Metal ion-dependent effects of clioquinol on the fibril growth of an amyloid β peptide

Although metal ions such as Cu2+, Zn2+, and Fe3+ are implicated to play a key role in Alzheimer disease, their role is rather complex, and comprehensive understanding is not yet obtained. We show that Cu2+ and Zn2+ but not Fe3+ renders the amyloid beta peptide, A beta(1-40), non-fibrillogenic in nature. However, preformed fibrils of A beta(1-40) were stable when treated with these metal ions. Consequently, fibril growth of A beta(1-40) could be switched on/off by switching the molecule between its apo- and holo-forms. Clioquinol, a potential drug for Alzheimer disease, induced resumption of the Cu2+-suppressed but not the Zn2+-suppressed fibril growth of A beta(1-40). The observed synergistic effect of clioquinol and Zn2+ suggests that Zn2+-clioquinol complex effectively retards fibril growth. Thus, clioquinol has dual effects; although it disaggregates the metal ion-induced aggregates of A beta(1-40) through metal chelation, it further retards the fibril growth along with Zn2+. These results indicate the mechanism of metal ions in suppressing A beta amyloid formation, as well as providing information toward the use of metal ion chelators, particularly clioquinol, as potential drugs for Alzheimer disease.