| A central feature of Alzheimer's disease is the formation of extracellular amyloid plaques deposits. The major protein constituent of amyloid plaques is beta-amyloid (Abeta). Abeta aggregation has been widely hypothesized to initiate the pathogenic event in AD. Recently, it has been proposed that Abeta toxicity is caused by the aggregation process rather than the final product of aggregation. If this hypothesis is true, a fundamental understanding of Abeta aggregation is required to design compounds that block the toxic aggregation step.; In this project, we used urea to reduce driving force for Abeta aggregation. Morphology of Abeta aggregates varied depending on urea concentration. Using a mathematical kinetic model, we proposed urea hindered filament initiation and elongation with more effect on filament initiation than elongation, but increased filament association into fibrils at intermediate concentration.; In previous work, we identified several small peptides, composed of a recognition element and a disruption element, which accelerate Abeta aggregation while decreasing its toxicity. In this project, we examined the interaction between Abeta and one of these peptides. Using a mathematical model of Abeta aggregation kinetics, we showed that the dominant effect of the peptide is to accelerate lateral association of Abeta filaments into fibrils. Further, we showed that the aggregation rate-enhancing activity of the disrupting element correlates with its ability to increase surface tension of solutions. Based on this hypothesis, we designed a novel peptide with terminal side-chain trimethylammonium groups in the disrupting domain. The derivatized peptide increased solvent surface tension and accelerated beta-amyloid aggregation kinetics by several-fold. Equivalent increases in surface tension without a recognition domain had no effect on beta-amyloid aggregation.; Major isoforms of Abeta are Abeta (1-40) and Abeta (1-42). Abeta (1-42) is more aggregation prone and toxic than Abeta (1-40). In research reported here, we propose a mathematical model for Abeta (1-42) aggregation kinetics based on the previously developed kinetic model for Abeta (1-40) with modification specific for Abeta (1-42). Characteristics of aggregated species of these Abeta variants were calculated using the model simulation. |
