Inhibitory action of macrocyclic platiniferous chelators on metal-induced Aβ aggregation

  • Wang X
  • Wang X
  • Zhang C
 et al. 
  • 14

    Readers

    Mendeley users who have this article in their library.
  • 28

    Citations

    Citations of this article.

Abstract

Alzheimer's disease (AD) is a neurodegenerative illness associated with amyloid β-peptide (Aβ) aggregation in the brain. Aβ shows high affinity for metal ions such as Zn2+ and Cu2+, which constitutes the major reason for the Aβ aggregation and related neurotoxicity. Metal chelators are potential therapeutic agents for AD because they could sequester metal ions from the Aβ aggregates and reverse the aggregation. In this study, two macrocyclic platiniferous chelators (PC1, PC2) with cyclen as the metal-chelating unit and Pt(bipyridine)Cl2 as the Aβ-binding unit have been designed as novel bifunctional inhibitors of the metal-induced Aβ aggregation. The interactions between the chelators and Aβ40 aggregates are studied by tandem mass spectrometry and 1H NMR. The platinum centers in PC1 and PC2 are shown to coordinate with histidine residues (His-14 or -13) of Aβ40. The inhibitory effect of the chelators on Aβ40 aggregation induced by Zn2+ and Cu2+ ions is investigated using turbidimetry, a BCA protein assay, and transmission electron microscopy. PC1 and PC2 show significant inhibition against the Aβ aggregation and the action is more effective than that exerted by cyclen. By contrast, the corresponding anticancer drug cisplatin exhibits no inhibition against the Aβ aggregation. PC1 and PC2 can also suppress the Cu-Aβ40 mediated generation of reactive oxygen species and their corresponding neurotoxicity in cortical neuronal cells of mice, and reduce the extent of Aβ aggregation in the brain homogenates of transgenic mice. These chelators may work through simultaneous metal chelation and peptide modification to interfere with the Aβ aggregation. Such an intramolecular synergism distinguishes PC1 and PC2 from other chelators as potential anti-AD agents.

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document

Get full text

Authors

  • Xiaohui Wang

  • Xiaoyong Wang

  • Changli Zhang

  • Yang Jiao

  • Zijian Guo

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free