Activation of Cu(II)-reducing ability of monoamine neurotransmitters triggered by amyloid-β fibrillization.

The reduction of Cu(II) to Cu(I) in oxidative extracellular environments contributes to oxidative stress because the reoxidation of Cu(I) back to Cu(II) generates reactive oxygen species. Monoamine neurotransmitters such as serotonin (5-HT) and dopamine (DA) possess Cu(II)-reducing ability and coexist with copper ions near the synapse, suggesting that they may serve as potential mediators of oxidative stress. The neurotoxicity of aggregated amyloid-β peptide (Aβ) observed in the brains of Alzheimer's disease patients is thought to arise from oxidative stress induced by complex formation of Aβ with redox-active metal ions. However, the absence of apparent Cu(II)-reducing activity in Aβ suggests the involvement of other reducing agents in the generation of oxidative stress. In this study, we examined the effects of Aβ on the redox reactions between copper and monoamine neurotransmitters 5-HT and DA. The Cu(II)-reducing activities of both neurotransmitters, together with the accompanying production of hydrogen peroxide, were inhibited by either unfibrillized Aβ1-40 or non-amyloidogenic Aβ1-16, whereas fibrillized Aβ1-40 enhanced them. Canonical small-molecule Cu(II) ligands, such as L-histidine, diminished these activities, whereas Cu(I) chelators exerted an enhancing effect. These findings suggest that the activation of monoamine-mediated copper reduction by fibrillized Aβ1-40 may be attributable to the Cu(I)-binding capability that is absent in the monomeric form. This study provides a partial mechanistic basis for the causal link between Aβ aggregation and the onset of Alzheimer's disease.