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 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.
Highlights
Alzheimer’s disease (AD) is the most common progressive neurodegenerative brain disorder in man
One of the pathological hallmarks observed in the brain of AD patients is senile plaques that are composed of Aβ peptides
The current work focuses on three polymorphic structural Aβ1−42 fibril-like oligomers that were solved by ssNMR: models A, B, and C (Figures 1a).[18−20] In two Aβ1−42 fibril-like oligomers the structural fibril is characterized by a “β-turn-β structure”, i.e. β-arch structure.[18,19]
Summary
Alzheimer’s disease (AD) is the most common progressive neurodegenerative brain disorder in man. The interactions between the insulin molecule with Aβ1−42 fibril-like oligomers across the fibril of models A and B in a specific orientation (as seen in Figure 2a) yield the disruption of β-sheet structure along the sequence of the β-arch. The interactions that were conserved along the MD simulations in these four models demonstrated a formation of β-strands along the sequence of insulin chain B that participates in the recognition motif (Figure 7a). In these models, the interactions are only between the insulin chain B and Aβ1−42 fibril-like oligomers.
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