Cu2{+} accentuates distinct misfolding for A{beta}(1-40) and A{beta}(1-42) peptides, and potentiates membrane disruption

Central to Alzheimer’s Disease is the misfolding of amyloid-beta (Aβ) peptide, which generates an assorted population of amorphous aggregates, oligomers and fibres. Metal ion homeostasis is disrupted in the brains of sufferers of Alzheimer’s disease and causes heightened Alzheimer’s disease phenotype in animal models. Here we illustrate that substochiometric Cu2+ effects the misfolding pathway of Aβ(1-40), and the more toxic Aβ(1-42), in markedly different ways. Cu2+ accelerates Aβ(1-40) fibre formation, in contrast, for Aβ(1-42) substoichiometric levels of Cu2+ almost exclusively promotes the formation of oligomeric and protofibrillar assemblies. Indeed, mature Aβ(1-42) fibres are disassembled into oligomers when Cu2+ is added. These Cu2+ stabilised oligomers of Aβ(1-42) interact with the lipid-bilayer, disrupting the membrane and increasing permeability. Our investigation of Aβ(1-40)/Aβ(1-42) mixtures with Cu2+ revealed that Aβ(1-40) neither contributed nor perturbed formation of Aβ(1-42) oligomers, though Cu2+-Aβ(1-42) will frustrate Cu2+-Aβ(1-40) fibre growth. Small amounts of Cu2+ accentuates differences in the propensity of Aβ(1-40) and Aβ(1-42) to form synaptotoxic oligomers, providing an explanation for the connection between disrupted Cu2+ homeostasis and elevated Aβ(...

Source: BJ Disease - December 4, 2014 Category: Biochemistry Authors: C J Matheou, N D Younan, J H Viles Tags: BJ Disease Source Type: research