Reactivity of Metal-Free and Metal-Associated Amyloid-β with Glycosylated Polyphenols and Their Esterified Derivatives.

Kyle J Korshavn,Mi Hee Lim,Silvia Vertuani,Anirban Bhunia,Stefano Manfredini,Ayyalusamy Ramamoorthy,Yeon Ju Kwak,Milim Jang,Akiko Kochi

doi:10.1038/srep17842

Abstract

Both amyloid-β (Aβ) and transition metal ions are shown to be involved in the pathogenesis of Alzheimer’s disease (AD), though the importance of their interactions remains unclear. Multifunctional molecules, which can target metal-free and metal-bound Aβ and modulate their reactivity (e.g., Aβ aggregation), have been developed as chemical tools to investigate their function in AD pathology; however, these compounds generally lack specificity or have undesirable chemical and biological properties, reducing their functionality. We have evaluated whether multiple polyphenolic glycosides and their esterified derivatives can serve as specific, multifunctional probes to better understand AD. The ability of these compounds to interact with metal ions and metal-free/-associated Aβ, and further control both metal-free and metal-induced Aβ aggregation was investigated through gel electrophoresis with Western blotting, transmission electron microscopy, UV-Vis spectroscopy, fluorescence spectroscopy, and NMR spectroscopy. We also examined the cytotoxicity of the compounds and their ability to mitigate the toxicity induced by both metal-free and metal-bound Aβ. Of the polyphenols investigated, the natural product (Verbascoside) and its esterified derivative (VPP) regulate the aggregation and cytotoxicity of metal-free and/or metal-associated Aβ to different extents. Our studies indicate Verbascoside represents a promising structure for further multifunctional tool development against both metal-free Aβ and metal-Aβ.

Highlights

The senile plaques in the Alzheimer’s disease (AD)-affected brain have been shown to contain elevated concentrations of transition metals, Cu, Zn, and Fe, which suggests that these metal ions interact with and alter the aggregation of Aβ 4,8–10
There remains a lack of understanding about the relationship between small molecules and their subsequent biological functions with regards to the multiple aspects associated with AD
It is believed that hydrophobic interactions drive early stages of Aβ aggregation and that compounds with hydrophobic regions may effectively disrupt these aggregation-promoting forces and act as modulators of amyloid formation; some compounds of this nature have been investigated previously[6]

Summary

Introduction

The senile plaques in the AD-affected brain have been shown to contain elevated concentrations of transition metals, Cu, Zn, and Fe, which suggests that these metal ions interact with and alter the aggregation of Aβ 4,8–10. Natural polyphenolic products have been previously shown to possess potential anti-amyloidogenic activity[19,20] Both Verbascoside and Rutin have demonstrated the capacity to alter the aggregation and toxicity of metal-free Aβ aggregation towards nontoxic species[21,22,23,24], and phloretin, the non-glycosidic version of Phlorizin, has exhibited an ability to prevent membrane-associated aggregation of Aβ25. We believe that esterification may tune the ability of these three compounds to interact with both metal-free Aβ and metal–Aβ species while simultaneously improving the bioavailability, making them more suitable for future in vivo applications than their non-esterified counterparts Using these six compounds, we aim to further expand the understanding of structure-function relationships between multifunctional probes towards both metal-free Aβ and metal-Aβ through a detailed, molecular level characterization

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