Brazilin inhibits the Zn-mediated aggregation of amyloid β-protein and alleviates cytotoxicity.

Interactions of Zn with amyloid β-protein (Aβ) and the subsequent induction of Aβ aggregation have been implicated in the pathogenesis of Alzheimer's disease (AD). The development of small-compound inhibitors against Zn-mediated Aβ aggregation is therefore greatly desired. In this study, brazilin was used to inhibit Zn-mediated Aβ aggregation and alleviate its cytotoxicity. The binding properties of brazilin and Zn were first probed using Fourier transform infrared (FTIR) spectroscopy and isothermal titration calorimetry (ITC) assays. Both the FTIR and ITC results have shown that brazilin is able to bind Zn in a physiologically suitable range of concentrations. The dissociation constant (K) between brazilin and Zn was about 46.0±6.8μM, which makes brazilin a potential drug model for the chelation of free Zn. Moreover, the higher affinity of brazilin for Aβ (K=2.5±1.6μM) than that of Zn (K=6.2±0. 9μM), enables brazilin to sequester Zn from the Aβ-Zn complex. In addition, the inhibitory effects of brazilin on Zn-mediated Aβ aggregation were examined using the Thioflavin T fluorescence assay, transmission electron microscopy and cytotoxicity assays. It was found that brazilin showed remarkable inhibitory capability against Zn-induced aggregation of Aβ. Furthermore, the Zn-mediated cytotoxicity of Aβ was also largely mitigated under the influence of brazilin. This study therefore provides further insights into the role of Zn in the Aβ aggregation pathway, indicating potential new strategies for the design of small compounds with therapeutic potential for AD.