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dc.contributor.authorGarrett, Hannah Mary
dc.date.accessioned2015-09-07T15:47:43Z
dc.date.available2015-09-07T15:47:43Z
dc.date.issued2012-05
dc.identifier.citationGarrett, H.M. 2012. A Study into the Influence of Amyloid-beta Peptide Oxidation on the Rate of Fibril Formation, with a Synthesis of 2-oxo-histidine. Queen Mary University of London.en_US
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/8485
dc.descriptionPhDen_US
dc.description.abstractThe Amyloid Cascade Hypothesis states that fibrillation of the amyloid beta (Aβ) peptide is the primary cause of Alzheimer’s pathology. The trigger for the fibrillation is a subject of much debate, although it is clear, oxidative stress is a key feature of Alzheimer’s aetiology. This thesis explores a possible role of oxidation of Aβ, in particular the effect of histidine and methionine side-chain oxidation, on Aβ fibril growth rates. Within chapters 2 and 3 of this thesis is a discussion of various approaches to chemical synthesis of 2-oxo-histidine with a view to the incorporation of the oxidised amino acids into Aβ peptide using Fmoc approaches. Chapter 2 describes attempted chemical transformation of (protected) L-histidine into L-oxohistidine. Dimethyldioxirane oxidised Boc-His-OMe yielded products containing isopropylidene groups, while oxidation using a Cu(II)/ascorbate generated 2-oxo-histidine but gave very low yields. Within chapter 3, a successful synthesis of protected 2-oxo-histidine is described, via the known imidazolin-2-one-4-carboxylic. Chapter 4 analyses Aβ(1-40) fibrillation kinetics by treating the intact peptide with various oxidants. Contrary to previous reports, hydrogen peroxide alone did not slow fibrillation rates. Cu(II)/Cu(I)- catalysed oxidation increased the likelihood of amorphous aggregation over fibrillation. This thesis shows oxidation of Aβ has a profound influence on fibril growth and that incorporation of a stable oxidised histidine into Aβ is a realisable goal.en_US
dc.description.sponsorshipEPSRC; Queen Mary, University of Londonen_US
dc.language.isoenen_US
dc.publisherQueen Mary University of Londonen_US
dc.subjectChemistryen_US
dc.subjectAlzheimer'sen_US
dc.titleA Study into the Influence of Amyloid-beta Peptide Oxidation on the Rate of Fibril Formation, with a Synthesis of 2-oxo-histidine.en_US
dc.typeThesisen_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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