Toxic aggregation of Aβ peptides is involved in Alzheimer's disease (AD) aetiology. Metals, including iron, are present in Aβ aggregates and are thought to contribute to their toxic effects. However, it is unclear how iron can actually mediate Aβ toxicity and whether such a mechanism is common to other protein-aggregation-related diseases (proteinopathies; such as Huntington's disease and amyotrophic lateral sclerosis). Here, Damian C. Crowther and collaborators generated different Drosophila models of proteinopathies and found that iron specifically mediates toxicity induced by Aβ and not by other aggregation-prone proteins. In particular, iron affects the aggregation of Aβ monomers but has a lower effect on aggregation when Aβ is pre-dimerised, both in vitro and in vivo. Further to this, the group investigated the effects of three histidine residues that are known to mediate iron-Aβ interactions, using site-directed mutagenesis to substitute histidines with alanines. Interestingly, they found that the total number of histidines determines the toxic effects of iron-Aβ interactions in oxidising conditions, whereas, in non-oxidising conditions, these effects depend on the presence of histidines in specific positions. These results suggest the importance of specific Aβ conformations and environmental factors in determining protein-aggregate toxicity. The use of aggregation blockers and metal-modifying agents might help reduce Aβ toxicity in AD. Page 657
The role of iron in Aβ toxicity
The role of iron in Aβ toxicity. Dis Model Mech 1 July 2015; 8 (7): e0702. doi:
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