Inhibitory Effect of a Flavonoid Dihydromyricetin against Aβ40 Amyloidogenesis and Its Associated Cytotoxicity

Abstract

Misfolding and fibrillogenesis of amyloid-β protein (Aβ) play a key role in the onset and progression of Alzheimer’s disease (AD). Screening for inhibitors against Aβ amyloidogenesis is helpful for rational designing and developing new anti-AD drugs and therapeutic strategies. Dihydromyricetin, a natural flavonoid extracted from a Chinese herb, Ampelopsis grossedentata, has been proven with antioxidative, anti-inflammatory, and neuroprotective effects against neurodegenerative disease. Herein, we found that dihydromyricetin could inhibit Aβ40 aggregation, impede the protofibril formation, disassemble preformed Aβ40 fibrils, and protect PC12 cells from the Aβ40-induced cytotoxicity using a series of biochemical and biophysical assays, including thioflavin T fluorescence, atomic force microscopy, and cell toxicity assays. Circular dichroism spectroscopy data proved that dihydromyricetin delayed the Aβ40 conformational conversion. In addition, the results of molecular dynamics simulations indicated that the interaction between dihydromyricetin and Aβ40 trimer is mainly nonpolar interactions. Key residues (i.e., V18, A21, and D23) of the Aβ40 interacting with dihydromyricetin were also identified. This study suggested that dihydromyricetin shows great potential to be developed as a novel Aβ40 inhibitor.

Nitrogen‐Doped Carbonized Polymer Dots: A Potent Scavenger and Detector Targeting Alzheimer's β‐Amyloid Plaques

“…CPDs have unique chemical compositions such as amino, nitro, pyrimidine rings, pyrrole rings, and benzene rings, so there could be multiple interactions, such as electrostatic interactions, H‐bonding, and hydrophobic interactions, between CPDs and Aβ fibrils, which might lead to the breaking of intermolecular Aβ salt bridges and disruption of highly ordered fibrillar structures stabilized by these interactions. [ 43,55,56 ]…”

“…CPDs have unique chemical compositions such as amino, nitro, pyrimidine rings, pyrrole rings, and benzene rings, so there could be multiple interactions, such as electrostatic interactions, H-bonding, and hydrophobic interactions, between CPDs and Aβ fibrils, which might lead to the breaking of intermolecular Aβ salt bridges and disruption of highly ordered fibrillar structures stabilized by these interactions. [43,55,56] The ThT results ( Figure 3a) indicate that the disassembly of Aβ fibrils was quite fast, finishing in less than 4 h. Therefore, to see more details in the disassembly, fast disaggregation kinetics of Aβ 40 fibrils modulated with CPDs was investigated by stopped-flow fluorescence spectroscopy (Figure 3c). From the fast kinetic curves, the ThT fluorescence intensity of Aβ 40 fibrils treated with CPDs exhibited a rapid decrease within 50 s, then continued to decline slowly, indicating that CPDs disrupted Aβ 40 fibrils on a time scale of seconds.…”

Molecular Level Insight Into the Benefit of Myricetin and Dihydromyricetin Uptake in Patients With Alzheimer’s Diseases

“…Secondly, Aβ monomer has a neurotrophic effect, but the oligomers and fibrils of Aβ have severe neurotoxicity (mainly including inflammation, oxidative stress, and destruction of cell membranes) (Jang et al, 2007;Umeda et al, 2011;Zhai et al, 2012). The oligomers and fibrils of Aβ are generated by excess Aβ through β-sheet (Jang et al, 2007) and MYR and DMY can inhibit the formation of this β-sheet (Shimmyo et al, 2008;Jia et al, 2019). The hydroxyl group of MYR forms a hydrogen bond with a carbonyl group and amino group in Aβ (Andarzi Gargari et al, 2018).…”

“…DMY can combine with the three sites on the Aβ structure to block its molecular conformation and break its intramolecular hydrogen bonds. This not only blocks the β-sheet but also has a dismantling effect on the already formed Aβ fibrils (Jia et al, 2019). Thus, MYR and DMY can hinder the formation of Aβ oligomers, which will reduce the neurotoxicity of Aβ oligomers, and release the symptoms of AD (Figure 2).…”

Tandem-Homodimer of a β-Sheet-Forming Short Peptide Inhibits Random-to-β Structural Transition of Its Original Monomer

“…Such Aβ fragment peptides may bind to the full-length Aβ peptide and inhibit subsequent elongation of Aβ fibrous arrangements. Additionally, nonpeptidyl small molecules [11][12][13][14] and polymeric macromolecules have been developed to modulate Aβ self-assembly, facilitating fibril formation and inhibiting Aβ peptide association processes [15,16].…”