Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of Aβ42 in a manner which may have consequences for metal chelation therapy in Alzheimer's disease
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作者:
House, E
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机构:Univ Keele, Lennard Jones Lab, Birchall Ctr Inorgan Chem & Mat Sci, Keele ST5 5BG, Staffs, England
House, E
Collingwood, J
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机构:Univ Keele, Lennard Jones Lab, Birchall Ctr Inorgan Chem & Mat Sci, Keele ST5 5BG, Staffs, England
Collingwood, J
Khan, A
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机构:Univ Keele, Lennard Jones Lab, Birchall Ctr Inorgan Chem & Mat Sci, Keele ST5 5BG, Staffs, England
Khan, A
Korchazkina, O
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机构:Univ Keele, Lennard Jones Lab, Birchall Ctr Inorgan Chem & Mat Sci, Keele ST5 5BG, Staffs, England
Korchazkina, O
Berthon, G
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机构:Univ Keele, Lennard Jones Lab, Birchall Ctr Inorgan Chem & Mat Sci, Keele ST5 5BG, Staffs, England
Berthon, G
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Exley, C
[1
]
机构:
[1] Univ Keele, Lennard Jones Lab, Birchall Ctr Inorgan Chem & Mat Sci, Keele ST5 5BG, Staffs, England
A beta(42);
amyloid;
aluminium;
iron;
zinc;
copper;
chelation;
Alzheimer's disease;
D O I:
暂无
中图分类号:
Q189 [神经科学];
学科分类号:
071006 ;
摘要:
Metals are found associated with beta-pleated sheets of Abeta(42) in vivo and may be involved in their formation. Metal chelation has been proposed as a therapy for Alzheimer's disease on the basis that it may safely dissolve precipitated Abeta peptides. We have followed fibrillisation of Abeta(42) in the presence of an additional metal ion (Al(III), Fe(III), Zn(II), Cu(II)) over a period of 32 weeks and we have investigated the dissolution of these aged peptide aggregates in the presence of both desferrioxamine (DFO) and ethylenediaminetetraacetic acid (EDTA). Abeta(42) either alone or in the presence of Al(III) or Fe(III) formed beta-pleated sheets of plaque-like amyloids which were dissolved upon incubation with either chelator. Zn(II) inhibited whilst Cu(II) prevented the formation of beta-pleated sheets of Abeta(42) and neither of these influences were affected by incubation of the aged peptide aggregates with either DFO or EDTA. Freshly prepared solutions of Abeta(42) either alone or in the presence of added AI(III) or Fe(III) did not form beta-pleated amyloid in the presence of DFO when incubated for up to 8 weeks. EDTA did not prevent beta-pleated amyloid formation in the same treatments and promoted beta-pleated amyloid formation in the presence of either Zn(II) or Cu(II). The presence of significant concentrations of Al(III) and Fe(III) as contaminants of Abeta(42) only' preparations suggested that both of these metals were involved in either triggering the formation or stabilising the structure of beta-pleated amyloid. If the formation of such amyloid is critical to the aetiology of AD then the chelation of Al(III) and Fe(III) may prove to be a protective mechanism whilst the chelation of Cu(II) and Zn(II) without also chelating AI(III) and Fe(III) might actually exacerbate the condition.
机构:
Chinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing 100101, Peoples R China
Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R ChinaChinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing 100101, Peoples R China
Luo YunFeng
Zhang Jie
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机构:
Rutgers State Univ, Dept Cell Biol, Piscataway, NJ 08854 USAChinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing 100101, Peoples R China
Zhang Jie
Liu NianQing
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Chinese Acad Sci, Inst High Energy Phys, Synchrotron Radiat Lab, Beijing 100049, Peoples R ChinaChinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing 100101, Peoples R China
Liu NianQing
Luo Yuan
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Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USAChinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing 100101, Peoples R China
Luo Yuan
Zhao BaoLu
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Chinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing 100101, Peoples R ChinaChinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing 100101, Peoples R China