Polyphenolic Biflavonoids Inhibit Amyloid-Beta Fibrillation and Disaggregate Preformed Amyloid-Beta Fibrils
10.4062/biomolther.2019.113
- Author:
Erika Y. CHOI
1
;
Sam Sik KANG
;
Sang Kook LEE
;
Byung Hee HAN
Author Information
1. Department of Pharmacology, A.T. Still University of Health Sciences, Kirksville, MO 63501, USA
- Publication Type:Original Article
- From:Biomolecules & Therapeutics
2020;28(2):145-151
- CountryRepublic of Korea
- Language:0
-
Abstract:
Alzheimer’s disease (AD) is a devastating neurodegenerative disease and a major cause of dementia in elderly individuals world-wide. 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.
