Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of Abeta42 in a manner which may have consequences for metal chelation therapy in Alzheimer's disease.
Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of Abeta42 in a manner which may have consequences for metal chelation therapy in Alzheimer's disease.
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DOI：
10.3233/jad-2004-6310
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
E. House;J. Collingwood;A. Khan;Olga Korchazkina;G. Berthon;C. Exley
中科院分区：
文献类型：
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作者：
E. House;J. Collingwood;A. Khan;Olga Korchazkina;G. Berthon;C. Exley
在体内发现金属与Abeta 42的β-折叠片相关，并可能参与其形成。金属螯合已被提出作为阿尔茨海默病的治疗方法，其基础是它可以安全地溶解沉淀的Abeta肽。我们已经跟踪了在另外的金属离子（Al（III）、Fe（III）、Zn（II）、Cu（II））的存在下A β 42在32周的时间段内的fifetisation，并且我们已经研究了这些老化的肽聚集体在去铁胺（DFO）和乙二胺四乙酸（EDTA）两者的存在下的溶解。A β 42单独或在Al（III）或Fe（III）存在下形成噬斑样淀粉样蛋白的β-折叠片，其在与任一螯合剂孵育时溶解。Zn（II）抑制，而Cu（II）防止形成β-折叠片的Abeta 42和这些影响都没有受到孵育的老化肽聚集体与DFO或EDTA。单独或在添加Al（III）或Fe（III）的存在下新鲜制备的A β 42溶液在DFO存在下孵育长达8周时不形成β-折叠淀粉样蛋白。EDTA没有防止β-折叠的淀粉样蛋白形成在相同的治疗和促进β-折叠的淀粉样蛋白形成的存在下，无论是锌（II）或铜（II）。作为“仅Abeta 42”制剂的污染物的显著浓度的Al（III）和Fe（III）的存在表明这两种金属参与触发β-折叠淀粉样蛋白的形成或稳定其结构。如果这种淀粉样蛋白的形成对于AD的病因学是关键的，那么Al（III）和Fe（III）的螯合可能被证明是一种保护机制，而Cu（II）和Zn（II）的螯合而不螯合Al（III）和Fe（III）实际上可能会加剧病情。
Metals are found associated with beta-pleated sheets of Abeta42 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 Abeta42 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). Abeta42 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 Abeta42and neither of these influences were affected by incubation of the aged peptide aggregates with either DFO or EDTA. Freshly prepared solutions of Abeta42 either alone or in the presence of added Al(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 'Abeta42 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 Al(III) and Fe(III) might actually exacerbate the condition.