Cu2+ accentuates distinct misfolding of Aβ(1-40) and Aβ(1-42) peptides, and potentiates membrane disruption

Central to Alzheimer's disease is the misfolding of amyloid-beta (A beta) peptide, which generates an assorted population of amorphous aggregates, oligomers and fibres. Metal ion homoeostasis is disrupted in the brains of sufferers of Alzheimer's disease and causes heightened Alzheimer's disease phenotype in animal models. In the present study, we demonstrate that substochiometric Cu2+ affects the misfolding pathway of A beta((1-40)), and the more toxic A beta((1-42)), in markedly different ways. Cu2+ accelerates A beta((1-40)) fibre formation. In contrast, for A beta((1-42)), substoichiometric levels of Cu2+ almost exclusively promote the formation of oligomeric and protofibrillar assemblies. Indeed, mature A beta((1-42)) fibres are disassembled into oligomers when Cu2+ is added. These Cu2+ stabilized oligomers of A beta((1-42)) interact with the lipid bilayer, disrupting the membrane and increasing permeability. Our investigation of A beta((1-40))/A beta((1-42)) mixtures with Cu2+ revealed that A beta((1-40)) neither contributed to nor perturbed formation of A beta((1-42)) oligomers, although Cu2+-A beta((1-42)) does frustrate Cu2+-A beta((1-40)) fibre growth. Small amounts of Cu2+ accentuate differences in the propensity of A beta((1-40)) and A beta((1-42)) to form synaptotoxic oligomers, providing an explanation for the connection between disrupted Cu2+ homoeostasis and elevated A beta A beta((1-42)) neurotoxicity in Alzheimer's disease.