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

Abstract

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, antiglycation, and antioxidation 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-turn region of Aβ(1-42) oligomers through hydrophobic interactions and hydrogen bonding. Compared with other natural compounds that have shown promise in anti-Aβ fibrillogenesis and ameliorating Aβ-induced cytotoxicity, GA is unique in that it exhibits a more efficient inhibition of Aβ aggregation at the very early stage through its strong interaction with Aβ monomers and exerts its inhibitory effect at a lower dosage.

• Authors: Qi Fan, Yonglan Liu, Xiaoying Wang, Zhuang Zhang, Yaru Fu, Luyao Liu, Pengcheng Wang, Hongmin Ma, Hang Ma, Navindra P Seeram, Jie Zheng, Feimeng Zhou
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 11 Issue 4 Pg. 638-647 (02 19 2020) ISSN: 1948-7193 [Electronic] United States
• PMID: 31967782 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid
• Amyloid beta-Peptides
• Peptide Fragments
• ginnalin A
• Gallic Acid
• Deoxyglucose

Topics

• Alzheimer Disease (metabolism)
• Amyloid (drug effects, metabolism)
• Amyloid beta-Peptides (drug effects, metabolism)
• Cell Survival (drug effects)
• Circular Dichroism (methods)
• Deoxyglucose (analogs & derivatives, pharmacology)
• Gallic Acid (analogs & derivatives, pharmacology)
• Humans
• Peptide Fragments (drug effects, metabolism)
• Surface Plasmon Resonance (methods)