Interaction of Glucagon-Like Peptide 1 and Its Analogues with Amyloid-β Peptide Affects Its Fibrillation and Cytotoxicity

Clinical data, animal and cell studies show that some antidiabetic drugs, including glucagon-like peptide 1 receptor agonists (GLP-1RAs), exert therapeutic effects in Alzheimer's disease (AD) via modulation of amyloid-β peptide (Aβ) metabolism. Meanwhile, the direct interactions of GLP-1RAs with Aβ and their functional consequences remain unexplored. The interaction with monomeric Aβ40/Aβ42 of GLP-1(7-37) and its several analogues (semaglutide (Sema), liraglutide (Lira), exenatide (Exen)) was studied by biolayer interferometry and surface plasmon resonance spectroscopy. Quaternary structure of the GLP-1RAs was investigated by dynamic light scattering. The effect of GLP-1RAs on Aβ fibrillation was assessed by Thioflavin T assay and electron microscopy. The impact of GLP-1RAs on Aβ cytotoxicity was studied using the MTT assay. Monomeric Aβ40 and Aβ42 directly bind to GLP-1(7-37), Sema, Lira, Exen, with highest affinity for Lira (the lowest estimates of equilibrium dissociation constants are 42-60 nM). The GLP-1RAs are prone to oligomerization, which may affect their binding to Aβ. GLP-1(7-37) and Exen inhibit Aβ40 fibrillation, whereas Sema shows the opposite effect. The GLP-1 analogues decreased Aβ cytotoxicity towards SH-SY5Y cells, while GLP-1(7-37) enhanced the Aβ40 cytotoxicity, not affecting the cytotoxic effect of Aβ42. Overall, the GLP-1RAs interact with Aβ, differentially modulating its fibrillation and cytotoxicity, suggesting the need for further clinical studies of GLP-1RAs to exclude the possibility of Aβ-mediated neuronal injury.