A Structural Effect of the Antioxidant Curcuminoids on the Aβ(1-42) Amyloid Peptide

Investigating amyloid-β (Aβ) peptides in solution is essential during the initial stages of developing lead compounds that can influence Aβ fibrillation while the peptide is still in a soluble state. The tendency of the Aβ(1-42) peptide to misfold in solution, correlated to the aetiology of Alzheimer's disease (AD), is one of the main hindrances to characterising its aggregation kinetics in a cell-mimetic environment. Moreover, the Aβ(1-42) aggregation triggers the unfolded protein response (UPR) in the endoplasmic reticulum (ER), leading to cellular dysfunction and multiple cell death modalities, exacerbated by reactive oxygen species (ROS), which damage cellular components and trigger inflammation. Antioxidants like curcumin, a derivative of Curcuma longa, help mitigate ER stress by scavenging ROS and enhancing antioxidant enzymes. Furthermore, evidence in the literature highlights the effect of curcumin on the secondary structure of Aβ(1-42). This explorative study investigates the Aβ(1-42) peptide conformational behaviour in the presence of curcumin and six derivatives using circular dichroism (CD) to explore their interactions with lipid bilayers, potentially preventing aggregate formation. The results suggest that the synthetic tetrahydrocurcumin (THC) derivative interacts with the amyloid peptide in all the systems presented, while cyclocurcumin (CYC) and bisdemethoxycurcumin (BMDC) only interact when the peptide is in a less stable conformation. Molecular dynamics simulations helped visualise the curcuminoids' effect in an aqueous system and hypothesise the importance of the peptide surface exposition to the solvent, differently modulated by the curcumin derivatives.