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

ABSTRACT: 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? aggregates and impedes A? aggregation. Yet, the specific interactions between insulin molecule and A? 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? fibrils and not to "S-shape" A? fibrils. Therefore, insulin is not expected to influence the "S-shape" A? fibrils. Second, insulin disrupts ?-strands along A? 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? fibrillation, but it is limited due to the specificity of the polymorphic A? fibril-like oligomer. Third, the current work proposes that insulin promotes A? aggregation, when interacting along the fibril axis of A? 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?. The current work reports the specific binding domains between insulin molecule and polymorphic A? fibril-like oligomers. This research provides insights into the molecular mechanisms of the functional activity of insulin on A? aggregation that strongly depends on the particular polymorphic A? aggregates.

SUBMITTER: Baram M 

PROVIDER: S-EPMC7467570 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature