Glucagon-Like Peptide-1 Receptor Agonists Inhibit the Initiation of Toxic Amyloid-β42 Aggregation

The aggregation of the 42-residue form of the amyloid-β peptide (Aβ₄₂) is important in Alzheimer's disease (AD). Preclinical and clinical findings support that glucagon-like peptide-1 receptor agonists (GLP-1RAs) can protect against neuroinflammation and neurodegeneration with potential therapeutic relevance for AD, but studies of their direct effects on Aβ₄₂ are limited. Herein, we investigated five FDA-approved GLP-1RAs, and show semaglutide, tirzepatide, and liraglutide inhibit Aβ₄₂ aggregation. Semaglutide and tirzepatide delayed Aβ₄₂ aggregation by targeting the primary nucleation microscopic step, with submicromolar IC₅₀ values for primary nucleation (K_IP). Liraglutide was highly effective at suppressing primary nucleation with a very low K_IP value, and it demonstrated an additional modest inhibition of secondary nucleation. Consistent with a dominant effect on primary nucleation, Aβ₄₂ formed β-sheet-rich fibrils in the presence of these GLP-1RAs. Aβ₄₂ fibrils formed with semaglutide or tirzepatide had morphological properties and templating efficiencies that were similar to unmodified fibrils, while liraglutide significantly reduced fibril maturity, increased fibril tortuosity and length, and attenuated the ability of fibrils to passively self-replicate whether they were formed in the presence of liraglutide or exposed to this GLP-1RA after their formation. These results provide molecular-level insight into how specific GLP-1RAs can selectively target the fundamental steps governing toxic Aβ₄₂ aggregation. Further studies are warranted to determine if current or next-generation anti-amyloid GLP-1RAs can delay or prevent AD through multifaceted protective mechanisms, including the direct inhibition of Aβ₄₂ aggregation.