Inhibitory action of macrocyclic platiniferous chelators on metal-induced A beta aggregation

Alzheimer's disease (AD) is a neurodegenerative illness associated with amyloid beta-peptide (A beta) aggregation in the brain. A beta shows high affinity for metal ions such as Zn2+ and Cu2+, which constitutes the major reason for the A beta aggregation and related neurotoxicity. Metal chelators are potential therapeutic agents for AD because they could sequester metal ions from the A beta aggregates and reverse the aggregation. In this study, two macrocyclic platiniferous chelators (PC1, PC2) with cyclen as the metal-chelating unit and Pt(bipyridine)Cl-2 as the A beta-binding unit have been designed as novel bifunctional inhibitors of the metal-induced A beta aggregation. The interactions between the chelators and A beta 40 aggregates are studied by tandem mass spectrometry and H-1 NMR. The platinum centers in PC1 and PC2 are shown to coordinate with histidine residues (His-14 or -13) of A beta 40. The inhibitory effect of the chelators on A beta 40 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 A beta aggregation and the action is more effective than that exerted by cyclen. By contrast, the corresponding anticancer drug cisplatin exhibits no inhibition against the A beta aggregation. PC1 and PC2 can also suppress the Cu-A beta 40 mediated generation of reactive oxygen species and their corresponding neurotoxicity in cortical neuronal cells of mice, and reduce the extent of A beta aggregation in the brain homogenates of transgenic mice. These chelators may work through simultaneous metal chelation and peptide modification to interfere with the A beta aggregation. Such an intramolecular synergism distinguishes PC1 and PC2 from other chelators as potential anti-AD agents.