A wealth of epidemiological evidence indicates a strong link between type 2 diabetes (T2D) and Alzheimer's disease (AD). The fiber deposition with cross‐β‐sheet structure formed by self‐aggregation and misfolding of amyloidogenic peptides is a common hallmark of both diseases. For the patients with T2D, the fibrils are mainly found in the islets of Langerhans that results from the accumulation of human islet amyloid polypeptide (hIAPP). The major component of aggregates located in the brain of AD patients is amyloid‐β (Aβ). Many biophysical and physiological properties are shared by hIAPP and Aβ, and both peptides show similar cytotoxic mechanisms. Therefore, it is meaningful to investigate the possible cross‐interactions of hIAPP and Aβ in both diseases. In this article, the segment 25–35 of Aβ was selected because Aβ_25–35 was a core region in the process of amyloid formation and showed similar aggregation tendency and toxicity with full‐length Aβ. The electrospray ionization‐ion mobility‐mass spectrometry analysis and thioflavin T fluorescence kinetic analysis combined with transmission electron microscopy were used to explore the effects of the coexistence of Aβ_25–35 and hIAPP on the self‐aggregation of both peptides and whether there was co‐assembly in fibrillation. The results indicated that the aggregation of hIAPP and Aβ_25–35 had two nucleation stages in the binary mixtures. hIAPP and Aβ_25–35 had a high binding affinity and a series of hetero‐oligomers formed in the mixtures of hIAPP and Aβ_25–35 in the early stage. The cross‐reaction between hIAPP monomers and Aβ_25–35 monomers as well as a little of oligomers during primary nucleation stage could accelerate the aggregation of Aβ_25–35. However, owing to the obvious difference in aggregation ability between hIAPP and Aβ_25–35, this cross‐interaction had no significant impact on the self‐assembly of hIAPP. Our study may offer a better understanding for exploring the molecular mechanism of the association between AD and T2D observed in clinical and epidemiological studies and developing therapeutic strategies against amyloid diseases.

中文翻译：

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电喷雾电离-离子淌度-质谱法研究hIAPP与Aβ25-35的相互作用及二元混合物的聚集过程。

大量的流行病学证据表明2型糖尿病（T2D）与阿尔茨海默氏病（AD）之间存在密切的联系。由淀粉样肽的自聚集和错误折叠形成的具有交叉β折叠结构的纤维沉积是这两种疾病的共同特征。对于T2D患者，原纤维主要存在于Langerhans的胰岛中，这是由于人类胰岛淀粉样多肽（hIAPP）的积累所致。AD患者大脑中聚集体的主要成分是淀粉样β（Aβ）。hIAPP和Aβ具有许多生物物理和生理特性，并且两种肽都显示出相似的细胞毒性机制。因此，研究两种疾病中hIAPP和Aβ可能的交叉相互作用是有意义的。在本文中，选择Aβ的第25–35段是因为Aβ_25-35是淀粉样蛋白形成过程中的核心区域，在全长Aβ中表现出相似的聚集趋势和毒性。所述电喷雾电离离子迁移率质谱分析和硫磺素T荧光的动力学分析用透射电子显微镜相结合被用来探索Aβ的共存的效果_25-35上两种肽的自聚集和hIAPP以及是否有共预组装纤颤。结果表明，hIAPP和Aβ的聚集_25-35曾在二元混合物2个核阶段。hIAPP和Aβ _25-35具有高的结合亲和力和形成在hIAPP和Aβ的混合物的一系列异寡聚体的_25-35在早期。hIAPP单体和Aβ之间的交叉反应_25-35单体的低聚物的过程中初级成核阶段一点以及可加速Aβ的聚集_25-35。然而，由于在hIAPP和Aβ之间聚集能力明显区别_25-35，这种跨交互作用对自组装hIAPP没有显著影响。我们的研究可能为探索在临床和流行病学研究中发现的AD与T2D之间的关联的分子机制以及制定针对淀粉样疾病的治疗策略提供更好的理解。