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dc.contributor.authorMatheou, Christian James
dc.identifier.citationMatheou, C.J. 2015: The Influence of Copper and Zinc on the Self-assembly of Amyloid-β from Alzheimer's Disease. Queen Mary University of London.en_US
dc.description.abstractAlzheimer’s disease is characterised by the misfolding and aggregation of a native peptide, Aβ, for which there are several isoforms, Aβ(1-40) being the most common, and Aβ(1-42) being most closely associated with Alzheimer’s disease. Upon misfolding, Aβ self-associates to form a number of aggregate species. What triggers this process of misfolding-aggregation, and determines which aggregate species forms, is not known. One possible determinant is metal homeostasis, which in Alzheimer’s patients is deregulated. Chapter 3 characterises how physiologically relevant levels of Cu2+ influence the misfolding pathway of Aβ. A ThT fluorescence assay found that Cu2+ is able to accelerate formation of Aβ(1-40) amyloid fibres; however, for Aβ(1-42), Cu2+ abolished fibre formation. Electron microscopy revealed that this is because Cu2+ stabilised Aβ(1-42) oligomers. These oligomers more readily disrupted lipid membranes than mature amyloid fibres, suggesting that the elevated levels of Cu2+ and the greater Aβ(1-42) synaptotoxicity in Alzheimer’s disease may be related. Chapter 4 investigates the effect of Zn2+ on Aβ misfolding. Trace levels of Zn2+ are demonstrated to entirely abolish fibre growth, for both Aβ(1-40) and Aβ(1-42). It is found that that Zn2+ likely exerts such a dramatic effect through a rapid exchange of Zn2+ between Aβ molecules. Chapter 5 found that Cu2+ accelerated Aβ(1-40) fibre growth regardless of growth conditions, despite growth conditions influencing fibril morphology. It was also found that Cu2+ generated Aβ(1-40) fibres did not exhibit an altered stability, further suggesting that the effect of Cu2+ upon Aβ(1-40) is limited to fibril growth kinetics, in contrast to the effect of Cu2+ on Aβ(1-42), as well as the effect of Zn2+ upon either peptide. The present research has identified a diversity of significant interactions between Aβ, and Cu2+ and Zn2+, highlighting a potential role for these metal ions in Alzheimer’s disease.en_US
dc.description.sponsorshipBiotechnology and Biological Sciences Research Councilen_US
dc.publisherQueen Mary University of Londonen_US
dc.subjectBiological and Chemical Sciencesen_US
dc.subjectmetal homeostasisen_US
dc.titleThe Influence of Copper and Zinc on the Self-assembly of Amyloid-β from Alzheimer's Disease.en_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author

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