Paper Citing NAMD - Abstract
Kai, Tianhan; Zhang, Lin; Wang, Xiaoying; Jing, Aihua; Zhao, Bingqing; Yu, Xiang; Zheng, Jie; Zhou, Feimeng
Tabersonine Inhibits Amyloid Fibril Formation and Cytotoxicity of A beta(1-42)
ACS CHEMICAL NEUROSCIENCE, 6:879-888, JUN 2015
The misfolding and aggregation of amyloid beta (A beta) peptides into amyloid fibrils are key events in the amyloid cascade hypothesis for the etiology of Alzheimer's 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 beta(1-42) aggregation and ameliorates A beta aggregate-induced cytotoxicity. A small amount of tabersonine (e.g., 10 mu M) can effectively inhibit the formation of A beta(1-42) (e.g., 80 mu M) fibrils or convert mature fibrils into largely innocuous amorphous aggregates. SPR results indicate that tabersonine binds to A beta(1-42) oligomers in a dose-dependent way. Molecular dynamics (MD) simulations further confirm that tabersonine can bind to oligomers such as the pentamer of A beta(1-42). Tabersonine preferentially interact with the beta-sheet grooves of A beta(1-42) containing aromatic and hydrophobic residues. The various binding sites and modes explain the diverse inhibitory effects of tabersonine on A beta 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-brain barrier make it a potential therapeutic drug candidate for treating AD.
