Role of PTA in the prevention of Cu(amyloid-β) induced ROS formation and amyloid-β oligomerisation in the presence of Zn.

Metal-targeting drugs are being widely explored as a possible treatment for Alzheimer's disease, but most of these ligands are developed to coordinate Cu(ii). In a previous communication (E. Atrián-Blasco, E. Cerrada, A. Conte-Daban, D. Testemale, P. Faller, M. Laguna and C. Hureau, Metallomics, 2015, 7, 1229-1232) we showed another strategy where Cu(i) was targeted with the PTA (1,3,5-triaza-7-phosphaadamantane) ligand that is able to target Cu(ii) as well, reduce it and keep it in a safe complexed species. Removal of Cu(ii) from the amyloid-β peptide prevents the stabilization of oligomers and protofibrils and the complexation of Cu(i) also stops the formation of reactive oxygen species. Besides, zinc, which is found in the synaptic cleft at a higher concentration than copper, can hamper the ability of metal-targeting drug candidates, an issue that is still poorly considered and studied. Here we show that PTA fully retains the above described properties even in the presence of zinc, thus fulfilling an additional pre-requisite for its use as a model of Cu(i)-targeting drug candidates in the Alzheimer's disease context.