Quercetin Disaggregates Prion Fibrils and Decreases Fibril-Induced Cytotoxicity and Oxidative Stress

Abstract

Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases caused by misfolding and aggregation of prion protein (PrP). Previous studies have demonstrated that quercetin can disaggregate some amyloid fibrils, such as amyloid β peptide (Aβ) and α-synuclein. However, the disaggregating ability is unclear in PrP fibrils. In this study, we examined the amyloid fibril-disaggregating activity of quercetin on mouse prion protein (moPrP) and characterized quercetin-bound moPrP fibrils by imaging, proteinase resistance, hemolysis assay, cell viability, and cellular oxidative stress measurements. The results showed that quercetin treatment can disaggregate moPrP fibrils and lead to the formation of the proteinase-sensitive amorphous aggregates. Furthermore, quercetin-bound fibrils can reduce the membrane disruption of erythrocytes. Consequently, quercetin-bound fibrils cause less oxidative stress, and are less cytotoxic to neuroblastoma cells. The role of quercetin is distinct from the typical function of antiamyloidogenic drugs that inhibit the formation of amyloid fibrils. This study provides a solution for the development of antiamyloidogenic therapy.

Combination of structure-based virtual screening, molecular docking and molecular dynamics approaches for the discovery of anti-prion fibril flavonoids

“…As reported previously, quercetin disaggregated mature prion fibrils ( Yu and Lee, 2020 ). We examined the stable binding of quercetin ( Figure 3A ) to fPrP 170–229 by a 162 ns MD simulation of quercetin-fPrP 170–229 complexes.…”

“…The binding of COMPs increases loop and helix contents in fPrP 170−229 ( Figures 7B, C ). Quercetin is shown to be highly effective for prion fibril treatment ( Yu and Lee, 2020 ). Herein, we found that quercetin binding decreases strand content and increases loop and helix contents in fPrP 170−229 .…”

“…Quercetin is commonly found in our diet and has many benefits for anti-inflammation, anti-cancer, anti-neurological diseases, and diabetes mellitus ( Ulusoy and Sanlier, 2020 ). Recently, we found that quercetin disaggregates mature prion fibrils, accelerates fibril clearance with PK, and reduces ROS levels in Neuro-2a cells ( Yu and Lee, 2020 ). In addition, quercetin binding accelerates the formation of PK-sensitive and structure-less fibrils ( Yu et al, 2022 ).…”

Investigating the Mechanism of Guizhi Fuling Formula in the Treatment of Primary Dysmenorrhea based on Network Pharmacology and Molecular Docking

“…According to a series of analysis above, we gained six signi cant compounds, keampferol concentrated in Baishao(Peony) ,quercetin and isorhamnetin were enriched in Danpi(Moutan Cortex),cerevisterol and 3,5-Dihydroxyergosta-7,22-dien-80-one were found in Fuling(Poria), glycosmisic acid existed in Guizhi(Cinnamomi Ramulus). Keampferol and quercetin always appeared at the same time due to the familiar effectiveness in antiin ammatory, antioxidation and proapoptosis [36][37][38][39].In a network study of TCM treating cancer-related pain [40], quercetin and kaempferol also worked as very important compounds, which could regulate the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)pathways to achieve the purpose of antitumor and alleviating pain.It might provide evidences for the effect of quercetin and kaempferol ameliorating the pain of menstruation. Cerevisterol and 3,5-Dihydroxyergosta-7,22-dien-80-one were usually isolated and identi ed from the mycelia, which could treat in ammatory diseases by targeting an MAPK, NF-κB, AP-1, and Nrf2-mediated HO-1 signaling cascade [41].…”

Autoxidation Enhances Anti-Amyloid Potential of Flavone Derivatives

“…Studies with flavones demonstrated properties against Aβ 42 aggregation in vitro [ 25 , 26 ]. In many cases, the anti-aggregation potential is evaluated via measurement of amyloidophilic dye thioflavin-T (ThT) fluorescence intensity [ 27 , 28 ], assuming that relatively lower fluorescence intensity correlates with fewer fibrils formed.…”