| A growing number of diseases, including Alzheimer's, type II diabetes and Huntington's, are associated with the misfolding and aggregation of proteins into fibrillar states. In these diseases, the amyloid fibers are present in the affected tissues. Increasing evidence suggests that the intermediate states, rather than mature fibrils are cytotoxic. Lipid membranes have been shown to mediate the fibrillogenesis and toxicity. Trehalose, a disaccharide of glucose, has been shown to be effective in preventing the aggregation of numerous proteins. It has also been shown to delay the onset of certain amyloid-related diseases in a mouse model. In this thesis, we first studied the effect of trehalose on the insertion of Alzheimer's amyloid beta peptide using Langmuir monolayers and molecular dynamics simulations. We then proceeded with the insertion of islet amyloid polypeptide into lipid monolayers, its aggregation in presence of lipid vesicles and membrane disruption by its interaction with lipid bilayers. We analyzed the effect of pH, lipid charge density and trehalose on these processes. Finally, we demonstrate that using a simple system of a Langmuir monolayer at a aqueous --- liquid crystal interface, the interaction of the peptides with the lipid monolayer can be characterized and aggregating structures can be detected. This method can be used to monitor beta-sheet formation and protein aggregation at very early stages at lipid-aqueous interfaces and only nanomolar concentrations of peptide are required. |
