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Title: The Spontaneous Generation of Hydrogen Peroxide from Amyloidogenic Peptides
Author: Hayes, Lee
ISNI:       0000 0001 3548 7152
Awarding Body: Lancaster University
Current Institution: Lancaster University
Date of Award: 2006
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The characteristic deposition of usually soluble amyloidogenic proteins into insoluble fibrillar aggregates is the major pathological feature of the amyloidoses. These deposits can affect many different organs and .tissues throughout the body, giving rise to a whole range of individual amyloid diseases, including Alzheimer's disease, Parkinson's disease, type 2 diabetes and motor neurone disease. The mechanisms of amyloid cytotoxicity are still unclear but one potential mechanism which has recently gathered mounting evidence is the metal ion mediated formation of reactive oxygen species;·' in particular, hydrogen peroxide during their aggregation. The present study attempts to quantitatively examine the spontaneous generation of hydrogen peroxide .and correlate this formation to the stage of aggregation from a number of amyloidogenic peptides. involved in Alzheimer's disease, Parkinson's disease and type 2 diabetes. The role of metal ions in hydrogen peroxide generation and aggregation was also examined by the use of a range of metal ion chelators. A newly available assay which is highly sensitive for the detection of hydrogen peroxide, called Amplex Red, was used with these amyloidogenic peptides. Hydrogen peroxide was also detected indirectly from some of the peptides using electron spin resonance spectroscopy. In addition, fully aggregated forms of the amyloidogenic peptides were identified by the use of thioflavin T, a benzothiazole dye, and soluble multimeric forms of some of the peptides were detected by a specific immunoassay.The study confirms hydrogen peroxide is generated from these amyloidogenic peptides and that the generation of hydrogen peroxide occurs immediately after incubation and during the early stages of aggregatio~.This implies that spontaneous hydrogen peroxide formation could playa major role in the toxicity of these peptides and it may be possible that many, ifnot ·all, amyloidogenic peptides share such a common toxic mechanism. However, data involving the effect of metal . ion chelators show inhibitory effects on hydrogen peroxide generation but not on aggregation. The Amplex Red assay proved to be highly sensiti~~ and particularly rapid in its use for detecting hydr?gen peroxide and is therefore potentially useful as a method for high throughput screening for inhibitors of hydrogen peroxide formation from amyloidogenic peptides.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available