Nickel chelator dimethylglyoxime inhibits amyloid beta aggregation in vitro and targets nickel-driven Alzheimer’s mechanisms Original paper

What was studied?

In this experimental study, the authors investigated how the nickel chelator dimethylglyoxime inhibits amyloid beta aggregation, focusing specifically on the recombinant human Aβ40 peptide and its interaction with transition metals, particularly nickel. Using inductively coupled plasma mass spectrometry (ICP-MS), thioflavin T (ThT) aggregation assays, isothermal titration calorimetry (ITC), and high-resolution mass spectrometry, they quantified the metal content of a commercial recombinant Aβ40 preparation, characterized the impact of Cu²⁺, Zn²⁺, and Ni²⁺ on in vitro aggregation kinetics, and tested whether the nickel chelator dimethylglyoxime (DMG) inhibits amyloid beta aggregation under different metal and pH conditions. They further evaluated whether dimethylglyoxime forms stable complexes with various metals and explored the capacity of orally administered dimethylglyoxime to reach the brain in a murine model, situating these findings within the broader “metal hypothesis” and “infection hypothesis” of Alzheimer’s disease.

Who was studied?

This is an in vitro biochemical and biophysical study using commercially available recombinant human Aβ40 peptide expressed in Escherichia coli, not a clinical or animal efficacy trial. The peptide preparation was analyzed for multi-element metal content and then subjected to aggregation and binding assays in buffered solutions. For the pharmacokinetic aspect, C57BL mice received repeated oral doses of dimethylglyoxime, after which brain tissue was harvested to detect dimethylglyoxime or dimethylglyoxime–metal complexes by FTICR-MS and NMR, although this arm was limited to detection rather than evaluation of behavioral or neuropathological outcomes. No human subjects or clinical Alzheimer’s disease populations were included; the work is best interpreted as mechanistic preclinical data that inform future translational strategies for metal-targeted interventions in Alzheimer’s disease.

Most important findings

ICP-MS of the recombinant Aβ40 peptide revealed substantial metal contamination intrinsic to the preparation, with selenium and nickel being most abundant and appreciable levels of aluminum, copper, manganese, zinc, barium, and strontium also detected, whereas iron was below detection limits. The table on page 3 (Table 1) quantifies a metal: peptide ratio of approximately 0.073 mol Ni per mol Aβ40, indicating that the peptide is already nickel-bound before any experimental supplementation. Functionally, ThT aggregation assays showed that exogenous Ni²⁺ significantly accelerated Aβ40 aggregation in a concentration-dependent manner, with a 2.5-fold increase in aggregation rate at 10 µM Ni²⁺ and 5.7-fold at 100 µM compared with metal-free control, while Zn²⁺ produced even larger enhancements and Cu²⁺ had minimal effect at neutral pH. pH modulation demonstrated that Ni-induced aggregation was facilitated under mildly acidic conditions (pH 6.5) and abolished at alkaline pH 8.5, reinforcing pH-sensitive nickel–peptide interactions. ITC confirmed direct nickel binding to Aβ40 with an apparent Kd of ~4.2 µM and a stoichiometry of ~0.7 Ni per peptide, and thermodynamic parameters (ΔH −5 kJ/mol, positive ΔS) consistent with an exothermic, spontaneous binding reaction.

Dimethylglyoxime robustly inhibited Aβ40 aggregation when added to metal-containing peptide preparations. In the absence of added metal, 100 µM dimethylglyoxime reduced aggregation by 40–85 %, and 500–1000 µM essentially abolished ThT signal, implying that chelation of intrinsic metals within the recombinant peptide (notably Ni²⁺) is sufficient to block β-sheet–rich fibril formation. In the presence of 100 µM Ni²⁺, dimethylglyoxime produced complete inhibition of aggregation at higher chelator concentrations, whereas inhibition in the presence of Cu²⁺ was partial and Zn²⁺-driven aggregation remained only partially suppressible even at 1 mM dimethylglyoxime, mirroring its weaker coordination with zinc. FTICR-MS confirmed stable [DMG]₂–Ni and [DMG]₂–Cu complexes and an absence of similar complexes with Fe, Zn, or Se, explaining the metal-selective chelation pattern. The schematic model on page 8 (Figure 4) integrates these findings into a dual mechanism in which nickel contributes to Alzheimer’s disease both by directly enhancing Aβ aggregation and by supporting nickel-dependent bacterial enzymes in pathogens implicated in Alzheimer’s pathology; dimethylglyoxime occupies an intersection point by depleting nickel for both Aβ and microbial systems. Attempts to detect dimethylglyoxime or its complexes in mouse brain after repeated oral dosing were unsuccessful, suggesting poor blood-brain barrier penetration or rapid metabolism under the tested conditions.

Key implications

The study provides strong mechanistic support for considering nickel as an under-recognized contributor to Aβ40 aggregation and, by extension, to the metal-driven component of Alzheimer’s disease pathogenesis. For clinicians and translational researchers, the data highlight that not all metal chelation strategies are equivalent: a nickel-selective agent such as dimethylglyoxime can inhibit amyloid aggregation driven by nickel while sparing essential metal pools for zinc and iron, at least at the level of direct coordination chemistry.

From a microbiome and microbial metallomics perspective, the work is particularly relevant because many candidate Alzheimer’s-associated pathogens, including Helicobacter pylori, Escherichia coli, and Salmonella Typhimurium, rely on nickel-dependent enzymes such as urease and NiFe hydrogenases; systemic nickel chelation might therefore modulate both host amyloidogenic processes and the viability or virulence of nickel-requiring pathobionts that could participate in brain infection or peripheral immune priming. In the microbiome signatures framework, these nickel-dependent taxa could be considered major microbial associations in an Alzheimer’s disease metallomic-microbiomic axis. However, the inability to demonstrate brain penetration of orally administered dimethylglyoxime underscores a key translational barrier: any clinical strategy based on nickel chelation will require optimization of pharmacokinetics, delivery route, and tissue targeting to influence central nervous system amyloid dynamics. Overall, the findings justify further preclinical work combining nickel chelation, microbiome-targeted interventions, and in vivo Alzheimer’s models.

Citation

Benoit SL, Maier RJ. The nickel-chelator dimethylglyoxime inhibits human amyloid beta peptide in vitro aggregation. Sci Rep. 2021;11:6622. doi:10.1038/s41598-021-86060-1.