Previous studies indicate that quercetin can disaggregate Aβ1-42 amyloid fibrils and α-synuclein fibrils, while the effect of quercetin on PrP fibrils is not clear. It is found that quercetin has several beneficial effects in both human cells and rodent models, including cancer prevention, cardiovascular protection, anti-inflammatory effects, and neurodegeneration prevention.
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Quercetin is a flavonoid with excellent activity to scavenge free radicals and is one of the dietary antioxidants commonly found in many kinds of food, including apples, onions, green tea, wine, and so on. Flavonoids are a group of polyphenols with high antioxidant ability to react with free radicals and to protect the cells from reactive oxygen species (ROS). Oxidative stress occurs in many neurodegenerative diseases. Several polyphenol molecules can inhibit Aβ, α-synuclein, or PrP amyloid fibril formation or disaggregate the fibrils, such as epigallocatechin 3-gallate (EGCG), curcumin, and nordihydroguaiaretic acid (NDGA). Several materials were found to disaggregate amylin or Aβ amyloid fibrils, including small peptides, nanoparticles, and polyphenols. These inter- and intramolecular interactions make prion fibrils highly stable and difficult to disaggregate. In addition, each protofilament is stabilized by backbone hydrogen bonds. According to a recent study on the structure of prion fibrils with a protease-resistant core, H111-D144 salt bridge is found in intrafilaments, and each protofilament interacts with hydrophobic force. PrP Sc is a stable material that is hard to inactivate. Therefore, foreign PrP fibrils possess cytotoxicity. It is highly associated with human intake of the BSE pathogen. Variant Creutzfeldt–Jakob disease (vCJD) is one of the prion diseases in humans. Evidently, cell membrane disruption caused by PrP fibrils leads to cell death. Several studies have shown that PrP Sc interacts with the lipid membrane and causes membrane permeabilization. Amyloid fibrils can lead to lipid bilayer disruption and cell death. Further accumulation of PrP Sc forms insoluble, protease-resistant amyloid fibrils or plaques. TSEs are fatal neurodegenerative diseases ascribed to the structural change of prion protein from α-helix-rich isoform (PrP C) to β-sheet-rich isoform (PrP Sc). TSEs have drawn more attention for cross-species transmission since the outbreak of bovine spongiform encephalopathy (BSE). In addition, type-2 diabetes in the pancreas and light chain amyloidosis in the heart, kidney, liver, and peripheral nervous system have been identified as amyloidoses. Amyloid fibrils can be found in various amyloidoses, such as Alzheimer’s disease, Parkinson’s disease, and transmissible spongiform encephalopathies (TSEs) in the brain and neuron.
Amyloid fibrils have a high tendency to accumulate into insoluble plaques and deposit in tissues and organs. This study provides a solution for the development of antiamyloidogenic therapy.Īmyloid fibrillation is caused by the misfolding of native proteins. The role of quercetin is distinct from the typical function of antiamyloidogenic drugs that inhibit the formation of amyloid fibrils. Consequently, quercetin-bound fibrils cause less oxidative stress, and are less cytotoxic to neuroblastoma cells. Furthermore, quercetin-bound fibrils can reduce the membrane disruption of erythrocytes. The results showed that quercetin treatment can disaggregate moPrP fibrils and lead to the formation of the proteinase-sensitive amorphous aggregates. 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. However, the disaggregating ability is unclear in PrP fibrils. Previous studies have demonstrated that quercetin can disaggregate some amyloid fibrils, such as amyloid β peptide (Aβ) and α-synuclein. Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases caused by misfolding and aggregation of prion protein (PrP).