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.
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.
House
Emily
E
Birchall Centre for Inorganic Chemistry and Materials Science, Keele University, Staffordshire, UK.
Collingwood
Joanna
J
Khan
Ayesha
A
Korchazkina
Olga
O
Berthon
Guy
G
Exley
Christopher
C
D000535:Aluminum; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D015913:Chelation Therapy / Q000379:methods*; D002851:Chromatography, High Pressure Liquid; D003300:Copper; D004492:Edetic Acid / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D007501:Iron; D010446:Peptide Fragments / Q000096:biosynthesis*; D015032:Zinc
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D003300:Copper; D004492:Edetic Acid; D000535:Aluminum; D007501:Iron; D015032:Zinc