Hypothesis: Soluble Aβ Oligomers in Association with Redox-Active Metal Ions Are the Optimal Generators of Reactive Oxygen Species in Alzheimer's Disease

Figure 2

Soluble oligomers, together with their associated redox-active metal ions, are potentially responsible for the generation of H₂O₂. (a) Stages of Aβ aggregation, assuming that soluble oligomers are “on pathway” to fibril formation. The optimal configuration for generation of ROS may be at the small (low-𝑛) oligomer stage. (b) Proposed mechanism for the generation of hydrogen peroxide. Here, Mⁿ and Mⁿ⁺¹ represent Cu(I) and Cu(II), or Fe(II) and Fe(III). The generation of H₂O₂ requires the synchronized transfer of two electrons from the bound metal ions and so reaction with the monomer is not favoured. Recent experimental evidence suggests that Cu ions remain bound to Aβ even in mature amyloid fibrils [26] and so the lack of activity of higher-order aggregates [25] is possibly due to some metal ions becoming sterically removed from any available O₂ molecules.