The Role of Metal Ions and Reactive Oxygen Species in beta-Amyloid Aggregation and Toxicity and Their Relevance to Alzheimer's Disease.

Mayes, Jennifer Helen (2010) The Role of Metal Ions and Reactive Oxygen Species in beta-Amyloid Aggregation and Toxicity and Their Relevance to Alzheimer's Disease. PhD thesis, Lancaster University.

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Abstract

The aggregation and deposition of beta-amyloid (AB) in the brain has long been implicated in the neurotoxic pathways causing Alzheimer's disease (AD). Recent data suggests that early, soluble oligomers of Ap are the toxic species. Oxidative stress may be partly responsible for the toxicity of the peptide as hydrogen peroxide (H2O2) has been found to be produced during the early stages of aggregation. This study investigates the generation of H2O2 by Abeta during the process of aggregation and presents evidence supporting the hypothesis that some form of Ap oligomer has the capacity for H2O2 generation. A technique developed to immobilise Abeta during its aggregation suggested H2O2 generation to be an event associated with early Abeta-Abeta interactions, whereas fibrillar Abeta degraded H2O2. The development of cross-linking techniques to generate stable oligomeric Ap found Ap42 to be the most susceptible to these reactions, correlating with its increased tendency for aggregation. Tyr10 was found to be critical for these reactions, but not for the formation of Abeta fibrils, nor the generation of H2O2 by Abeta, indicating that dityrosine dimers are not the sole source of H2O2 generation from Abeta. The binding of copper to Ap, but not iron, was found to be central to the redox reactions enabling generation of H2O2, in addition to having complex effects on the aggregation of Ap. Zinc may also play a regulatory role in mediating Ap aggregation state and redox potential. Research of potentially toxic Ap oligomers is problematic due to the heterogeneous and dynamic nature of Abeta solutions. Development of techniques to cross-link and immobilise Abeta may be useful for studying early oligomeric Ap, not only in respect of H2O2 generation but also in identification of Ap oligomers responsible for neurotoxicity in AD. This may enable identification of a potential diagnostic marker and also a potential therapeutic target.