Litus Ekaterina A, Shevelyova Marina P, Vologzhannikova Alisa A, Deryusheva Evgenia I, Chaplygina Alina V, Rastrygina Victoria A, Machulin Andrey V, Alikova Valeria D, Nazipova Aliya A, Permyakova Maria E, Dotsenko Victor V, Permyakov Sergei E, Nemashkalova Ekaterina L
Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, 142290 Pushchino, Russia.
Skryabin Institute of Biochemistry and Physiology of Microorganisms, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, 142290 Pushchino, Russia.
Int J Mol Sci. 2025 Apr 25;26(9):4095. doi: 10.3390/ijms26094095.
Clinical data as well as animal and cell studies indicate that certain antidiabetic drugs, including glucagon-like peptide 1 receptor agonists (GLP-1RAs), exert therapeutic effects in Alzheimer's disease (AD) by modulating amyloid-β peptide (Aβ) metabolism. Meanwhile, the direct interactions between GLP-1RAs and Aβ and their functional consequences remain unexplored. In this study, the interactions between monomeric Aβ40/Aβ42 of GLP-1(7-37) and its several analogs (semaglutide (Sema), liraglutide (Lira), exenatide (Exen)) were studied using biolayer interferometry and surface plasmon resonance spectroscopy. The quaternary structure of GLP-1RAs was investigated using dynamic light scattering. The effects of GLP-1RAs on Aβ fibrillation were assessed using the thioflavin T assay and electron microscopy. The impact of GLP-1RAs on Aβ cytotoxicity was evaluated via the MTT assay. Monomeric Aβ40 and Aβ42 directly bind to GLP-1(7-37), Sema, Lira, and Exen, with the highest affinity for Lira (the lowest estimates of equilibrium dissociation constants were 42-60 nM). GLP-1RAs are prone to oligomerization, which may affect their binding to Aβ. GLP-1(7-37) and Exen inhibit Aβ40 fibrillation, whereas Sema promotes it. GLP-1 analogs decrease Aβ cytotoxicity toward SH-SY5Y cells, while GLP-1(7-37) enhances Aβ40 cytotoxicity without affecting the cytotoxic effect of Aβ42. Overall, GLP-1RAs interact with Aβ and differentially modulate its fibrillation and cytotoxicity, suggesting the need for further studies of our observed effects in vivo.
临床数据以及动物和细胞研究表明，某些抗糖尿病药物，包括胰高血糖素样肽1受体激动剂（GLP-1RAs），可通过调节淀粉样β肽（Aβ）代谢在阿尔茨海默病（AD）中发挥治疗作用。与此同时，GLP-1RAs与Aβ之间的直接相互作用及其功能后果仍未得到探索。在本研究中，使用生物层干涉术和表面等离子体共振光谱研究了GLP-1(7-37)及其几种类似物（司美格鲁肽（Sema）、利拉鲁肽（Lira）、艾塞那肽（Exen））与单体Aβ40/Aβ42之间的相互作用。使用动态光散射研究了GLP-1RAs的四级结构。使用硫黄素T测定法和电子显微镜评估了GLP-1RAs对Aβ纤维化的影响。通过MTT测定法评估了GLP-1RAs对Aβ细胞毒性的影响。单体Aβ40和Aβ42直接与GLP-1(7-37)、Sema、Lira和Exen结合，对Lira的亲和力最高（平衡解离常数的最低估计值为42 - 60 nM）。GLP-1RAs易于寡聚化，这可能会影响它们与Aβ的结合。GLP-1(7-37)和Exen抑制Aβ40纤维化，而Sema则促进其纤维化。GLP-1类似物降低Aβ对SH-SY5Y细胞的细胞毒性，而GLP-1(7-37)增强Aβ40的细胞毒性，且不影响Aβ42的细胞毒性作用。总体而言，GLP-1RAs与Aβ相互作用并差异性地调节其纤维化和细胞毒性，这表明需要对我们在体内观察到的效应进行进一步研究。
