004-1015
- 全文大小：584K
- 年卷期：v.4,no.6(June 19, 2013)
- ISSN：1948-7193
文摘
The misfolding and aggregation of amyloid-尾 (A尾) peptides into amyloid fibrils is regarded as one of the causative events in the pathogenesis of Alzheimer鈥檚 disease (AD). Tanshinones extracted from Chinese herb Danshen (Salvia Miltiorrhiza Bunge) were traditionally used as anti-inflammation and cerebrovascular drugs due to their antioxidation and antiacetylcholinesterase effects. A number of studies have suggested that tanshinones could protect neuronal cells. In this work, we examine the inhibitory activity of tanshinone I (TS1) and tanshinone IIA (TS2), the two major components in the Danshen herb, on the aggregation and toxicity of A尾1鈥?2 using atomic force microscopy (AFM), thioflavin-T (ThT) fluorescence assay, cell viability assay, and molecular dynamics (MD) simulations. AFM and ThT results show that both TS1 and TS2 exhibit different inhibitory abilities to prevent unseeded amyloid fibril formation and to disaggregate preformed amyloid fibrils, in which TS1 shows better inhibitory potency than TS2. Live/dead assay further confirms that introduction of a very small amount of tanshinones enables protection of cultured SH-SY5Y cells against A尾-induced cell toxicity. Comparative MD simulation results reveal a general tanshinone binding mode to prevent A尾 peptide association, showing that both TS1 and TS2 preferentially bind to a hydrophobic 尾-sheet groove formed by the C-terminal residues of I31-M35 and M35-V39 and several aromatic residues. Meanwhile, the differences in binding distribution, residues, sites, population, and affinity between TS1-A尾 and TS2-A尾 systems also interpret different inhibitory effects on A尾 aggregation as observed by in vitro experiments. More importantly, due to nonspecific binding mode of tanshinones, it is expected that tanshinones would have a general inhibitory efficacy of a wide range of amyloid peptides. These findings suggest that tanshinones, particularly TS1 compound, offer promising lead compounds with dual protective role in anti-inflammation and antiaggregation for further development of A尾 inhibitors to prevent and disaggregate amyloid formation.