Abstract
The misfolding and aggregation of amyloid beta (Aβ) 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 Aβ(1–42) aggregation and ameliorates Aβ aggregate-induced cytotoxicity. A small amount of tabersonine (e.g., 10 μM) can effectively inhibit the formation of Aβ(1–42) (e.g., 80 μM) fibrils or convert mature fibrils into largely innocuous amorphous aggregates. SPR results indicate that tabersonine binds to Aβ(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 Aβ(1–42). Tabersonine preferentially interact with the β-sheet grooves of Aβ(1–42) containing aromatic and hydrophobic residues. The various binding sites and modes explain the diverse inhibitory effects of tabersonine on Aβ 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.
Supporting Information
Figure S1: Chromatogram of 1 mg/mL tabersonine extracted from Voacanga africana beans. Figure S2: SEC standard calibration curve. Figure S3: Surface plasmon resonance sensorgrams. Table S1: Experimentally measured and theoretical isotopic peaks of tabersonine. This material is available free of charge via the Internet at http://pubs.acs.org/.
