Polyphenolic Biflavonoids Inhibit Amyloid-Beta Fibrillation and Disaggregate Preformed Amyloid-Beta Fibrils
Erika Y. Choi1, Sam Sik Kang2, Sang Kook Lee2 and Byung Hee Han1,*
1Department of Pharmacology, A.T. Still University of Health Sciences, Kirksville, MO 63501, USA
2School of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
*E-mail: bhhan01@atsu.edu
Tel: +1-660-626-2730, Fax: +1-660-626-2320
Received: July 2, 2019; Revised: September 14, 2019; Accepted: September 16, 2019; Published online: November 7, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

Alzheimer's disease (AD) is a devastating neurodegenerative disease and a major cause of dementia in elderly individuals worldwide. Increased deposition of insoluble amyloid β (Aβ) fibrils in the brain is thought be a key neuropathological hallmark of AD. Many recent studies show that natural products such as polyphenolic flavonoids inhibit the formation of insoluble Aβ fibrils and/or destabilize β-sheet-rich Aβ fibrils to form non-cytotoxic aggregates. In the present study, we explored the structure-activity relationship of naturally-occurring biflavonoids on Aβ amyloidogenesis utilizing an in vitro thioflavin T assay with Aβ1-42 peptide which is prone to aggregate more rapidly to fibrils than Aβ1-40 peptide. Among the biflavonoids we tested, we found amentoflavone revealed the most potent effects on inhibiting Aβ1-42 fibrillization (IC50: 0.26 µM), as well as on disassembling preformed Aβ1-42 fibrils (EC50: 0.59 µM). Our structure-activity relationship study suggests that the hydroxyl groups of biflavonoid compounds play an essential role in their molecular interaction with the dynamic process of Aβ1-42 fibrillization. Our atomic force microscopic imaging analysis demonstrates that amentoflavone directly disrupts the fibrillar structure of preformed Aβ1-42 fibrils, resulting in conversion of those fibrils to amorphous Aβ1-42 aggregates. These results indicate that amentoflavone affords the most potent anti-amyloidogenic effects on both inhibition of Aβ1-42 fibrillization and disaggregation of preformed mature Aβ1-42 fibrils.
Keywords: Alzheimer's disease, Amyloid β (Aβ), Fibrillization, Disaggregation, Structure-activity relationship, Biflavonoids

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