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

Authors

Qi Fan, University of Jinan
Yonglan Liu, University of Akron
Xiaoying Wang, University of Jinan
Zhuang Zhang, University of Jinan
Yaru Fu, University of Jinan
Luyao Liu, University of Jinan
Pengcheng Wang, University of Jinan
Hongmin Ma, University of Jinan
Hang Ma, University of Rhode Island
Navindra P. Seeram, University of Rhode Island
Jie Zheng, University of Akron
Feimeng Zhou, University of Jinan

Document Type

Article

Date of Original Version

2-19-2020

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.

Publication Title, e.g., Journal

ACS Chemical Neuroscience

Volume

11

Issue

4

Citation/Publisher Attribution

Fan, Qi, Yonglan Liu, Xiaoying Wang, Zhuang Zhang, Yaru Fu, Luyao Liu, Pengcheng Wang, Hongmin Ma, Hang Ma, Navindra P. Seeram, Jie Zheng, and Feimeng Zhou. "Ginnalin A Inhibits Aggregation, Reverses Fibrillogenesis, and Alleviates Cytotoxicity of Amyloid β(1-42)." ACS Chemical Neuroscience 11, 4 (2020): 638-647. doi: 10.1021/acschemneuro.9b00673.