Amyloid-β Binds Cu<sup>2+</sup> in a Mononuclear Metal Ion Binding Site

Karr, Jesse W.; Kaupp, Lauren J.; Szalai, Veronika A.

doi:10.1021/ja0488028

Cited by 158 publications

(265 citation statements)

References 37 publications

(73 reference statements)

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“…These results are concordant with those obtained previously on working with individual metal ions [29][30][31][32]. Although blood and internal biochemical environment is characterized by a…”

Section: Discussionsupporting

confidence: 92%

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Interaction of β-amyloid(1-40) peptide with pairs of metal ions: An electrospray ion trap mass spectrometric model study

Drochioiu

Manea

Drăguşanu

et al. 2009

Biophysical Chemistry

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 2 AbstractThe stoichiometries and the affinity toward simple and paired metal ions of synthetic amyloid-β(1-40)peptide (Aβ1-40) were investigated by electrospray ion trap mass spectrometry (ESI-MS), circular dichroism (CD), and atomic force microscopy (AFM). The results lead to the working hypothesis that pHdependent metal binding to Aβ1-40 may induce conformational changes, which affect the affinity toward other metals. A significant copper and zinc binding to Aβ1-40 peptide at pH 5.5 was found, whereas nickel ions commonly bind to each molecule of β-amyloid peptide. Some complexes of Aβ1-40 with more than one nickel ion were identified by ESI-MS. In addition, nickel ions proved to enhance Aβ oligomerization. On increasing pH, up to 12 ions of zinc may bind to a single Aβ molecule. Under the same pH and concentration conditions, the binding pattern of the independent copper and silver ions to Aβ1-40 was different from that of the equimolecular mixture of the two metal ions. One might assume that some conformational changes due to water loss altered the capacity of Aβ peptide to bind certain heavy metal ions. As a consequence, copper-silver interaction with the binding process to Aβ1-40 became highly complex. A competition between silver and nickel ions for Aβ1-40 binding sites at high pH was also observed. New strategies were proposed to identify the characteristic signals for some important metal ion-peptide complexes in the spectra recorded at high pH or high concentrations of metal ions. To explain the formation of such a large number of high metal ion-Aβ complexes, we took into consideration the participation of both histidine residues and free amino groups as well as carboxylate ones in the binding process. Finally, CD and AFM studies supported the mass spectrometric data.

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Section: Discussionsupporting

confidence: 92%

“…Several spectroscopic studies have indicated that the copper-binding site of Aβ consists of the three histidine residues His6, His13 and His14 and an as yet undefined fourth ligand; proposed ligands include Tyr10 [19,[38][39][40], the Nterminal nitrogen [30] or an as yet unidentified carboxylate side chain [31,32].…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Interaction of β-amyloid(1-40) peptide with pairs of metal ions: An electrospray ion trap mass spectrometric model study

Drochioiu

Manea

Drăguşanu

et al. 2009

Biophysical Chemistry

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“…1B, blue squares) contained copper in a 1:1 stoichiometry. This is compatible with the notion that A␤ 1-40 has one high affinity Cu(II)-binding site (33,39) and that Cu(II) is bound to the aggregates in a 1:1 ratio (32,44). In addition, ICP-MS data showed that the copper stays bound to the aggregates during the entire time course of the experiment (72 h).…”

Section: Cu(ii):a␤ 1-40 Ratiosupporting

confidence: 86%

“…An intriguing approach for elucidating the complex role of Cu(II) in the A␤ aggregation mechanism would be the use of complementary kinetic methods as advocated in a recent review (31). In particular, kinetic studies on Cu(II) bound to A␤ have been lacking, and to our knowledge only end point determination of the copper content in the amyloid aggregates has been performed (32,33). Nevertheless, this information is as important as the out-come of studies on the peptide disappearance or aggregation formation kinetics for elucidating the A␤-Cu(II) interplay and will form the basis for studies of neuro-cytotoxicity under defined metallopeptide conditions.…”

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confidence: 99%

Cu(II) Mediates Kinetically Distinct, Non-amyloidogenic Aggregation of Amyloid-β Peptides

Pedersen

Østergaard

Rozlosnik

et al. 2011

Journal of Biological Chemistry

118

160

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Cu(II) ions are implicated in the pathogenesis of Alzheimer disease by influencing the aggregation of the amyloid-␤ (A␤)peptide. Elucidating the underlying Cu(II)-induced A␤ aggregation is paramount for understanding the role of Cu(II) in the pathology of Alzheimer disease. The aim of this study was to characterize the qualitative and quantitative influence of Cu(II) on the extracellular aggregation mechanism and aggregate morphology of A␤ 1-40 using spectroscopic, microelectrophoretic, mass spectrometric, and ultrastructural techniques. We found that the Cu(II):A␤ ratio in solution has a major influence on (i) the aggregation kinetics/mechanism of A␤, because three different kinetic scenarios were observed depending on the Cu(II):A␤ ratio, (ii) the metal:peptide stoichiometry in the aggregates, which increased to 1.4 at supra-equimolar Cu(II):A␤ ratio; and (iii) the morphology of the aggregates, which shifted from fibrillar to non-fibrillar at increasing Cu(II):A␤ ratios. We observed dynamic morphological changes of the aggregates, and that the formation of spherical aggregates appeared to be a common morphological end point independent on the Cu(II) concentration. Experiments with A␤ 1-42 were compatible with the conclusions for A␤ 1-40 even though the low solubility of A␤ 1-42 precluded examination under the same conditions as for the A␤ 1-40 . Experiments with A␤ 1-16 and A␤ 1-28 showed that other parts than the Cu(II)-binding His residues were important for Cu(II)-induced A␤ aggregation. Based on this study we propose three mechanistic models for the Cu(II)-induced aggregation of A␤ 1-40 depending on the Cu(II):A␤ ratio, and identify key reaction steps that may be feasible targets for preventing Cu(II)-associated aggregation or toxicity in Alzheimer disease.Extracellular cerebral plaques composed mainly of amyloid ␤-peptide (A␤) 1-40 and 1-42 fibrils are a histopathological hallmark of Alzheimer disease (AD) 3 (1, 2). These plaques contain elevated levels of metals, in particular zinc and copper (3). Also, it has been shown that these metal ions can promote the aggregation of A␤ in vitro (4, 5). This implies a key role of the metal ions in the A␤-mediated pathology of AD (6), although the subject is still under much debate (7,8), and a role of amyloid-independent pathways in AD neurodegeneration have recently been reviewed (9).Specifically regarding the role of metal ions in the amyloidmediated pathology of AD, it is believed that Zn(II) acts as a neuroprotector (10, 11), whereas Cu(II) is considered to mediate neurotoxicity (12)(13)(14). The latter effect is thought to occur through early stage soluble A␤ and A␤-Cu oligomeric intermediates (15-18) that may be involved in the formation of reactive oxygen species (6). It was discovered that Cu(II) may be released postsynaptically at glutamatergic synapses in hippocampus (19,20), the site for initial A␤ deposition in AD. This provides an explanation for how Cu(II) can interact with A␤. Seemingly in contrast to the support for the neurotoxic effects of Cu(II),...

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“…The identity of the fourth ligand includes tyrosine at position 10 (Tyr10) (16,(19)(20)(21), the N-terminal nitrogen (22), or an undefined carboxylate side chain (23). Our EPR studies indicate that increasing the Cu 2+ above ∼0.3 mol/mol peptide-induced line broadening in the Cu 2+ EPR spectra suggests the presence of dipolar or exchange effects (17,19).…”

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confidence: 82%

Concentration Dependent Cu²⁺Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β Peptide

et al. 2007

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The Amyloid peptide (A ) of Alzheimer's diseases (AD) is closely linked to the progressive cognitive decline associated with the disease. Cu 2+ ions can induce the de noVo aggregation of the A peptide into non-amyloidogenic aggregates and the production of a toxic species. The mechanism by which Cu 2+ mediates the change from amyloid material toward Cu 2+ induced aggregates is poorly defined. Here we demonstrate that the aggregation state of A 1-42 at neutral pH is governed by the Cu 2+ :peptide molar ratio. By probing amyloid content and total aggregation, we observed a distinct Cu 2+ switching effect centered at equimolar Cu 2+ :peptide ratios. At sub-equimolar Cu 2+ :peptide molar ratios, A 1-42 forms thioflavin-T reactive amyloid; conversely, at supra-equimolar Cu 2+ :peptide molar ratios, A 1-42 forms both small spherical oligomers approximately 10-20 nm in size and large amorphous aggregates. We demonstrate that these insoluble aggregates form spontaneously via a soluble species without the presence of an observable lag phase. In seeding experiments, the Cu 2+ induced aggregates were unable to influence fibril formation or convert into fibrillar material. Aged Cu 2+ induced aggregates are toxic when compared to A 1-42 aged in the absence of Cu 2+ . Importantly, the formation of dityrosine crosslinked A , by the oxidative modification of the peptide, only occurs at equimolar molar ratios and above. The formation of dityrosine adducts occurs following the initiation of aggregation and hence does not drive the formation of the Cu 2+ induced aggregates. These results define the role Cu 2+ plays in modulating the aggregation state and toxicity of A 1-42.

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Amyloid-β Binds Cu²⁺ in a Mononuclear Metal Ion Binding Site

Cited by 158 publications

References 37 publications

Interaction of β-amyloid(1-40) peptide with pairs of metal ions: An electrospray ion trap mass spectrometric model study

Interaction of β-amyloid(1-40) peptide with pairs of metal ions: An electrospray ion trap mass spectrometric model study

Cu(II) Mediates Kinetically Distinct, Non-amyloidogenic Aggregation of Amyloid-β Peptides

Concentration Dependent Cu²⁺Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β Peptide

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Amyloid-β Binds Cu2+ in a Mononuclear Metal Ion Binding Site

Cited by 158 publications

References 37 publications

Interaction of β-amyloid(1-40) peptide with pairs of metal ions: An electrospray ion trap mass spectrometric model study

Interaction of β-amyloid(1-40) peptide with pairs of metal ions: An electrospray ion trap mass spectrometric model study

Cu(II) Mediates Kinetically Distinct, Non-amyloidogenic Aggregation of Amyloid-β Peptides

Concentration Dependent Cu2+Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β Peptide

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Amyloid-β Binds Cu²⁺ in a Mononuclear Metal Ion Binding Site

Concentration Dependent Cu²⁺Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β Peptide