Ginnalin A Inhibits Aggregation, Reverses Fibrillogenesis and Alleviates Cytotoxicity of Amyloid β(1–42)

Aggregation of misfolded amyloid beta (Aβ) peptides into neurotoxic oligomers and fibrils has been implicated as a key event in the etiopathogenesis of Alzheimer’s disease (AD). Ginnalin A (GA), a polyphenolic compound isolated from the red maple (Acer rubrum), has been found to possess anticancer, anti-glycation, and anti-oxidation properties. Using thioflavin-T (ThT) fluorescence, surface plasmon resonance (SPR), and atomic force microscopy (AFM), we demonstrate that GA can also effectively inhibit Aβ aggregation by primarily binding to Aβ monomers in a dose-dependent manner. Furthermore, GA can bind to multiple sites of Aβ aggregates to disassemble preformed fibrils and convert them into small aggregates. Circular dichroism (CD) spectra showed that these small aggregates are much less abundant in β-sheets, while cell viability assay confirms that they are essentially innocuous. Molecular dynamics (MD) simulations revealed that GA preferentially contacts with the C- and N-terminal β-sheets and the U-tur...