Iron promotes the toxicity of amyloid beta peptide by impeding its ordered aggregation

We have previously shown that overexpressing subunits of the iron-binding protein ferritin can rescue the toxicity of the amyloid ß (Aß) peptide in our Drosophila model system. These data point to an important pathogenic role for iron in Alzheimer disease. In this study, we have used an iron-selective chelating compound and RNAi-mediated knockdown of endogenous ferritin to further manipulate iron in the brain. We confirm that chelation of iron protects the fly from the harmful effects of Aß. To understand the pathogenic mechanisms, we have used biophysical techniques to see how iron affects Aß aggregation. We find that iron slows the progression of the Aß peptide from an unstructured conformation to the ordered cross-ß fibrils that are characteristic of amyloid. Finally, using mammalian cell culture systems, we have shown that iron specifically enhances Aß toxicity but only if the metal is present throughout the aggregation process. These data support the hypothesis that iron delays the formation of well ordered aggregates of Aß and so promotes its toxicity in Alzheimer disease.