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

Michal Baram, Yifat Miller

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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

Original languageEnglish
Pages (from-to)445-452
Number of pages8
JournalACS Chemical Neuroscience
Issue number3
StatePublished - 5 Feb 2020


  • Alzheimer's disease
  • Polymorphism
  • amyloid aggregation
  • amyloid inhibitors
  • amyloid β
  • insulin

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology


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