Carvedilol inhibits Aβ25-35 fibrillation by intervening the early stage helical intermediate formation: A biophysical investigation.

Self-assembly of disordered amyloid-beta (Aβ) peptides results in highly ordered amyloid fibrils. The structural information of the early-stage events and also in the presence of inhibitors is of great significance. It is challenging to acquire due to the nature of the amyloids and experimental constraints. Here, we demonstrate the cascade of aggregation (early to late) of the Aβ25-35 peptide in the absence and presence of carvedilol, a nonselective β-adrenergic receptor blocker. The aggregation process of Aβ25-35 peptide is monitored using Thioflavin T (ThT) fluorescence, dynamic light scattering (DLS), circular dichroism (CD), Raman spectroscopic techniques, and imaging experiments. We find that the Aβ25-35 peptide undergoes an early-stage (3-6 h) helical intermediate formation across the fibrillation pathway using CD and Raman measurements. Carvedilol obstructs the helical intermediate formation of Aβ25-35 peptide resulting in inhibition. CD spectra and deconvolution of the Raman bands suggest the β-sheet formation (24-100 h) in the absence of carvedilol. Spectroscopic results indicate a disordered structure for the peptide in the presence of carvedilol (24-100 h). Electron microscopy (EM) shows the formation of polymorphic fibrils for the peptide alone and non-amyloidal aggregates in the presence of carvedilol. Molecular docking study suggests that the plausible mode of interaction with carvedilol involves the C-terminal residues of the peptide.