Inhibitory Activity of Insulin on Aβ Aggregation Is Restricted Due to Binding Selectivity and Specificity to Polymorphic Aβ States

Clinical trials of intranasal insulin treatment for Alzheimer's patients have shown cognitive and memory improvement, but the effect of insulin has shown a limitation. It was suggested that insulin molecule binds to A beta aggregates and impedes A beta aggregation. Yet, the specific interactions between insulin molecule and A beta aggregates at atomic resolution are still elusive. Three main conclusions are observed in this work. First, insulin can interact across the fibril only to "U-shape" A beta fibrils and not to "S-shape" A beta fibrils. Therefore, insulin is not expected to influence the "S-shape" A beta fibrils. Second, insulin disrupts beta-strands along A beta fibril-like oligomers via interaction with chain A, which is not a part of the recognition motif. It is suggested that insulin affects as an inhibitor of A beta fibrillation, but it is limited due to the specificity of the polymorphic A beta fibril-like oligomer. Third, the current work proposes that insulin promotes A beta aggregation, when interacting along the fibril axis of A beta fibril-like oligomer. The coaggregation could be initiated via the recognition motif. The lack of the interactions of insulin in the recognition motif impede the coaggregation of insulin and A beta. The current work reports the specific binding domains between insulin molecule and polymorphic A beta fibril-like oligomers. This research provides insights into the molecular mechanisms of the functional activity of insulin on A beta aggregation that strongly depends on the particular polymorphic A beta aggregates.