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.

DFT Investigation of the Molecular Properties of the Dimethylglyoximato Complexes [M(Hdmg)2] (M = Ni, Pd, Pt)

“…On the other hand, some applications as the analytical photometric determination of traces of Ni, Pd or Pt [32,35,52] or their use in (medical) coordination chemistry [52][53][54][55][56] seem to make use of the properties of the molecular units and UV-vis absorption spectra of [Ni(Hdmg)2] in solution have been discussed as to stem from monomolecular units [15,16,46,57]. However, other spectroscopic data from species in solution is not reported and the frequently reported virtual insolubility of the materials sheds doubts on the question of the monomolecular species cause the absorptions of [Ni(Hdmg)2] [15,16,52,57] and are responsible for the biological effects of [Ni(Hdmg)2] [53] and [Pt(Hdmg)2] [54]. Recent quantum chemical calculations on [Ni(Hdmg)2] gave absorption bands at 180, 220, 248sh, and 359 nm for the monomer and marked shifted bands (183, 218, 254sh, 368 nm) for the dimer in the gas phase letting us assume that the reported solution spectra represent dissolved, but very probably oligomeric species.…”

Therapeutic roles of plants for 15 hypothesised causal bases of Alzheimer’s disease

“…Such metals interact with amyloid and tau, promoting their aggregation and neuronal toxicity [343]. These effects have been ameliorated by the application of iron, copper, zinc and nickel metal chelators in AD animal/ in vitro models [344][345][346]. Such chelators bind with the metal to form less toxic metal complexes which can be excreted [347].…”

Influence of Certain D-Metals on Formation of Advanced Glycation End Products, Aggregation and Amyloid Transformation of Albumin in Glycation Reaction

“…Способность меди и цинка трансформировать белки в амилоидную форму ранее была неоднократно описана. Полученные нами неожиданные результаты в отношении слабой активности никеля согласуются с недавно установленной ролью никеля в образовании человеческого β-амилоида [24]. ОБСУЖДЕНИЕ В результате исследования установлено, что при отсутствии металлов реакция гликирования не влияет на интенсивность флуоресценции тирозина и триптофана (интенсивность флуоресценции гликированных и негликированных проб одинакова).…”

“…), так и опосредованно, через влияние на активность ферментов (секретазы и др.) [22][23][24][25]10]. Таким образом, патогенетически связанными оказываются реакция гликирования, амилоидная трансформация белков, и активность ионов d-металлов, способных влиять на оба указанных процесса.…”