Characterisation of metal-amyloid B peptide interactions and the effect of metals on the gene expression of amyloid precursor protein

Abstract

AD is a devastating neurodegenerative condition that poses major challenges to human health, with a prevalence of around 35 million patients worldwide. One of the neuropathological hallmarks in AD patients is extracellular amyloid plaques which are composed of amyloid I² peptide (AI²) aggregates. The amyloid cascade hypothesis suggests that aggregation of the AI² peptide into soluble oligomers and senile plaques is the main driver of AD. Metal ions are found to be present in amyloid plaques, including Cu2+, Fe2+/3+, Zn2+ and Al3+. The experimental evidence from the literatures thus far points to a role of metal ions in AI² aggregation and pathogenesis of AD. To this end, the metal ion hypothesis for AD is proposed, which suggests that disruption of metal ion homeostasis promotes AI² aggregation and onset of AD. However, such a link is still premature, clinical, epidemiological and molecular studies are needed. Therefore, this thesis takes a molecular approach by NMR (nuclear magnetic resonance) spectroscopy to investigate the interaction of metal ions with AI² peptide, AI²1-28, and to analyse potential metal chelators for future therapeutic application, and to unravel the effect of metal ions on the expression of APP gene (the gene encoding amyloid precursor protein) as well as the antagonising effect of metal chelators against metal ions in APP gene expression. The main discoveries presented in this PhD analysis are: 1. the determination of the solution structure of synthetic AI²1-28 complexed with Al3+ by NMR spectroscopy, 2. the characterisation of the metal binding sites on AI²1-28, 3. the upregulation of the expression of APP gene by Al3+, and 4. the presence of metal chelating ligands can lower the metal-induced APP gene expression, which should subsequently reduce the accumulation of AI².

Date of Award	2019
Original language	English