**3. The Role of Phenolic Hydroxyl Groups in Anti-A**β **Aggregation and Pro-Oxidant Activities of Polyphenols**

The phenolic hydroxyl groups of polyphenols are considered to be essential for its anti-Aβ aggregation activity. Quinones generated from phenolic hydroxyl groups can react with the lysine side chains of proteins [126]. Lys28 of Aβ has been reported to be critical for Aβ42 aggregation [127]. Therefore, quinones, especially catechol-type quinones, may contribute to the inhibition of Aβ aggregation. This is supported by the finding that the interactions between quinones from several polyphenols and lysine of Aβ play an important role in the inhibition of Aβ aggregation [103,128]. In contrast, our studies have shown ROS generation by several polyphenols through their autoxidation and quinone formation in the presence of metal ions such as Cu(II) [36,42,45,46,54,60,129]. In addition, some metabolites of target polyphenols also display pro-oxidant activities via quinone formation, even though target polyphenols themselves are not pro-oxidant [42,60].

Some studies have reported binding of the phenolic hydroxyl groups with histidine in anti-amyloid aggregation activity [9,130]. Histidine residues of Aβ impact Aβ aggregation by affecting the oligomeric equilibria [131] and interacting with metal ions [132]. Morin interacts with His13, His14, and Gln15 of Aβ42, corresponding to the intermolecular regions of β-sheets, and prevents Aβ assembly likely via its aromatic rings [9]. In the case of islet amyloid polypeptide, curcumin was shown to prevent inter-peptide interaction between Phe15 and His18, which is important for the aggregation of amyloids [130]. However, we have suggested that phenolic hydroxyl groups of morin and a metabolite of curcumin react with Cu(II), which leads to ROS generation and oxidative DNA damage [36,42].

Interestingly, copper is also thought to be associated with the enhancement of Aβ aggregation. The level of copper is elevated in the blood of AD patients [133] and Aβ plaques in an AD mouse model [134]. Cu(II) interacts with Aβ and enables the formation of β-sheets via its binding to His13 and His14, thereby forming a brace between Aβ strands [135]. Several polyphenols enable the chelating of various metal ions [136,137]. A recent report has shown that EGCG inhibits Cu(II)-associated amyloid aggregation of α-synuclein [138]. These findings suggest that polyphenols may inhibit Aβ aggregation via a Cu(II) chelating mechanism. However, as mentioned above, the interaction of polyphenols with Cu(II) leads to concomitant oxidative DNA damage [36,42,45,46,54,60,129].

These findings suggest that polyphenols can block Aβ aggregation and cause oxidative damage under certain circumstances, such as when they are in proximity to DNA.

#### **4. Conclusions**

Naturally occurring polyphenols are generally regarded as safe, based on their long history of use in the diet. However, when used at pharmacological concentrations, they have potential risks [18–20]. In this review, the pro-oxidant properties and the associated toxic effects of several naturally occurring polyphenols with anti-Aβ aggregation activity have been summarized. The pro-oxidant and anti-Aβ aggregation effects can be attributed to the structural features of polyphenols, suggesting a potential risk of oxidative damage. Therefore, we would like to emphasize the importance of assessing pro-oxidant properties of polyphenols from the point of view of safety.

**Author Contributions:** H.K. and S.O. wrote the first draft of the manuscript; M.M. and S.K. read the draft and made substantial and critical revisions. All authors have read and agreed to the published version of the manuscript.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Abbreviations**


#### **References**


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