Iron is a specific cofactor for distinct oxidation- and aggregation-dependent Aβ toxicity mechanisms in a Drosophila model
Metals, including iron, are present at high concentrations in amyloid plaques in individuals with Alzheimer's disease, where they are also thought to be cofactors in generating oxidative stress and modulating amyloid formation. In this study, we present data from several Drosophila models of ne...
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doaj-4c28afbbf13d4058b39bbce889668a792020-11-24T21:35:43ZengThe Company of BiologistsDisease Models & Mechanisms1754-84111754-84032015-07-018765766710.1242/dmm.019042019042Iron is a specific cofactor for distinct oxidation- and aggregation-dependent Aβ toxicity mechanisms in a Drosophila modelStanislav Ott0Nikolas Dziadulewicz1Damian C. Crowther2 Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK Metals, including iron, are present at high concentrations in amyloid plaques in individuals with Alzheimer's disease, where they are also thought to be cofactors in generating oxidative stress and modulating amyloid formation. In this study, we present data from several Drosophila models of neurodegenerative proteinopathies indicating that the interaction between iron and amyloid beta peptide (Aβ) is specific and is not seen for other aggregation-prone polypeptides. The interaction with iron is likely to be important in the dimerisation of Aβ and is mediated by three N-terminal histidines. Transgenic fly lines systematically expressing all combinations of His>Ala substitutions in Aβ were generated and used to study the pathological role of these residues. Developmental eye phenotypes, longevity and histological examinations indicate that the N-terminal histidines have distinct position-dependent and -independent mechanisms. The former mediate the toxic effects of metals and Aβ aggregation under non-oxidising conditions and the latter are relevant under oxidising conditions. Understanding how Aβ mediates neurotoxic effects in vivo will help to better target pathological pathways using aggregation blockers and metal-modifying agents.http://dmm.biologists.org/content/8/7/657IronMetalAmyloid beta peptideAlzheimer's diseaseOxidative stressDrosophila |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Stanislav Ott Nikolas Dziadulewicz Damian C. Crowther |
spellingShingle |
Stanislav Ott Nikolas Dziadulewicz Damian C. Crowther Iron is a specific cofactor for distinct oxidation- and aggregation-dependent Aβ toxicity mechanisms in a Drosophila model Disease Models & Mechanisms Iron Metal Amyloid beta peptide Alzheimer's disease Oxidative stress Drosophila |
author_facet |
Stanislav Ott Nikolas Dziadulewicz Damian C. Crowther |
author_sort |
Stanislav Ott |
title |
Iron is a specific cofactor for distinct oxidation- and aggregation-dependent Aβ toxicity mechanisms in a Drosophila model |
title_short |
Iron is a specific cofactor for distinct oxidation- and aggregation-dependent Aβ toxicity mechanisms in a Drosophila model |
title_full |
Iron is a specific cofactor for distinct oxidation- and aggregation-dependent Aβ toxicity mechanisms in a Drosophila model |
title_fullStr |
Iron is a specific cofactor for distinct oxidation- and aggregation-dependent Aβ toxicity mechanisms in a Drosophila model |
title_full_unstemmed |
Iron is a specific cofactor for distinct oxidation- and aggregation-dependent Aβ toxicity mechanisms in a Drosophila model |
title_sort |
iron is a specific cofactor for distinct oxidation- and aggregation-dependent aβ toxicity mechanisms in a drosophila model |
publisher |
The Company of Biologists |
series |
Disease Models & Mechanisms |
issn |
1754-8411 1754-8403 |
publishDate |
2015-07-01 |
description |
Metals, including iron, are present at high concentrations in amyloid plaques in individuals with Alzheimer's disease, where they are also thought to be cofactors in generating oxidative stress and modulating amyloid formation. In this study, we present data from several Drosophila models of neurodegenerative proteinopathies indicating that the interaction between iron and amyloid beta peptide (Aβ) is specific and is not seen for other aggregation-prone polypeptides. The interaction with iron is likely to be important in the dimerisation of Aβ and is mediated by three N-terminal histidines. Transgenic fly lines systematically expressing all combinations of His>Ala substitutions in Aβ were generated and used to study the pathological role of these residues. Developmental eye phenotypes, longevity and histological examinations indicate that the N-terminal histidines have distinct position-dependent and -independent mechanisms. The former mediate the toxic effects of metals and Aβ aggregation under non-oxidising conditions and the latter are relevant under oxidising conditions. Understanding how Aβ mediates neurotoxic effects in vivo will help to better target pathological pathways using aggregation blockers and metal-modifying agents. |
topic |
Iron Metal Amyloid beta peptide Alzheimer's disease Oxidative stress Drosophila |
url |
http://dmm.biologists.org/content/8/7/657 |
work_keys_str_mv |
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1725944365832994816 |