Ferulic Acid Inhibits the Transition of Amyloid-β 42 Monomers to Oligomers but Accelerates the Transition from Oligomers to Fibrils

Abstract

Alzheimer's disease (AD) is neurodegenerative disease that occurs among the aging population and is associated with impaired cognitive function. Amyloid-β (Aβ) oligomers initiate the pathological cascade and represent a neuropathic hallmark of AD. Therefore, an approach that inhibits Aβ aggregation is an attractive therapeutic strategy for the treatment of AD. Ferulic acid (FA) is a phenolic compound that can inhibit Aβ₄₂ fibril-induced cytotoxicity both in vitro and in vivo. However, few studies have demonstrated that FA interacts with Aβ₄₂ oligomers. Here, we investigated whether FA inhibits Aβ₄₂ oligomer-induced cytotoxicity and the effect of FA on Aβ aggregation. Our results showed that FA reduced Aβ₄₂-induced neurotoxicity in SH-SY5Y cells. Moreover, using CD spectroscopy, we found that FA inhibited the formation of the β-sheets that are required for the Aβ₄₂ monomer-to-oligomer transition but accelerated the Aβ₄₂ oligomer-to-fibril transition. These phenomena were confirmed by transmission electron microscopy and thioflavin T fluorescence assay. The docking analysis between FA and Aβ₄₂ monomer showed that FA may inhibit the aggregation of Aβ₄₂ oligomers by blocking the hydrogen bond with the forming β-sheets. Taken together, we have identified a novel phenomenon in which FA inhibits the formation of Aβ₄₂ oligomers while accelerating the transition of Aβ₄₂ oligomers to fibrils, and we have shown that FA protects against Aβ₄₂-induced toxicity in vitro by preventing Aβ₄₂ from forming oligomers.