The Dissociation Of Cu²⁺/Zn²⁺-Aβ₄₂Aggregates Induced By Benzothiazole And Benzoxazole Derivatives

Alzheimer’s disease (AD) is a severe dementia form caused by cognitive deterioration. Senile plaques (SPs) and neurofibrillary tangles (NFTs) are the most iconic pathological features. SPs are composed of fibrous aggregates and β-sheet structure formed by Aβ peptides. NFTs are the metabolic events of Aβ peptides. The content of Aβ40peptides is ten times of Aβ42peptides, but Aβ42peptides is the major components of SPs. It is found high concentration of Cu2+, Zn2+and Fe3+in the brain of AD patients, and confirms that these metal ions can promote SPs formation, while metal chelators can induce dissociation of metal-mediated Ap aggregates. Due to the non specific chelators can not selectively bind metal ions, it may cause undesirable effects. Therefore, we focus on bifunctional chelators which can specificly bind metal-Aβ species now.Based on the P-amyloid imaging reagent Thioflavin-S (ThT), metal chelators8-Hydroxyquinoline and DPA, we synthesized and characterized FC-30, FC-31and FC-32with MS, NMR, elemental analysis and IR. We studied the interactions between these compounds and Cu2+/Zn2+in order to evaluate if they can specificly bind Cu2+/Zn2+. We measured the binding ratio of FC-30and Cu2+and the binding constant Kg of these compounds with Cu2+/Zn2+by UV-Vis and fluorescence titration methods. Through detected Aβ aggregates by the fluorescence change of ThT, we found that FC-31and FC-31can make the fluorescence change more significant. The results of BCA indirectly show the interactions between these compounds and Cu2+/Zn2+-Aβ42aggregates. Through MTT assay, we evaluated the cytotoxicity of these compounds.These results suggest that all of them can specificly bind Cu2+/Zn2+, FC-30and FC-31are likely formed stable complexes with Cu2+/Zn2+, which need to be confirmed by the crystal structure data. The Ka of these compounds is among the Ka of Aβ42with Cu2+/Zn2+reported in the literature. Detecting the Aβ42aggregates by ThT, we have found that FC-31and FC-32can make the dissociation of Cu2+/Zn2+-Aβ42aggregates, and there are corresponding fluorescence changes. They are expected to be bifunctional chelators, which can make detection of Aβ42aggregates as well as dissociation, it need to test the possibility by more experimental methods further.