Affiliations: [a] Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical College, Zhanjiang, PR China | [b] Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun, PR China
Correspondence:
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Correspondence to: Yingjiu Zhang, Key Laboratory of Molecular Enzymology and Engineering of Ministry of Education, Jilin University, 2699 Qian-Jin Street, Changchun 130012, PR China. Tel.: +86 431 85155217; Fax: +86 0431 85155200; E-mail: yingjiu@jlu.edu.cn; Keshen Li, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Guangdong Medical College, 57 Ren-min Avenue, Xiashan District, Zhanjiang 524001, PR China. Tel.: +86 759 2386772; Fax: +86 759 2386772; E-mail: likeshen1971@126.com.
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.
