The nickel-chelator dimethylglyoxime inhibits human amyloid beta peptide in vitro aggregation

Stéphane L Benoit,Robert J Maier

doi:10.1038/s41598-021-86060-1

Abstract

One of the hallmarks of the most common neurodegenerative disease, Alzheimer’s disease (AD), is the extracellular deposition and aggregation of Amyloid Beta (Aβ)-peptides in the brain. Previous studies have shown that select metal ions, most specifically copper (Cu) and zinc (Zn) ions, have a synergistic effect on the aggregation of Aβ-peptides. In the present study, inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the metal content of a commercial recombinant human Aβ40 peptide. Cu and Zn were among the metals detected; unexpectedly, nickel (Ni) was one of the most abundant elements. Using a fluorescence-based assay, we found that Aβ40 peptide in vitro aggregation was enhanced by addition of Zn2+ and Ni2+, and Ni2+-induced aggregation was facilitated by acidic conditions. Nickel binding to Aβ40 peptide was confirmed by isothermal titration calorimetry. Addition of the Ni-specific chelator dimethylglyoxime (DMG) inhibited Aβ40 aggregation in absence of added metal, as well as in presence of Cu2+ and Ni2+, but not in presence of Zn2+. Finally, mass spectrometry analysis revealed that DMG can coordinate Cu or Ni, but not Fe, Se or Zn. Taken together, our results indicate that Ni2+ ions enhance, whereas nickel chelation inhibits, Aβ peptide in vitro aggregation. Hence, DMG-mediated Ni-chelation constitutes a promising approach towards inhibiting or slowing down Aβ40 aggregation.

Highlights

One of the hallmarks of the most common neurodegenerative disease, Alzheimer’s disease (AD), is the extracellular deposition and aggregation of Amyloid Beta (Aβ)-peptides in the brain
Based on the time of onset, AD is classified into two types: early-onset AD (EOAD), which typically develops before the age of 65, and late-onset AD (LOAD) for those older than 653
The role of Cu(I), Cu(II), or Zn(II) has been well documented[24,25,26]. Both Aβ40 and Aβ42 peptides have been shown to bind Cu(II) or Zn(II) with significant affinity in vitro, leading to Aβ aggregation[19,27,28,29,30]; secondly, a similar effect was observed in vivo, leading to plaque build-up and toxicity in AD animal models, for instance with Cu(II) in r abbits[31], or with Zn(II) in m ice[32]; thirdly, post-mortem analysis revealed that respective Cu, Fe and Zn levels in plaques of AD brains were 5.7, 2.8, and 3.1-fold higher compared to normal b rains[33]; fourthly, accumulation of Cu and Zn co-localized with Aβ peptide d eposits[34]

Summary

Introduction

One of the hallmarks of the most common neurodegenerative disease, Alzheimer’s disease (AD), is the extracellular deposition and aggregation of Amyloid Beta (Aβ)-peptides in the brain. Both Aβ40 and Aβ42 peptides have been shown to bind Cu(II) or Zn(II) with significant affinity in vitro, leading to Aβ aggregation[19,27,28,29,30]; secondly, a similar effect was observed in vivo, leading to plaque build-up and toxicity in AD animal models, for instance with Cu(II) in r abbits[31], or with Zn(II) in m ice[32]; thirdly, post-mortem analysis revealed that respective Cu, Fe and Zn levels in plaques of AD brains were 5.7, 2.8, and 3.1-fold higher compared to normal b rains[33]; fourthly, accumulation of Cu and Zn co-localized with Aβ peptide d eposits[34] Taken together, these results have given birth to a theory known as the “metal hypothesis of AD”, that links metal homeostasis (especially that of Cu, Fe and Zn) and AD35. Alternative ways to target and modulate the toxicity of metal-bound (or metal-free) Aβ species include the use of (i) glycosylated polyphenols and their esterified derivatives, which present the advantage of using natural low toxicity c ompounds[41]; (ii) synthetic flavonoids and amino-isoflavones, which have shown promising results towards targeting metal s ites[42]; (iii) small molecules, such as N1,N1‐dimethyl‐N4‐(pyridin‐2‐ ylmethyl)benzene‐1,4‐diamine (“L2-b”) and its d erivatives[43,44]; (iv) β-sheet breakers, which are small peptides (five amino-acids long) effective in reducing the Aβ1-40 aggregation, even in the presence of metal ions[45]

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Results

Conclusion