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Review
. 2021;82(s1):S335-S357.
doi: 10.3233/JAD-200185.

Polyphenols as Potential Metal Chelation Compounds Against Alzheimer's Disease

Johant Lakey-Beitia  1 , Andrea M Burillo  1 , Giovanni La Penna  2 , Muralidhar L Hegde  3   4   5 , K S Rao  6   7
Affiliations
Review

Polyphenols as Potential Metal Chelation Compounds Against Alzheimer's Disease

Johant Lakey-Beitia et al. J Alzheimers Dis. 2021.

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease affecting more than 50 million people worldwide. The pathology of this multifactorial disease is primarily characterized by the formation of amyloid-β (Aβ) aggregates; however, other etiological factors including metal dyshomeostasis, specifically copper (Cu), zinc (Zn), and iron (Fe), play critical role in disease progression. Because these transition metal ions are important for cellular function, their imbalance can cause oxidative stress that leads to cellular death and eventual cognitive decay. Importantly, these transition metal ions can interact with the amyloid-β protein precursor (AβPP) and Aβ42 peptide, affecting Aβ aggregation and increasing its neurotoxicity. Considering how metal dyshomeostasis may substantially contribute to AD, this review discusses polyphenols and the underlying chemical principles that may enable them to act as natural chelators. Furthermore, polyphenols have various therapeutic effects, including antioxidant activity, metal chelation, mitochondrial function, and anti-amyloidogenic activity. These combined therapeutic effects of polyphenols make them strong candidates for a moderate chelation-based therapy for AD.

Keywords: Alzheimer’s disease; amyloid-β; copper; iron; metal chelation therapy; metalloproteins; polyphenols; zinc.

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Figures

Fig. 1.
Fig. 1.
Potential therapeutic effects of polyphenols. Metal chelation occurs via coordination with oxophilic transition metals, such as Cu, Zn, and Fe, which are abundant in the CNS. Transition metals can induce ROS, which damage the genome. Therefore, polyphenols have DNA protection activity. Polyphenols modulate the AβPP pathway in two different ways. One pathway activates α-secretase by removing the pro-domain, which induces the non-amyloidogenic pathway. A second pathway favors neuroprotection, wherein polyphenols inhibit the β-site amyloid protein precursor cleaving enzyme 1 (BACE1), leading to decreased Aβ concentration. Polyphenols also promote Aβ clearance through non-covalent interactions with amino acid residues that disrupt Aβ structure stability, thus leading to fibril disaggregation. Polyphenols can also induce mitochondrial biogenesis by stimulating PGC-1α.
Fig. 2.
Fig. 2.
Cu binding interactions with AβPP and Aβ42. a) Configuration of Cu with residues His147, His151, Tyr168 in APP’s copper binding region and two water molecules in a trigonal bipyramidal geometry. b) Configuration of Cu with residues His388, His457, His507, and His511 in APP E2 domain. c) Cu binding with Aβ42 residues Ala2, His6, His13, and His14 in a tetrahedral square planar configuration. d) Cu binding to Aβ42 residues His6, Tyr10, His13, His14, and a water molecule in a trigonal bipyramidal configuration. e) Square-base pyramidal arrangement of Cu with Aβ42 residues Asp1, His6, His 13 or 14, and the carboxylate of Asp1, Glu3, Asp7, or Glu11.
Fig. 3.
Fig. 3.
One-electron transfer cycle during ROS production within the synaptic cleft. DH2 is ascorbic acid and D is dehydroascorbic acid. The blood-brain barrier (BBB) is in contact with cerebrospinal fluid (CSF).
Fig. 4.
Fig. 4.
Types of metal chelation compounds. Compounds a–d are approved for treating metal ion excess. Compounds e–f are considered metal-protein attenuating compounds (MPAC).
Fig. 5.
Fig. 5.
Classification of polyphenols according to the number of metal binding sites (common names in parenthesis).
Fig. 6.
Fig. 6.
Polyphenols interact with transition metal ions to form a stable 5- membered ring as EGCG or 6-membered ring as curcumin.
Fig. 7.
Fig. 7.
Polyphenols interact with transition metal ions and avoid Haber-Weiss and Fenton reactions.
Fig. 8.
Fig. 8.
Bifunctionality of polyphenols, which form an Aβ-M-PP ternary complex and also interact with ROS.
Fig. 9.
Fig. 9.
Potential mechanism of polyphenol neuroprotection caused by the ternary complex Aβ-M-PP, which may prevent Aβ-M aggregation.
Fig. 10.
Fig. 10.
Structural comparison between donepezil and curcumin.
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