Synthesis And Characterization Of Polymeric Nanoparticles For Inhibition Of Amyloid ? Protein Aggregation

Alzheimer's disease(AD)is a most common neurodegenerative disorder which is caused by the self-assembly of amyloid ?-protein(A?)into fibrils in human brain.Many studies suggest that polymeric nanoparticles can inhibit A? fibrillogenesis depending on the special surface properties of nanoparticles;however,the underlying molecular mechanism remains unknown.Herein,the inhibitory effect of nanoparticles with similar surface hydrophobicity but different surface negative charge densities on A? fibrillogenesis was examined.Firstly,the polymeric nanoparticles with similar size were synthesized by copolymerizing equal proportion of N-isopropylacrylamide and different proportion of N-t-butylacrylamide and acrylic acid.Then,the inhibitory effects of these nanoparticles on A?42 fibrillization and the corresponding cytotoxicity were investigated.It is found that these nanoparticles showed remarkable inhibitory capability against A?42 fibrillogenesis and alleviated its corresponding cytotoxicity.The inhibitory capability significantly depended on the capacity of negative surface charge carried by nanoparticles with an increase-decrease trend.The best inhibitory efficiency was obtained at the optimal surface negative charge density of nanoparticles.Based on these findings,a mechanistic model was proposed considering the two interactions between A?42 and nanoparticles,namely,hydrophobic binding and electrostatic repulsion(HyBER).The model suggested that at an appropriate negative charge capacity(NP10),the two opposite forces could be well-balanced,and thus led to the stretching of A?42 molecules instead of the formation of a harmful ?-sheet structure.Many small molecules from natural extract,eg.Epigallocatechin-3-gallate(EGCG),have been discovered with inhibition effect on A? aggregation.Herein,the effects of the combination of EGCG and NP10 on A? aggregation and its amyloid cytotoxicity were investigated.It is found that the dual-inhibitor system at low concentrations was more effective on the inhibition and detoxification of A? fibrillation than the additive effects of these two substances working individually.Based on the results,a synergistic working mechanism is proposed.The synergism of the dual-inhibitor system at low concentrations may open new perspectives for drug development in the prevention and treatment of AD.It is thought that the binding of metal ions,especially zinc ion(Zn2+),associate with the aggregation process of A?.Zn2+ accelerates A? amorphous aggregating and leads to oxidative stress and neuronal damage.In this study,we synthesized synthesis 2-hydroxy propylester-conjugated nanoparticles(IDA-NP)to retard A? aggregation in the presence or absence of Zn2+.This research reveals that IDA-NP is a bifunctional agent to prevent the aggregations of A?42 in the presence of Zn2+ and significantly mitigating the amyloid cytotoxicity.