A Study into the Influence of Amyloid-beta Peptide Oxidation on the Rate of Fibril Formation, with a Synthesis of 2-oxo-histidine.
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 MaryCollections
- Theses [3705]