Glycosides and Their Corresponding Small Molecules Inhibit Aggregation and Alleviate Cytotoxicity of Aβ40

Polyphenols are the class of naturally synthesized compounds in the secondary metabolism of plants, which are widely distributed in fruits and vegetables. Their potential health treatment strategies have attracted wide attention in the scientific community. The abnormal aggregation of Aβ to form mature fibrils is pathologically related to Alzheimer's disease (AD). Therefore, inhibiting Aβ40 fibrillogenesis was considered to be the major method for the intervention and therapy of AD. Glycosides, as a cluster of natural phenolic compounds, are widely distributed in Chinese herbs, fruits, and vegetables. The inhibitory effect of glycosides (phloridzin, salidroside, polydatin, geniposide, and gastrodin) and their corresponding small molecules (phloretin, 4-hydroxyphenyl ethanol, resveratrol, genipin, and 4-hydroxybenzyl alcohol) on Aβ40 aggregation and fibrils prolongation, disaggregation against mature fibrils, and the resulting cytotoxicity were studied by systematical biochemical, cell biology and molecular docking techniques, respectively. As a result, all inhibitors were observed against Aβ40 aggregation and fibrils prolongation and disaggregated mature Aβ40 fibrils in a dose-dependent manner. Besides, the cell validity experiments also showed that all inhibitors could effectively alleviate the cytotoxicity induced by Aβ40 aggregates, and the glycoside groups played important roles in this inhibiting process. Finally, molecular docking was performed to study the interactions between these inhibitors and Aβ40. Docking showed that all inhibitors were bound to the similar region of Aβ40, and glycoside group formed hydrogen bonds with the pivotal residues Lys16. These results indicated that the glycoside groups could increase the inhibitory effects and reduce cytotoxicity. Glycosides have tremendous potential to be developed as an innovative type of aggregation inhibitor to control and treat neurodegenerative diseases.