Abstract
For decades, a link between increased levels of iron and areas of Alzheimer's disease (AD) pathology has been recognized, including AD lesions comprised of the peptide β-amyloid (Aβ). Despite many observations of this association, the relationship between Aβ and iron is poorly understood. Using X-ray microspectroscopy, X-ray absorption spectroscopy, electron microscopy and spectrophotometric iron(II) quantification techniques, we examine the interaction between Aβ(1–42) and synthetic iron(III), reminiscent of ferric iron stores in the brain. We report Aβ to be capable of accumulating iron(III) within amyloid aggregates, with this process resulting in Aβ-mediated reduction of iron(III) to a redox-active iron(II) phase. Additionally, we show that the presence of aluminium increases the reductive capacity of Aβ, enabling the redox cycling of the iron. These results demonstrate the ability of Aβ to accumulate iron, offering an explanation for previously observed local increases in iron concentration associated with AD lesions. Furthermore, the ability of iron to form redox-active iron phases from ferric precursors provides an origin both for the redox-active iron previously witnessed in AD tissue, and the increased levels of oxidative stress characteristic of AD. These interactions between Aβ and iron deliver valuable insights into the process of AD progression, which may ultimately provide targets for disease therapies.
Highlights
Iron is fundamentally involved in multiple processes within the human brain, including myelin synthesis, neurotransmitter function, along with energy production made possible via its ability to change valence states [1,2]
Iron(II) quantification assays confirmed the reduction of iron(III) by Ab in suspension, while the addition of aluminium(III) was shown to enhance the reductive capacity of Ab upon iron and enabled iron redox cycling. Taken together these results offer an explanation for the increased iron levels witnessed in areas of Alzheimer’s disease (AD) pathology, and suggest an origin for the redox-active iron forms and oxidative stress previously witnessed in AD tissue, thereby shedding light on the process of AD pathogenesis
It is apparent that Ab is capable of interacting with iron in a manner that leads to the accumulation and co-aggregation of iron within Ab structures, resulting in the chemical reduction of redox-inactive ferric iron to a redoxactive ferrous iron form
Summary
Iron is fundamentally involved in multiple processes within the human brain, including myelin synthesis, neurotransmitter function, along with energy production made possible via its ability to change valence states [1,2]. It is this ability to change valence states that can lead to iron toxicity. When ferritin function is compromised, or excess iron concentrations are reached, increased levels of redox-active labile iron form [4,5,6,7] This labile iron is free to participate in the Fenton reaction resulting in the generation of reactive oxygen species (ROS) which go on to induce oxidative stress and neuronal damage [8,9,10,11].
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