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

TL;DR

This study explores how GLP-1 drugs interact with amyloid-beta peptides, affecting their formation into harmful structures and toxicity in Alzheimer's disease.

Contribution

The study reveals direct interactions between GLP-1 receptor agonists and amyloid-beta peptides, and their differential effects on fibrillation and cytotoxicity.

Findings

Liraglutide shows the highest affinity for amyloid-beta peptides with dissociation constants of 42–60 nM.

GLP-1 analogs inhibit or promote amyloid-beta fibrillation depending on the specific drug.

GLP-1 drugs reduce amyloid-beta cytotoxicity in SH-SY5Y cells, except for GLP-1(7-37) with Aβ40.

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.

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