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

Kun-Hua Yu,Cheng-I Lee

doi:10.3390/pharmaceutics12111081

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.

Highlights

Amyloid fibrillation is caused by the misfolding of native proteins
We used transmission electron microscopy (TEM) to examine how quercetin affects the morphology of mouse prion protein (moPrP) fibrils
After treatment of PrP106-126 fibrils with bacoside A, the fibrils accumulate into large aggregates and reduce the permeation of membrane bilayers [47]. These findings indicate that the membrane disruption is stronger by small fibrils than by large aggregates

Summary

Introduction

Amyloid fibrillation is caused by the misfolding of native proteins. Amyloid fibrils have a high tendency to accumulate into insoluble plaques and deposit in tissues and organs. Amyloid fibrils can be found in various amyloidoses, such as Alzheimer’s disease [1], Parkinson’s disease [2], and transmissible spongiform encephalopathies (TSEs) [3] in the brain and neuron. TSEs have drawn more attention for cross-species transmission since the outbreak of bovine spongiform encephalopathy (BSE) [6]. Further accumulation of PrPSc forms insoluble, protease-resistant amyloid fibrils or plaques [3]. Amyloid fibrils can lead to lipid bilayer disruption [7] and cell death [8]. Cell membrane disruption caused by PrP fibrils leads to cell death

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Results

Conclusion