Tabersonine Inhibits Amyloid Fibril Formation and Cytotoxicity of Aβ(1–42)

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.

The effects of fluorescent labels on Aβ42 aggregation detected by fluorescence correlation spectroscopy

“…The aggregation and neurotoxicity of Aβ oligomers, especially for Aβ 42 oligomers, are subjects of intense AD research. Several techniques can be used to analyze Aβ oligomers, including fluorescence correlation spectroscopy (FCS), fluorescence resonance energy transfer, magic angle spinning (MAS) NMR spectroscopy (MAS NMR), total internal reflection fluorescence microscopy, SDS polyacrylamide gel electrophoresis (SDS‐PAGE), size‐exclusion chromatography, mass spectrometry (MS), dynamic light scattering, atomic force microscopy (AFM), and Thioflavin T spectroscopic assay …”

Molecular Simulations of Amyloid Structures, Toxicity, and Inhibition

“…Tabersonine . We discovered a new natural product of tabersonine, an ingredient extracted from the bean of Voacanga africana as a traditional medicine in Africa, which has been widely used in different diseases of leprosy, convulsions in children, and infant tonic seizures. Tabersonine was already demonstrated to have high permeability through the BBB.…”

A BAHD acyltransferase catalyzing 19‐O‐acetylation of tabersonine derivatives in roots of Catharanthus roseus enables combinatorial synthesis of monoterpene indole alkaloids

“…Furthermore, combining TAT with previously identified MIA biosynthetic enzymes ultimately allowed the engineered synthesis of unnatural tabersonine derivatives. Such a system thus constitutes a valuable tool to perform tailor‐made decorations of the tabersonine scaffold yielding potential anti‐cancer or anti‐Alzheimer compounds (Lim et al ., ; Frei et al ., ; Kai et al ., ; Chung et al ., ).…”