dc.contributor.author | Garrett, Hannah Mary | |
dc.date.accessioned | 2015-09-07T15:47:43Z | |
dc.date.available | 2015-09-07T15:47:43Z | |
dc.date.issued | 2012-05 | |
dc.identifier.citation | Garrett, 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.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/8485 | |
dc.description | PhD | en_US |
dc.description.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. | en_US |
dc.description.sponsorship | EPSRC; Queen Mary, University of London | en_US |
dc.language.iso | en | en_US |
dc.publisher | Queen Mary University of London | en_US |
dc.subject | Chemistry | en_US |
dc.subject | Alzheimer's | en_US |
dc.title | A 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.type | Thesis | en_US |
dc.rights.holder | 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 | |