Stoichiometry of Heavy Metal Binding to Peptides Involved in Alzheimer’s Disease: Mass Spectrometric Evidence

Jureschi, Monica; Lupaescu, Ancuta Veronica; Ion, Laura; Petre, Brînduşa Alina; Drochioiu, Gabi

doi:10.1007/978-3-030-15950-4_23

Cited by 8 publications

(4 citation statements)

References 108 publications

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“…[19] In addition, when out of balance, these metal ions can also trigger the aggregation of 𝛽-amyloid peptide (A𝛽) and its deposition into amyloid plaques. [20] Evidence of the link between AD and redox metal dysregulation has been supported by post-mortem analyses of amyloid plaques, which revealed the accumulation of Cu, Fe, and Zn by 5.7, 2.8, and 3.1 times, respectively, the levels observed in normal brains. [21] Chelating compounds might thus prevent the harmful effects of the accumulation of metals.…”

Section: Introductionmentioning

confidence: 97%

Copper‐Binding Peptides Attenuate Microglia Inflammation through Suppression of NF‐kB Pathway

Caetano‐Silva

Rund

Vailati-Riboni

et al. 2021

Molecular Nutrition Food Res

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Scope: Activation of microglia, the resident immune cells of the central nervous system, has been related to the etiology and progression of neurodegenerative diseases; thus, finding novel approaches to suppress the neuroinflammatory process is of utmost relevance. Methods and Results: The anti-inflammatory activity of whey Cu-, Fe-, and Zn-binding peptides and their possible underlying mechanism of action were evaluated in microglia. Whey metal-binding peptides decreased nitric oxide production and tumor necrosis factor 𝜶 (TNF-𝜶) at mRNA and protein levels by stimulated BV-2 microglia in comparison to the control with no peptide treatment. The hydrophobicity, specific sequences, and possible synergistic effects seem to play a role. Cu-binding peptides (Cu-bp) presented anti-inflammatory activity both in BV-2 and primary microglia cultures. These peptides exert their action by suppressing nuclear factor kappa B (NF-kB) pathway since nuclear translocation of NF-kB p65 is decreased by roughly 30% upon Cu-bp treatment. Specific sequences identified in Cu-bp showed high affinity to bind NF-kB p65 by molecular docking (up to -8.8 kcal mol −1 ), corroborating the immunofluorescence studies. Conclusion: Cu-bp represent food-derived peptides that may be useful for neuroprotective purposes. Chelation of copper excess in the CNS and the bioavailability of such peptides, as well as their behavior in in vivo models, deserve further research for future applications.

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Section: Introductionmentioning

confidence: 97%

Copper‐Binding Peptides Attenuate Microglia Inflammation through Suppression of NF‐kB Pathway

Caetano‐Silva

Rund

Vailati-Riboni

et al. 2021

Molecular Nutrition Food Res

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“…Experiments based on MS, infrared (IR), UV–vis and microscopic techniques revealed significant changes in the structure of peptides, including their aggregation and fibrillation, associated with metal binding [ 26 , 27 , 28 , 29 ]. We have recently been looking for evidence of such complexity using MS and other bioanalytical techniques [ 30 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Aluminium Binding to Modified Amyloid-β Peptides: Implications for Alzheimer’s Disease

2020

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Aluminium (Al) is clearly neurotoxic and considerable evidence exists that Al may play a role in the aetiology or pathogenesis of Alzheimer’s disease (AD). Nevertheless, the link between AD pathology and Al is still open to debate. Therefore, we investigated here the interaction of aluminium ions with two Aβ peptide fragments and their analogues. First, we synthesised by the Fmoc/tBu solid-phase peptide synthesis (SPPS) strategy using an automated peptide synthesiser two new peptides starting from the Aβ(1–16) native peptide fragment. For this purpose, the three histidine residues (H6, H13, and H14) of the Aβ(1–16) peptide were replaced by three alanine and three serine residues to form the modified peptides Aβ(1–16)A36,13,14 and Aβ(1–16)S36,13,14 (primary structures: H-1DAEFRADSGYEVAAQK16-NH2 and H-1DAEFRSDSGYEVSSQK16-NH2). In addition, the Aβ(9–16) peptide fragment (H-9GYEVHHQK16-NH2) and its glycine analogues, namely Aβ(9–16)G110, (H-9GGEVHHQK16-NH2), Aβ(9–16)G213,14 (H-9GYEVGGQK16-NH2), and Aβ(9–16)G310,13,14 (H-9GGEVGGQK16-NH2), were manually synthesised in order to study Al binding to more specific amino acid residues. Both the peptides and the corresponding complexes with aluminium were comparatively investigated by mass spectrometry (MS), circular dichroism spectroscopy (CD), atomic force microscopy (AFM), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FT-IR). Al–peptide molecular ions and Al-fragment ions were unambiguously identified in the MS and MS/MS spectra. AFM images showed dramatic changes in the film morphology of peptides upon Al binding. Our findings from the investigation of N-terminal 1-16 and even 9-16 normal and modified sequences of Aβ peptides suggest that they have the capability to be involved in aluminium ion binding associated with AD.

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“…The coordination chemistry and binding properties of the AD-related peptides have been studied and well described using mass spectrometry (MS) techniques. 4 Different metal ions can bind and contribute to the aggregation of Aβ and fibrillation that worsen this neuropathology. 5 Thus, chelating agents can be used to prevent the harmful effects of the accumulation of metals.…”

Section: ■ Introductionmentioning

confidence: 99%

“…These metal ions, when out of balance, can trigger the aggregation of a β-amyloid peptide (Aβ) and its deposition into amyloid plaques, a hallmark of Alzheimer’s disease (AD). , This occurs because of the presence of a metal-binding domain in Aβ, specifically its N-terminal Aβ peptide fragment (1–16). The coordination chemistry and binding properties of the AD-related peptides have been studied and well described using mass spectrometry (MS) techniques . Different metal ions can bind and contribute to the aggregation of Aβ and fibrillation that worsen this neuropathology …”

Section: Introductionmentioning

confidence: 99%

Isolation and Sequencing of Cu-, Fe-, and Zn-Binding Whey Peptides for Potential Neuroprotective Applications as Multitargeted Compounds

Caetano‐Silva¹,

Simabuco

Bezerra

et al. 2020

J. Agric. Food Chem.

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This study aims to isolate metal-binding peptides and synthesize promising amino acid sequences to potentially act as neuroprotective compounds in the future, targeting different mechanisms. Fractions of whey metal-binding peptides (Cu, Fe, and Zn) isolated by immobilized metal affinity chromatography showed different amino acid profiles according to the metal. The Cu-binding peptides presented roughly twofold increase in the in vitro antioxidant, as assessed by oxygen radical absorbance capacity and anticholinesterase activities over the hydrolysate. This is probably because of the higher concentration of aromatic and basic residues, the latter being crucial for binding to the anionic sites of acetylcholinesterase. Six peptide sequences were synthesized based on the metal-binding sites, molecular mass, hydrophobicity, and bioactivity probability. Among the synthetic peptides, the VF dipeptide stood out both for its in vitro antioxidant and anticholinesterase activities. This peptide, as well as the fraction of Cu-binding peptides, should be further studied because it may act through different mechanisms related to neurodegenerative diseases, in addition to the chelation of the excess of metals in the central nervous system.

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Stoichiometry of Heavy Metal Binding to Peptides Involved in Alzheimer’s Disease: Mass Spectrometric Evidence

Cited by 8 publications

References 108 publications

Copper‐Binding Peptides Attenuate Microglia Inflammation through Suppression of NF‐kB Pathway

Copper‐Binding Peptides Attenuate Microglia Inflammation through Suppression of NF‐kB Pathway

Aluminium Binding to Modified Amyloid-β Peptides: Implications for Alzheimer’s Disease

Isolation and Sequencing of Cu-, Fe-, and Zn-Binding Whey Peptides for Potential Neuroprotective Applications as Multitargeted Compounds

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