Study On The Regulation Of β-amyloid Aggregation By Polydopamine Nanoparticles Using AFM

Neurotoxic oligomers and insoluble amyloid fibrils formed by the abnormal aggregation ofβ-amyloid（Aβ）has been considered as important factors for predisposing Alzheimer’s disease（AD）.At present,there is no effective treatment for AD.In addition,a large number of Researchs had shown that metal ions can accelerate Aβaggregation to form the more toxic Aβ-metal complexes,and the generation of reactive oxygen species to lead neuronal death,then exacerbate AD symptoms.Therefore,the design and development of inhibitors with highly efficient,simple synthesis and good biocompatibility for the regulation of Aβself-assembly and metal-induced Aβaggregation have been considered as a potential strategie for AD prevention and treatment.Polydopamine（PDA）nanoparticles are a class of easily synthesized and biocompatible nanomaterials with metal chelation,chemical reactivity,adhesion,and good photothermal properties.PDA nanoparticles have broad application prospects in the fields of surface functionalization,biosensing,drug release,catalytic degradation,and photothermal therapy.It has been reported that dopamine monomers can inhibit Aβaggregation throughπ-πstacking and hydrophobic interactions,and can also regulate Cu²⁺,Zn²⁺-induced Aβaggregation.It is speculated that PDA nanoparticles formed by dopamine polymerization may also have a modulating effect on the Aβaggregation process.Given its ability to chelate a variety of metal ions,it may also interfere with metal-induced Aβaggregation.Unfortunately,there were few reports on the role of PDA nanoparticles in the regulation of Aβaggregation.Therefore,it is necessary to investigate the effect of PDA nanoparticles on Aβself-assembly and metal-induced Aβaggregation to facilitate the study of Aβmultipath aggregation regulation.Accordingly,two kinds of PDA nanoparticles were synthesized in this paper,and their regulatory effects on Aβself-assembly and metal-induced Aβaggregation were studied based on atomic force microscope（AFM）.The details are as follows:1.The effect of copolymerized PDA（CPDA）nanoparticles on Aβself-assembly and metal-induced Aβaggregation by AFMFirstly,the regulation of Aβmonomer and oligomer fibrillation by CPDA nanoparticles and the effect on Aβmature fibril were studied based on AFM.Secondly,the effects of CPDA nanoparticles on Aβaggregation induced by six metal ions(Cu²⁺,Fe³⁺,Ni²⁺,Mg²⁺,Zn²⁺,Al³⁺)and the formation of Aβ-metal complexes were also investigated.The results showed that CPDA nanoparticles can not only effectively inhibit the self-assembly of Aβmonomers,oligomers and metal-induced aggregation,but also can disaggregate the structure of Aβfibrils and Aβ-metal complexes,then formed low-toxic Aβfragments.It was speculated that the reasons for the inhibitory effect of CPDA nanoparticles on Aβmultipath aggregation mainly included:（I）CPDA nanoparticles can interfere with the hydrophobic core of Aβthrough non-covalent and covalent interactions;（II）CPDA nanoparticles have metal chelating properties and can coordinate with metal ions.These two reasons ultimately enabled CPDA nanoparticles to effectively regulate Aβself-assembly and metal-induced Aβaggregation.In addition,transwell experiments showed that when CPDA nanoparticles were incubated with b End.3 cells for 8 h,the transport efficiency was 73.7%,indicating that CPDA nanoparticles have better potential for in vivo applications.This work was expected to provide a facile and efficient regulator for the regulation of multipath Aβaggregation.2.The photothermal regulation of PDA nanoparticles on Aβself-assembly and metal-induced Aβaggregation by AFMIn view of the photothermal properties of PDA nanoparticles,as well as the non-invasiveness,flexible operation and high spatiotemporal resolution of photothermal regulation,PDA nanoparticles with good photothermal properties were synthesized in this study.Firstly,the effects of PDA nanoparticles on Aβself-assembly and metal-induced Aβaggregation under NIR illumination were investigated.Then the effects of PDA nanoparticles on Aβfibrils and Aβ-metal complexes under NIR illumination were also investigated.It was found that PDA nanoparticles can effectively inhibit Aβself-assembly and metal-induced Aβaggregation under NIR illumination.More importantly,NIR-irradiated PDA nanoparticles can also disaggregate Aβ-metal complexes to form low-toxic aggregate fragments,which significantly reduced the cytotoxicity induced by Aβfibrils and Aβ-metal complexes.At the same time,PDA nanoparticles can also effectively cross the blood-brain barrier model in vitro.This work combined photothermal regulation with covalent and non-covalent interactions to regulate Aβself-assembly and metal-induced Aβaggregation,which is expected to improve the ability to regulate Aβaggregation.