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    A Study into the Influence of Amyloid-beta Peptide Oxidation on the Rate of Fibril Formation, with a Synthesis of 2-oxo-histidine. 
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    • A Study into the Influence of Amyloid-beta Peptide Oxidation on the Rate of Fibril Formation, with a Synthesis of 2-oxo-histidine.
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    A Study into the Influence of Amyloid-beta Peptide Oxidation on the Rate of Fibril Formation, with a Synthesis of 2-oxo-histidine.

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    Garrett_H_PhD_final.pdf (6.510Mb)
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    Queen Mary University of London
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    Abstract
    The 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.
    Authors
    Garrett, Hannah Mary
    URI
    http://qmro.qmul.ac.uk/xmlui/handle/123456789/8485
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    • Theses [3705]
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    The 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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