Role of metal ions in the self-assembly of the Alzheimer's amyloid-β peptide

Abstract

Aggregation of amyloid-β (Aβ) by self-assembly into oligomers or amyloids is a central event in Alzheimer's disease. Coordination of transition-metal ions, mainly copper and zinc, to Aβ occurs in vivo and modulates the aggregation process. A survey of the impact of Cu(II) and Zn(II) on the aggregation of Aβ reveals some general trends: (i) Zn(II) and Cu(II) at high micromolar concentrations and/or in a large superstoichiometric ratio compared to Aβ have a tendency to promote amorphous aggregations (precipitation) over the ordered formation of fibrillar amyloids by self-assembly; (ii) metal ions affect the kinetics of Aβ aggregations, with the most significant impact on the nucleation phase; (iii) the impact is metal-specific; (iv) Cu(II) and Zn(II) affect the concentrations and/or the types of aggregation intermediates formed; (v) the binding of metal ions changes both the structure and the charge of Aβ. The decrease in the overall charge at physiological pH increases the overall driving force for aggregation but may favor more precipitation over fibrillation, whereas the induced structural changes seem more relevant for the amyloid formation.