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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

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@article{61f63af4c5f84adb93bb04c4c7665cdc,
title = "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",
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.",
keywords = "Alzheimers disease , Free radicals, Hydrogen peroxide , Oxidative stress , Reactive oxygen species (ROS) , beta-amyloid, copper ions , peptide aggregation , zinc ions",
author = "Jennifer Mayes and Claire Tinker-Mill and Oleg Kolosov and Hao Zhang and Brian Tabner and David Allsop",
year = "2014",
month = "4",
day = "25",
doi = "10.1074/jbc.M113.525212",
language = "English",
volume = "289",
pages = "12052--12062",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",

}

RIS

TY - JOUR

T1 - 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

AU - Mayes, Jennifer

AU - Tinker-Mill, Claire

AU - Kolosov, Oleg

AU - Zhang, Hao

AU - Tabner, Brian

AU - Allsop, David

PY - 2014/4/25

Y1 - 2014/4/25

N2 - 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.

AB - 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.

KW - Alzheimers disease

KW - Free radicals

KW - Hydrogen peroxide

KW - Oxidative stress

KW - Reactive oxygen species (ROS)

KW - beta-amyloid

KW - copper ions

KW - peptide aggregation

KW - zinc ions

U2 - 10.1074/jbc.M113.525212

DO - 10.1074/jbc.M113.525212

M3 - Journal article

VL - 289

SP - 12052

EP - 12062

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

ER -