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Cu(II) mediates kinetically distinct, non-amyloidogenic aggregation of amyloid-beta peptides.

ABSTRACT: 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.

SUBMITTER: Pedersen JT

PROVIDER: S-EPMC3143654 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Cu(II) mediates kinetically distinct, non-amyloidogenic aggregation of amyloid-beta peptides.

Pedersen Jeppe T JT Østergaard Jesper J Rozlosnik Noemi N Gammelgaard Bente B Heegaard Niels H H NH

The Journal of biological chemistry 20110603 30

Cu(II) ions are implicated in the pathogenesis of Alzheimer disease by influencing the aggregation of the amyloid-β (Aβ) peptide. Elucidating the underlying Cu(II)-induced Aβ 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 Aβ(1-40) using spectroscopic, microelectrophoretic, mass s ...[more]

PMID: 21642429

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Project description:Despite their unique advantages, the full potential of molecular probes for fluorescent monitoring of amyloid-β (Aβ) aggregates has not been fully exploited. This limited utility stems from the lack of knowledge about the hydrophobic interactions between the molecules of Aβ probes, as well as those between the probe and the Aβ aggregate. Herein, we report the first mechanistic study, which firmly establishes a structure-signaling relationship of fluorescent Aβ probes. We synthesized a series of five fluorescent Aβ probes based on an archetypal donor-acceptor-donor scaffold (denoted as SN1-SN5). The arylamino donor moieties were systematically varied to identify molecular factors that could influence the interactions between molecules of each probe and that could influence their fluorescence outcomes in conditions mimicking the biological milieu. Our probes displayed different responses to aggregates of Aβ, Aβ40 and Aβ42, two major isoforms found in Alzheimer's disease: SN2, having pyrrolidine donors, showed noticeable ratiometric fluorescence responses (Δν = 797 cm-1) to the Aβ40 and Aβ42 samples that contained oligomeric species, whereas SN4, having N-methylpiperazine donors, produced significant fluorescence turn-on signaling in response to Aβ aggregates, including oligomers, protofibrils, and fibrils (with turn-on ratios of 14 and 10 for Aβ42 and Aβ40, respectively). Mechanistic investigations were carried out by performing field-emission scanning electron microscopy, X-ray crystallography, UV-vis absorption spectroscopy, and steady-state and transient photoluminescence spectroscopy experiments. The studies revealed that the SN probes underwent preassembly prior to interacting with the Aβ species and that the preassembled structures depended profoundly on the subtle differences between the amino moieties of the different probes. Importantly, the studies demonstrated that the mode of fluorescence signaling (i.e., ratiometric response versus turn-on response) was primarily governed by stacking geometries within the probe preassemblies. Specifically, ratiometric fluorescence responses were observed for probes capable of forming J-assembly, whereas fluorescence turn-on responses were obtained for probes incapable of forming J-aggregates. This finding provides an important guideline to follow in future efforts at developing fluorescent probes for Aβ aggregation. We also conclude, on the basis of our study, that the rational design of such fluorescent probes should consider interactions between the probe molecules, as well as those between Aβ peptides and the probe molecule.

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Cu(II) mediates kinetically distinct, non-amyloidogenic aggregation of amyloid-beta peptides.

Publications

Cu(II) mediates kinetically distinct, non-amyloidogenic aggregation of amyloid-beta peptides.

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