Interactions of Zn(ii) and Cu(ii) ions with Alzheimer's amyloid-beta peptide. Metal ion binding, contribution to fibrillization and toxicity

Tõugu, Vello; Tiiman, Ann; Palumaa, Peep

doi:10.1039/c0mt00073f

Cited by 203 publications

(214 citation statements)

References 135 publications

(282 reference statements)

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“…Remarkably high concentrations of copper (400 lM), zinc (1 mM), and iron (1 mM) have been found within the amyloid deposits of AD-affected brains [7][8][9]. In vitro and in vivo studies suggest that zinc and copper may mediate the aggregation of these peptides [10]. Furthermore, treatment of AD brain extracts with metal chelators results in the dissolution of aggregated Ab [11,12].…”

Section: Introductionmentioning

confidence: 97%

Calorimetric investigation of copper(II) binding to Aβ peptides: thermodynamics of coordination plasticity

et al. 2012

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Metal ions have been shown to play a critical role in β-amyloid (Aβ) neurotoxicity, thus prompting an intense investigation into the formation of metal-Aβ complexes. Isothermal titration calorimetry (ITC) has been widely used to determine binding constants (K) for a variety of metal-protein interactions, including those in metal-Aβ complexes. In this study, ITC was used to more fully quantify the thermodynamics (K, ΔG, ΔH, and TΔS) of Cu(2+) binding to Aβ16, N-acetyl-Aβ16, Aβ28, N-acetyl-Aβ28, and Aβ28 variants (H6A, H13A, H14A) at pH 7.4 and 37 °C. After deconvolution of competing reactions, K for Aβ16 was found to be 1.1 (±0.13) × 10(9) and is in strong agreement with literature values measured under similar conditions. Further, a similar K value was obtained at two additional concentrations of competing ligand, suggesting that ternary complex formation is not significant. The acetylated peptide analogs reveal a marked decrease in the overall free energy upon binding, which is the result of less favorable enthalpic and entropic contributions. Circular dichroism spectroscopy shows conformational changes that are consistent with these results. Most importantly, data for Aβ28 variants lacking a potential Cu(2+)-binding histidine residue reveal that the overall free energy of binding remains constant, which is the result of entropy/enthalpy compensation. These data provide fundamental thermodynamic evidence for coordination plasticity in Cu(2+) binding to Aβ and other intrinsically disordered peptides.

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Section: Introductionmentioning

confidence: 97%

Calorimetric investigation of copper(II) binding to Aβ peptides: thermodynamics of coordination plasticity

et al. 2012

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“…One of the metals that has attracted attention is copper (Cu 21 ), whose concentration is threefold greater in AD patients than in normal patients, with concentrations between 340 and 400 mM. 6,7 The interaction between Ab-fibrils and Cu 21 is important not only because of its role in amyloidosis but also because it has been associated with the generation of oxidative stress. 8 Therefore, several experimental and computational methods have focused on the analysis of the interaction between Ab 1242 and Cu 21 .…”

Section: Introductionmentioning

confidence: 99%

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

et al. 2013

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The formation of fibrils and oligomers of amyloid beta (Aβ) with 42 amino acid residues (Aβ1–42) is the most important pathophysiological event associated with Alzheimer's disease (AD). The formation of Aβ fibrils and oligomers requires a conformational change from an α‐helix to a β‐sheet conformation, which is encouraged by the formation of a salt bridge between Asp 23 or Glu 22 and Lys 28. Recently, Cu2+ and various drugs used for AD treatment, such as galanthamine (Reminyl®), have been reported to inhibit the formation of Aβ fibrils. However, the mechanism of this inhibition remains unclear. Therefore, the aim of this work was to explore how Cu2+ and galanthamine prevent the formation of Aβ1–42 fibrils using molecular dynamics (MD) simulations (20 ns) and in vitro studies using fluorescence and circular dichroism (CD) spectroscopies. The MD simulations revealed that Aβ1–42 acquires a characteristic U‐shape before the α‐helix to β‐sheet conformational change. The formation of a salt bridge between Asp 23 and Lys 28 was also observed beginning at 5 ns. However, the MD simulations of Aβ1−42 in the presence of Cu2+ or galanthamine demonstrated that both ligands prevent the formation of the salt bridge by either binding to Glu 22 and Asp 23 (Cu2+) or to Lys 28 (galanthamine), which prevents Aβ1−42 from adopting the U‐characteristic conformation that allows the amino acids to transition to a β‐sheet conformation. The docking results revealed that the conformation obtained by the MD simulation of a monomer from the 1Z0Q structure can form similar interactions to those obtained from the 2BGE structure in the oligomers. The in vitro studies demonstrated that Aβ remains in an unfolded conformation when Cu2+ and galanthamine are used. Then, ligands that bind Asp 23 or Glu 22 and Lys 28 could therefore be used to prevent β turn formation and, consequently, the formation of Aβ fibrils.

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“…Previous data has shown that reduced DHA levels in AD brains were associated with an increase in intracellular zinc levels [6], which could suggest a direct interaction between DHA and zinc in the progression of AD. Zinc-mediated brain injury has been implicated as a neurotoxin in models of AD [7]. However, the mechanism of zinc toxicity is unknown, but evidence suggests that zinc induces cellular apoptosis through inhibition of adenosine triphosphate (ATP) synthesis [8,9], increase in the production of reactive oxygen species (ROS) and eventual loss of mitochondrial membrane potential ∆Ψ m [9].…”

Section: Introductionmentioning

confidence: 99%

Effect of DHA and CoenzymeQ10 Against A�- and Zinc-Induced Mitochondrial Dysfunction in Human Neuronal Cells

Sadli¹,

Barrow²,

McGee

et al. 2013

Cell Physiol Biochem

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Background: Beta-amyloid (Aβ) protein is a key factor in the pathogenesis of Alzheimer's disease (AD) and it has been reported that mitochondria is involved in the biochemical pathway by which Aβ can lead to neuronal dysfunction. Coenzyme Q10 (CoQ10) is an essential cofactor involved in the mitochondrial electron transport chain and has been suggested as a potential therapeutic agent in AD. Zinc toxicity also affects cellular energy production by decreasing oxygen consumption rate (OCR) and ATP turnover in human neuronal cells, which can be restored by the neuroprotective effect of docosahexaenoic acid (DHA). Method: In the present study, using Seahorse XF-24 Metabolic Flux Analysis we investigated the effect of DHA and CoQ10 alone and in combination against Aβ- and zinc-mediated changes in the mitochondrial function of M17 neuroblastoma cell line. Results: Here, we observed that DHA is specifically neuroprotective against zinc-triggered mitochondrial dysfunction, but does not directly affect Aβ neurotoxicity. CoQ10 has shown to be protective against both Aβ- and zinc-induced alterations in mitochondrial function. Conclusion: Our results indicate that DHA and CoQ10 may be useful for the prevention, treatment and management of neurodegenerative diseases such as AD.

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Interactions of Zn(ii) and Cu(ii) ions with Alzheimer's amyloid-beta peptide. Metal ion binding, contribution to fibrillization and toxicity

Cited by 203 publications

References 135 publications

Calorimetric investigation of copper(II) binding to Aβ peptides: thermodynamics of coordination plasticity

Calorimetric investigation of copper(II) binding to Aβ peptides: thermodynamics of coordination plasticity

In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

Effect of DHA and CoenzymeQ10 Against A�- and Zinc-Induced Mitochondrial Dysfunction in Human Neuronal Cells

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Interactions of Zn(ii) and Cu(ii) ions with Alzheimer's amyloid-beta peptide. Metal ion binding, contribution to fibrillization and toxicity

Cited by 203 publications

References 135 publications

Calorimetric investigation of copper(II) binding to Aβ peptides: thermodynamics of coordination plasticity

Calorimetric investigation of copper(II) binding to Aβ peptides: thermodynamics of coordination plasticity

In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

Effect of DHA and CoenzymeQ10 Against A�- and Zinc-Induced Mitochondrial Dysfunction in Human Neuronal Cells

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In silico and in vitro studies to elucidate the role of Cu²⁺ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process