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

Abstract

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.

Exploration of Isoquinoline Alkaloids as Potential Inhibitors against Human Islet Amyloid Polypeptide

“…Many inhibitors may remodel mature fibrils and hold great promise in drug development. − In our study, the remodeling of hIAPP fibrils was evaluated by ThT kinetic analysis and AFM images. A total of 20 μM hIAPP was cultured at 310 K for 72 h to form mature fibrils, then the alkaloids were added into the peptide solution at a molar ratio of 1:5, and the ThT fluorescence intensity was observed within 36 h. As expected, all three alkaloids showed remarkable disaggregation ability to hIAPP fibrils after excluding the interaction of alkaloid with ThT over time (Figures A and S3).…”

Aspartic Acid-Modified Phospholipids Regulate Cell Response and Rescue Memory Deficits in APP/PS1 Transgenic Mice

“…Considering the targeting and long-acting properties of drugs, the advantages of liposomes should be fully exploited, especially the enhancement of structural design and functional regulation. Taken together, these findings offer a new approach to develop drugs that inhibit Aβ aggregation and/or neurotoxicity and are expected to become a potential drug for preventing and treating AD in the future. − …”

Polydatin as a therapeutic alternative for central nervous system disorders: A systematic review of animal studies

“…Polydatin has shown only in vitro effects in the inhibition of amyloid‐beta (Aβ) aggregation, a critical pathogenic event of AD (Hao et al, 2022; Rivière et al, 2007, 2010; Rivière, Delaunay, Immel, Cullin, & Monti, 2009). In addition, polydatin prevented the neuronal apoptosis induced by mitochondrial dysfunction mitochondria‐induced neuron apoptosis, upregulated nicotinic acetylcholine receptors expression as well as showed antioxidant effects and no cytotoxicity in in vitro models of AD (Hao et al, 2022; Phan et al, 2019; Tang, 2021; X. Wang et al, 2017; H. Xiao et al, 2014). Nevertheless, in vivo polydatin effects have not yet been explored in neurological disorders such as Huntington's disease, Lewy body dementia, or epilepsy.…”

“…We also noticed a lack of in vivo evidence about the effects of polydatin on some prominent CNS disorders. Polydatin has shown only in vitro effects in the inhibition of amyloid-beta (Aβ) aggregation, a critical pathogenic event of AD (Hao et al, 2022;Rivière et al, 2007Rivière et al, , 2010Rivière, Delaunay, Immel, Cullin, & Monti, 2009). In addition, polydatin prevented the neuronal apoptosis induced by mitochondrial dysfunction mitochondria-induced neuron apoptosis, upregulated nicotinic acetylcholine receptors expression as well as showed antioxidant effects and no cytotoxicity in in vitro models of AD (Hao et al, 2022;Phan et al, 2019;Tang, 2021;X.…”