Amyloid-β fibrils in Alzheimer's Disease are not inert when bound to copper ions but can degrade hydrogen peroxide and generate reactive oxygen species

Mayes, Jennifer and Tinker-Mill, Claire and Kolosov, Oleg and Zhang, Hao and Tabner, Brian and Allsop, David (2014) Amyloid-β fibrils in Alzheimer's Disease are not inert when bound to copper ions but can degrade hydrogen peroxide and generate reactive oxygen species. Journal of Biological Chemistry, 289. pp. 12052-12062. ISSN 0021-9258

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Abstract

According to the 'amyloid cascade' hypothesis of Alzheimer's disease, the formation of Aβ fibrils and senile plaques in the brain initiates a cascade of events leading to the formation of neurofibrillary tangles, neurodegeneration, and to the symptom of dementia. Recently, however, emphasis has shifted away from amyloid fibrils as the predominant toxic form of Aβ towards smaller aggregates, referred to as 'soluble oligomers'. These oligomers have become one of the prime suspects for involvement in the early oxidative damage that is evident in this disease. This raises the question as to whether or not Aβ fibrils are actually 'inert tombstones' present at the end of the aggregation process. Here we show that when Aβ(1-42) aggregates, including fibrils, are bound to Cu(II) ions, they retain their redox activity, and are able to degrade hydrogen peroxide (H2O2) with the formation of hydroxyl radicals and the consequent oxidation of the peptide (detected by formation of carbonyl groups). We find that this ability increases as the Cu(II):peptide ratio increases and is accompanied by changes in aggregate morphology as determined by atomic force microscopy. When aggregates are prepared in the co-presence of Cu(II) and Zn(II) ions, the ratio of Cu(II):Zn(II) becomes an important factor in the degeneration of H2O2, the formation of carbonyl groups in the peptide, and in aggregate morphology. We believe, therefore, that Aβ fibrils can destroy H2O2 and generate damaging hydroxyl radicals, and so are not necessarily inert endpoints.

Item Type:
Journal Article
Journal or Publication Title:
Journal of Biological Chemistry
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1303
Subjects:
?? alzheimers disease free radicalshydrogen peroxide oxidative stress reactive oxygen species (ros) beta-amyloidcopper ions peptide aggregation zinc ionsbiochemistrycell biologymolecular biology ??
ID Code:
69006
Deposited By:
Deposited On:
27 Mar 2014 09:19
Refereed?:
Yes
Published?:
Published
Last Modified:
15 Jul 2024 14:34