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

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.