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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Interaction Between Glucagon-like Peptide 1 and Its Analogs with Amyloid-β Peptide Affects Its Fibrillation and Cytotoxicity

by
Ekaterina A. Litus
1,*,†,
Marina P. Shevelyova
1,†,
Alisa A. Vologzhannikova
1,
Evgenia I. Deryusheva
1,
Alina V. Chaplygina
1,
Victoria A. Rastrygina
1,
Andrey V. Machulin
2,
Valeria D. Alikova
1,
Aliya A. Nazipova
1,
Maria E. Permyakova
1,
Victor V. Dotsenko
3,
Sergei E. Permyakov
1 and
Ekaterina L. Nemashkalova
1
1
Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, 142290 Pushchino, Russia
2
Skryabin Institute of Biochemistry and Physiology of Microorganisms, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, 142290 Pushchino, Russia
3
Department of Organic Chemistry and Technologies, Kuban State University, 149 Stavropolskaya St., 350040 Krasnodar, Russia
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2025, 26(9), 4095; https://doi.org/10.3390/ijms26094095
Submission received: 25 March 2025 / Revised: 22 April 2025 / Accepted: 23 April 2025 / Published: 25 April 2025
(This article belongs to the Special Issue New Insights into Bioactive Peptides: Design, Synthesis, Structure-Activity Relationship (2nd Edition))
Review Reports Versions Notes

Abstract

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.
Keywords: diabetes mellitus; glucagon-like peptide-1; liraglutide; exenatide; semaglutide; Alzheimer’s disease; amyloid-β peptide (Aβ); protein–protein interaction; Aβ fibrillation; Aβ cytotoxicity diabetes mellitus; glucagon-like peptide-1; liraglutide; exenatide; semaglutide; Alzheimer’s disease; amyloid-β peptide (Aβ); protein–protein interaction; Aβ fibrillation; Aβ cytotoxicity

Share and Cite

MDPI and ACS Style

Litus, E.A.; Shevelyova, M.P.; Vologzhannikova, A.A.; Deryusheva, E.I.; Chaplygina, A.V.; Rastrygina, V.A.; Machulin, A.V.; Alikova, V.D.; Nazipova, A.A.; Permyakova, M.E.; et al. Interaction Between Glucagon-like Peptide 1 and Its Analogs with Amyloid-β Peptide Affects Its Fibrillation and Cytotoxicity. Int. J. Mol. Sci. 2025, 26, 4095. https://doi.org/10.3390/ijms26094095

AMA Style

Litus EA, Shevelyova MP, Vologzhannikova AA, Deryusheva EI, Chaplygina AV, Rastrygina VA, Machulin AV, Alikova VD, Nazipova AA, Permyakova ME, et al. Interaction Between Glucagon-like Peptide 1 and Its Analogs with Amyloid-β Peptide Affects Its Fibrillation and Cytotoxicity. International Journal of Molecular Sciences. 2025; 26(9):4095. https://doi.org/10.3390/ijms26094095

Chicago/Turabian Style

Litus, Ekaterina A., Marina P. Shevelyova, Alisa A. Vologzhannikova, Evgenia I. Deryusheva, Alina V. Chaplygina, Victoria A. Rastrygina, Andrey V. Machulin, Valeria D. Alikova, Aliya A. Nazipova, Maria E. Permyakova, and et al. 2025. "Interaction Between Glucagon-like Peptide 1 and Its Analogs with Amyloid-β Peptide Affects Its Fibrillation and Cytotoxicity" International Journal of Molecular Sciences 26, no. 9: 4095. https://doi.org/10.3390/ijms26094095

APA Style

Litus, E. A., Shevelyova, M. P., Vologzhannikova, A. A., Deryusheva, E. I., Chaplygina, A. V., Rastrygina, V. A., Machulin, A. V., Alikova, V. D., Nazipova, A. A., Permyakova, M. E., Dotsenko, V. V., Permyakov, S. E., & Nemashkalova, E. L. (2025). Interaction Between Glucagon-like Peptide 1 and Its Analogs with Amyloid-β Peptide Affects Its Fibrillation and Cytotoxicity. International Journal of Molecular Sciences, 26(9), 4095. https://doi.org/10.3390/ijms26094095

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