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Amyloid-Beta Peptides Trigger Aggregation of Alpha-Synuclein In Vitro.

ABSTRACT: Alzheimer's disease (AD) and Parkinson's disease (PD), including dementia with Lewy bodies (DLB), account for the majority of dementia cases worldwide. Interestingly, a significant number of patients have clinical and neuropathological features of both AD and PD, i.e., the presence of amyloid deposits and Lewy bodies in the neocortex. The identification of ?-synuclein peptides in amyloid plaques in DLB brain led to the hypothesis that both peptides mutually interact with each other to facilitate neurodegeneration. In this article, we report the influence of A?(1-42) and pGlu-A?(3-42) on the aggregation of ?-synuclein in vitro. The aggregation of human recombinant ?-synuclein was investigated using thioflavin-T fluorescence assay. Fibrils were investigated by means of antibody conjugated immunogold followed by transmission electron microscopy (TEM). Our data demonstrate a significantly increased aggregation propensity of ?-synuclein in the presence of minor concentrations of A?(1-42) and pGlu-A?(3-42) for the first time, but without effect on toxicity on mouse primary neurons. The analysis of the composition of the fibrils by TEM combined with immunogold labeling of the peptides revealed an interaction of ?-synuclein and A? in vitro, leading to an accelerated fibril formation. The analysis of kinetic data suggests that significantly enhanced nucleus formation accounts for this effect. Additionally, co-occurrence of ?-synuclein and A? and pGlu-A?, respectively, under pathological conditions was confirmed in vivo by double immunofluorescent labelings in brains of aged transgenic mice with amyloid pathology. These observations imply a cross-talk of the amyloid peptides ?-synuclein and A? species in neurodegeneration. Such effects might be responsible for the co-occurrence of Lewy bodies and plaques in many dementia cases.

SUBMITTER: Koppen J

PROVIDER: S-EPMC7037551 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Amyloid-Beta Peptides Trigger Aggregation of Alpha-Synuclein In Vitro.

Köppen Janett J Schulze Anja A Machner Lisa L Wermann Michael M Eichentopf Rico R Guthardt Max M Hähnel Angelika A Klehm Jessica J Kriegeskorte Marie-Christin MC Hartlage-Rübsamen Maike M Morawski Markus M von Hörsten Stephan S Demuth Hans-Ulrich HU Roßner Steffen S Schilling Stephan S

Molecules (Basel, Switzerland) 20200129 3

Alzheimer's disease (AD) and Parkinson's disease (PD), including dementia with Lewy bodies (DLB), account for the majority of dementia cases worldwide. Interestingly, a significant number of patients have clinical and neuropathological features of both AD and PD, i.e., the presence of amyloid deposits and Lewy bodies in the neocortex. The identification of α-synuclein peptides in amyloid plaques in DLB brain led to the hypothesis that both peptides mutually interact with each other to facilitate ...[more]

PMID: 32013170

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Project description:While several polyphenols were found to either inhibit or modulate the aggregation of proteins implicated in neurodegenerative diseases, such as Parkinson's disease (PD), discrepant action mechanisms have been reported. This, in addition to some polyphenols' pan-assay interference compounds' reputation, casts some doubts concerning their therapeutic relevance. Here, we studied, through molecular dynamics and enhanced sampling methods, the aggregation of 11-mer peptides from the non-amyloid-β component, an aggregation-prone domain of α-synuclein (α-syn) implicated in PD and other synucleinopathies, in neat water and aqueous solutions of resveratrol (RSV) and gallic acid (GA). Further, simulations of the complete protein were carried out in aqueous urea, RSV, and GA solutions. Our results show that peptide aggregation is not disrupted by either phenolic compound. Thus, instead, intrusion of RSV and GA in the inter-peptide region induces a peptide-peptide re-orientation, favoring terminal interactions that manifest in the formation of barrierless solvent-separated configurations. Moreover, although the (poly)phenols induce a pronounced peptide dewetting at high concentrations, β-sheet-rich regions, a hallmark of α-syn aggregation, are not disrupted. Thus, our results indicate that, if anything, RSV and GA delay or modulate peptide aggregation at high concentrations via the stabilization of solvent-separated conformations as opposed to aggregation inhibition. Structural analysis of the full protein, however, shows that the (poly)phenols induce more extended conformations of α-syn, similar to urea, possibly also influencing its aggregation propensity. However, opposite to urea, the (poly)phenols reduce α-syn's conformational space, likely due to steric effects and a slowdown of the solvent dynamics. These effects are concentration-dependent and possibly unattainable at therapeutic-relevant concentrations. These results suggest that the aggregation inhibition activity of RSV and GA in vitro should involve, instead, either the non-covalent binding to oligomeric intermediates or the stabilization of the monomer and/or oligomers through the formation of covalent bonds of the respective quinones with α-syn. In addition, the enhanced aggregation tendency of the peptides observed here could be associated with the formation of non-toxic oligomers, reported for some polyphenols.

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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Amyloid-Beta Peptides Trigger Aggregation of Alpha-Synuclein In Vitro.

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Amyloid-Beta Peptides Trigger Aggregation of Alpha-Synuclein In Vitro.

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