Self-Propagating, Molecular-Level Polymorphism in Alzheimer's -Amyloid Fibrils

Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, MD 20892-0520, USA.
Science (Impact Factor: 33.61). 02/2005; 307(5707):262-5. DOI: 10.1126/science.1105850
Source: PubMed


Amyloid fibrils commonly exhibit multiple distinct morphologies in electron microscope and atomic force microscope images,
often within a single image field. By using electron microscopy and solid-state nuclear magnetic resonance measurements on
fibrils formed by the 40-residue β-amyloid peptide of Alzheimer's disease (Aβ1–40), we show that different fibril morphologies have different underlying molecular structures, that the predominant structure
can be controlled by subtle variations in fibril growth conditions, and that both morphology and molecular structure are self-propagating
when fibrils grow from preformed seeds. Different Aβ1–40 fibril morphologies also have significantly different toxicities in neuronal cell cultures. These results have implications
for the mechanism of amyloid formation, the phenomenon of strains in prion diseases, the role of amyloid fibrils in amyloid
diseases, and the development of amyloid-based nano-materials.

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    • "For fibrils formed without stirring, the dominant morphology is twisted fibrils, whereas with the activation fibrils of a less twisted shape and a tendency to lateral association are prevailing. In this case, the non-activated twisted fibrils are the most toxic to the cells [29]. This observation emphasizes the importance of studying of all populations of oligomers and fibrils. "
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    ABSTRACT: The aim of this study was to investigate the process of amyloidogenesis of amyloid-β (Aβ)42 peptide, by means of fluorescence spectroscopy, electron microscopy, X-ray diffraction, and mass spectrometry. It has been repeatedly reported in the literature that the process of fibril formation by Aβ 42 peptide depends considerably not only upon the specific conditions (ionic conditions, pH, temperature, mixing, etc.), as well as the manufacturing route (synthetic or recombinant), but also on the methods of synthesis and purification. We have, for the first time, systematically analyzed samples of Aβ 42 peptide supplied by five different companies (Anaspec, Invitrogen, Enzo, Sigma-Aldrich, and SynthAssist) and obtained evidence of significant variability, including lot to lot variations. All studied samples formed amyloid-like fibrils at pH3-6, and the fibrils contained cross-β structures. Samples from Anaspec, Invitrogen, and Enzo formed one particular type of amyloid-like fibrils, while the samples from Sigma-Aldrich and SynthAssist formed another distinct type of fibrils. The observed polymorphism emphasizes the capacity of the Aβ 42 peptide to act as a prion agent with varying structural characteristics. The presented data have allowed us to propose a possible mechanism of formation of amyloid-like fibrils.
    Journal of Alzheimer's disease: JAD 09/2015; 47(3):583-593. DOI:10.3233/JAD-150147 · 4.15 Impact Factor
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    • "To form different amyloid strains de novo using the same protein, different environmental conditions, such as temperature (Tanaka et al., 2005), shear forces (Makarava et al., 2009), concentration of denaturants (Cobb et al., 2014) or co-solvents (Dzwolak et al., 2004) are involved. Once nuclei are formed, they are able to carry strain-specific properties even in unfavorable environments (Dzwolak et al., 2004; Petkova et al., 2005; Makarava et al., 2009; Cobb et al., 2014; Surmacz-Chwedoruk, Babenko & Dzwolak, 2014). This indicates that environment defines different strains during primary nucleation, but affects only kinetics, not the structure, of fibrils formed via elongation. "
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    ABSTRACT: Prions are infectious proteins where the same protein may express distinct strains. The strains are enciphered by different misfolded conformations. Strain-like phenomena have also been reported in a number of other amyloid-forming proteins. One of the features of amyloid strains is the ability to self-propagate, maintaining a constant set of physical properties despite being propagated under conditions different from those that allowed initial formation of the strain. Here we report a cross-seeding experiment using strains formed under different conditions. Using high concentrations of seeds results in rapid elongation and new fibrils preserve the properties of the seeding fibrils. At low seed concentrations, secondary nucleation plays the major role and new fibrils gain properties predicted by the environment rather than the structure of the seeds. Our findings could explain conformational switching between amyloid strains observed in a wide variety of in vivo and in vitro experiments.
    PeerJ 09/2015; 3(8):e1207. DOI:10.7717/peerj.1207 · 2.11 Impact Factor
    • "The relationship between the morphology of fibrillar aggregates and their toxicity was reported by Petkova and colleagues who examined the action of mature amyloid fibrils of Alzheimer's amyloid-beta peptide, Aβ 1–40, on neuronal cell cultures (Petkova et al. 2005). The absence of direct correlation between disease symptoms and total amyloid deposition was considered as the main evidence of the nontoxic nature of mature fibrils. "
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    ABSTRACT: Amyloid fibrils are an intriguing class of protein aggregates with distinct physicochemical, structural and morphological properties. They display peculiar membrane-binding behavior, thus adding complexity to the problem of protein-lipid interactions. The consensus that emerged during the past decade is that amyloid cytotoxicity arises from a continuum of cross-β-sheet assemblies including mature fibrils. Based on literature survey and our own data, in this chapter we address several aspects of fibril-lipid interactions, including (i) the effects of amyloid assemblies on molecular organization of lipid bilayer; (ii) competition between fibrillar and monomeric membrane-associating proteins for binding to the lipid surface; and (iii) the effects of lipids on the structural morphology of fibrillar aggregates. To illustrate some of the processes occurring in fibril-lipid systems, we present and analyze fluorescence data reporting on lipid bilayer interactions with fibrillar lysozyme and with the N-terminal 83-residue fragment of amyloidogenic mutant apolipoprotein A-I, 1-83/G26R/W@8. The results help understand possible mechanisms of interaction and mutual remodeling of amyloid fibers and lipid membranes, which may contribute to amyloid cytotoxicity.
    Advances in Experimental Medicine and Biology 07/2015; 855:135-155. DOI:10.1007/978-3-319-17344-3_6 · 1.96 Impact Factor
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