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Iron promotes the toxicity of amyloid β peptide by impeding its ordered aggregation
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Liu, B., Moloney, A., Meehan, S., Morris, Kyle L., Thomas, S. E., Serpell, Louise C., Hider, R., Marciniak, Stefan J., Lomas, D. A. and Crowther, D. C. (2011) Iron promotes the toxicity of amyloid β peptide by impeding its ordered aggregation. Journal of Biological Chemistry, 286 (6). pp. 4248-4256. doi:10.1074/jbc.M110.158980 ISSN 0021-9258.
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Official URL: http://dx.doi.org/10.1074/jbc.M110.158980
Abstract
We have previously shown that overexpressing subunits of the iron-binding protein ferritin can rescue the toxicity of the amyloid β (Aβ) 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 Aβ. To understand the pathogenic mechanisms, we have used biophysical techniques to see how iron affects Aβ aggregation. We find that iron slows the progression of the Aβ peptide from an unstructured conformation to the ordered cross-β fibrils that are characteristic of amyloid. Finally, using mammalian cell culture systems, we have shown that iron specifically enhances Aβ 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 Aβ and so promotes its toxicity in Alzheimer disease.
| Item Type: | Journal Article | ||||||
|---|---|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||
| Journal or Publication Title: | Journal of Biological Chemistry | ||||||
| Publisher: | American Society for Biochemistry and Molecular Biology | ||||||
| ISSN: | 0021-9258 | ||||||
| Official Date: | 11 February 2011 | ||||||
| Dates: |
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| Volume: | 286 | ||||||
| Number: | 6 | ||||||
| Number of Pages: | 9 | ||||||
| Page Range: | pp. 4248-4256 | ||||||
| DOI: | 10.1074/jbc.M110.158980 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Open Access (Creative Commons) |
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