Structure and Biomedical Applications of Amyloid Oligomer Nanoparticles

Kumar, Senthil T.; Meinhardt, Jessica; Fuchs, Ann-Kathrin; Aumüller, Tobias; Leppert, Jörg; Büchele, Berthold; Knüpfer, Uwe; Ramachandran, Ramadurai; Yadav, Jay Kant; Prell, Erik; Morgado, Isabel; Ohlenschläger, Oliver; Horn, Uwe; Simmet, Thomas; Görlach, Matthias; Fändrich, Marcus

doi:10.1021/nn503960h

Cited by 28 publications

(29 citation statements)

References 71 publications

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“…1À3 The structure of the species 4 and the nature of its interaction with membranes have therefore attracted intense scrutiny. 5 In the case of Alzheimer's amyloid-β, some solution-state structural parameters of the early oligomeric species 6,7 have been obtained recently.…”

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confidence: 99%

Cell-Membrane-Mimicking Lipid-Coated Nanoparticles Confer Raman Enhancement to Membrane Proteins and Reveal Membrane-Attached Amyloid-β Conformation

et al. 2015

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Identifying the structures of membrane bound proteins is critical to understanding their function in healthy and diseased states. We introduce a surface enhanced Raman spectroscopy technique which can determine the conformation of membrane-bound proteins, at low micromolar concentrations, and also in the presence of a substantial membrane-free fraction. Unlike conventional surface enhanced Raman spectroscopy, our approach does not require immobilization of molecules, as it uses spontaneous binding of proteins to lipid bilayer-encapsulated Ag nanoparticles. We apply this technique to probe membrane-attached oligomers of Amyloid-β40 (Aβ40), whose conformation is keenly sought in the context of Alzheimer's disease. Isotope-shifts in the Raman spectra help us obtain secondary structure information at the level of individual residues. Our results show the presence of a β-turn, flanked by two β-sheet regions. We use solid-state NMR data to confirm the presence of the β-sheets in these regions. In the membrane-attached oligomer, we find a strongly contrasting and near-orthogonal orientation of the backbone H-bonds compared to what is found in the mature, less-toxic Aβ fibrils. Significantly, this allows a "porin" like β-barrel structure, providing a structural basis for proposed mechanisms of Aβ oligomer toxicity.

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confidence: 99%

Cell-Membrane-Mimicking Lipid-Coated Nanoparticles Confer Raman Enhancement to Membrane Proteins and Reveal Membrane-Attached Amyloid-β Conformation

et al. 2015

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“…Self‐assembled amyloid fibril networks or microgels from peptides have previously been suggested as potential drug‐delivery systems . The reported RFFFR spheres and fibers may also be used for such applications.…”

Section: Resultsmentioning

confidence: 99%

The Physical Properties and Self‐Assembly Potential of the RFFFR Peptide

2016

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The self-assembly of fibers from peptides has attracted a tremendous amount of attention due to its many applications, such as in drug-delivery systems, in tissue engineering, and in electronic devices. Recently, the self-assembly potential of the designer peptide RFFFR has been reported. Here it is experimentally verified that the peptide forms fibers that are entangled and form solid spheres without water inside. Upon dilution below the critical fiber concentration, the fibers untangle and become totally separated prior to dissolution. These structures readily bind thioflavin T, resulting in a characteristic change in fluorescent properties consistent with β-sheet-rich amyloid structures with aromatic/hydrophobic grooves. The circular dichroism spectroscopy data are dominated by a π→π* transition, thus indicating that the fibers are stabilized by π-stacking. Contrary to what was expected, the dissolution of the spheres/fibers results in increasing fluorescence anisotropy over time. This is explained in terms of HomoFRET between phenylalanine residues with a T-shaped π-stacking mode, which was determined in another study to be the dominant mode through atomistic simulations and semiempirical calculations. Kelvin probe force microscopy measurements indicate that the spheres and fibers have a conductivity comparable to that of gold. Hence, these self-assembled structures might be applicable in organic solid-state electronic devices. The dissolution properties of the spheres further suggest that they might be used as drug-delivery systems.

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“…As oligomer binding to cellular structures of low polarity, and specifically lipid assemblies, may be a key step within the pathophysiology of Aβ peptide [41,42], addressing this question could be of significant biological impact. The reversibility of this β-to-α switch could be of practical relevance for understanding and devising peptide disaggregation/ re-aggregation protocols to be applied during loading or coupling of low-molecular-weight compounds to oligomeric Aβ assemblies in the course of derivatisation for diagnostic or therapeutic purposes [6]. As we have shown here, such nanoscale assemblies should adopt their initial principal architecture [5,6] upon exposing them to a physiologically compatible aqueous environment.…”

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confidence: 88%

“…Nevertheless, our recent studies have shown that these aggregates possess a compact, quasi-crystalline architecture with significant nanoscale regularity and that they bear potential as carriers for fluorescent dyes or iron oxide nanoparticles for medical applications [6].…”

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confidence: 99%