Effect of metal chelators on the aggregation of beta-amyloid peptides in the presence of copper and iron

Amyloid beta (A beta) fibrils and amorphous aggregates are found in the brain of patients with Alzheimer's disease (AD), and are implicated in the etiology of AD. The metal imbalance is also among leading causes of AD, owing to the fact that A beta aggregation takes place in the synaptic cleft where A beta, Cu(II) and Fe(III) are found in abnormally high concentrations. A beta 40 and A beta 42 are the main components of plaques found in afflicted brains. Coordination of Cu(II) and Fe(III) ions to A beta peptides have been linked to A beta aggregation and production of reactive oxygen species, two key events in the development of AD pathology. Metal chelation was proposed as a therapy for AD on the basis that it might prevent A beta aggregation. In this work, we first examined the formation of A beta 40 and A beta 42 aggregates in the presence of metal ions, i.e. Fe(III) and Cu(II), which were detected by fluorescence spectroscopy and atomic force microscopy. Second, we studied the ability of the two chelators, ethylenediaminetetraacetic acid and 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol), to investigate their effect on the availability of these metal ions to interact with A beta and thereby their effect on A beta accumulation. Our findings show that Fe(III), but not Cu(II), promote aggregation of both A beta 40 and A beta 42. We also found that only clioquinol decreased significantly iron ion-induced aggregation of A beta 42. The presence of ions and/or chelators also affected the morphology of A beta aggregates.