Study On Detection And Aggregation Inhibition Of Amyloid β Based On Nanomaterials

Alzheimer’s disease (AD) is a progressive and neurodegenerative disorder. In recent years, the incidence rate of the AD is becoming more and more high. The main clinical symptoms of AD are memory loss, cognitive dysfunction and abnormal behavior, and the typical pathological hallmark is the extracellular accumulation of amyloid plaques and neurofibrillary tangles in the brain. The pathogenesis of AD has not been clearly explained due to its complexity. Studies found that the amyloid plaques are primarily composed of amyloid-β peptides (Aβ) derived through proteolysis of the amyloid precursor protein (APP) with β-and y-secretases, Aβ monomers containing 39-43 amino acids tend to aggregate into oligomers, protofibrils and mature fibrils under abnormal conditions. Recent studies have shown that soluble Aβ oligomers are more toxic to neurons, but the Aβ monomers are not neurotoxic. Therefore, Aβ aggregates are not only the target of AD treatment, but also can be used to as a marker of clinical diagnosis of AD. Therefore, detection and inhibition of Aβ aggregates are of great significance to AD diagnosis and treatment. In this paper, we constructed an aptasensor based on graphene oxide platform to detect Aβ oligomers, and synthesized a drug-loaded photodynamic micelles and functional gold nanoclusters to disaggregate or inhibit Aβ aggregates, which provide new methods for the diagnosis and treatment of AD.Chapter 1. IntroductionIn this chapter, we first introduced the research progress of AD, the methods of detection, degradation and inhibition to Aβ. Then, we expounded the detection method of protein based on aptamers. In addition, some nanomaterials including graphene, micelle and Au cluster, and their application were introduced.Chapter 2. Aptasensor for amyloid β oligomers based on graphene oxide platformIn this chapter, aptamer which is specific to Aβ oligomers and graphene oxide (GO) was combined to develop fluorescent aptasensor for Aβ oligomers. When the Aβ oligomers does not exist, single-stranded aptamer sequence adsorbed on GO surface, the fluorescene of the dye labeled on aptamer was quenched because of FRET, the aptamer’s fluorescene "turn off’. However, the addition of Aβ oligomers leads to the fluorescence recovery due to the binding of Aβ oligomers with aptamers which have weak affinity to GO and keep the dye away from GO surface, the aptamer’s fluorescene "turn on". Therefore, Aβ oligomers can be detected by fluorescence recovery and this method was used for Aβ inhibitor screening.Chapter 3. Tanshinone-Ioaded micelle nanoparticles for photodegradation of amyloid-β aggregates or inhibition of amyloid-β aggregationIn this chapter, the photosensitizers chlorin e6 (Ce6) are covalently conjugated with amphiphilic polymeric PEG-b-PDPA, the PEG is hydrophilic and the PDPA-Ce6 is hydrophobic. The amphiphilic copolymer can self-assemble into Ce6-micelles with a hydrophilic shell and a hydrophobic core. Ce6 is a photosensitizer that can produce ROS under laser-irradiation. So the Ce6-micelles were expected to degrade Aβ fibrils under the laser-irradiation conditions. Tanshinone I (TAS) is hydrophobic molecule that can effectively degrade Aβ aggregates and inhibit Aβ aggregation. TAS can be encapsulated into Ce6 micelles due to hydrophobic effect. Therefore, the TAS that released from TAS-Ce6 micelles can greatly improve degradation efficiency of Aβ aggregates. The result showed that the TAS-Ce6 micelles can not only degradate Aβ aggregates but also can effectively inhibit Aβ aggregation. So TAS-Ce6 micelles can reduce Ap aggregates, which provides new methods for the diagnosis and treatment of AD.Chapter4. Synthesis of functional gold clusters and its role in Aβ fibrillizationIn this chapter, we have synthesized functional gold clusters with peptide and investigated their role in promoting or inhibiting Aβ fibrillization. Firstly, a peptide with three functional domains was designed. Domain A, which is a sequence derived from Aβ peptides, can combine Aβ by hydrophobic interaction. Domain C is CCY, the phenolic group of tyrosine (Y) can reduce Au ions into atoms, and the SH group of cysteine (C) can capture the Au atoms. Domain C can connect B and C. The results showed that the functional gold clusters can promote Aβ fibrillization in low concentrations, while inhibit Aβ fibrillization in high concentrations, which greatly reduced the neurotoxicity of Aβ aggregates.