Baram Michal, Miller Yifat
Department of Chemistry , Ben-Gurion University of the Negev , Be'er Sheva 84105 , Israel.
The Ilse Katz Institute for Nanoscale Science & Technology , Ben-Gurion University of the Negev , Be'er Sheva 84105 , Israel.
ACS Chem Neurosci. 2020 Feb 5;11(3):445-452. doi: 10.1021/acschemneuro.9b00645. Epub 2020 Jan 10.
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.
针对阿尔茨海默病患者的鼻内胰岛素治疗临床试验已显示出认知和记忆功能的改善，但胰岛素的作用存在局限性。有研究表明，胰岛素分子与淀粉样β蛋白（Aβ）聚集体结合并阻碍Aβ聚集。然而，胰岛素分子与Aβ聚集体在原子分辨率下的具体相互作用仍不清楚。本研究观察到三个主要结论。第一，胰岛素只能与“U形”Aβ纤维相互作用，而不能与“S形”Aβ纤维相互作用。因此，预计胰岛素不会影响“S形”Aβ纤维。第二，胰岛素通过与A链相互作用破坏沿Aβ纤维样寡聚体的β链，而A链不是识别基序的一部分。研究表明，胰岛素作为Aβ纤维化的抑制剂起作用，但由于多态性Aβ纤维样寡聚体的特异性，其作用有限。第三，目前的研究表明，当胰岛素沿Aβ纤维样寡聚体的纤维轴相互作用时，它会促进Aβ聚集。共聚集可通过识别基序启动。胰岛素在识别基序中缺乏相互作用会阻碍胰岛素与Aβ的共聚集。本研究报道了胰岛素分子与多态性Aβ纤维样寡聚体之间的特异性结合结构域。这项研究深入探讨了胰岛素对Aβ聚集功能活性的分子机制，该机制强烈依赖于特定的多态性Aβ聚集体。
