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Issue 7, 2015
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The Aβ40 and Aβ42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation

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Abstract

The assembly of proteins into amyloid fibrils, a phenomenon central to several currently incurable human diseases, is a process of high specificity that commonly tolerates only a low level of sequence mismatch in the component polypeptides. However, in many cases aggregation-prone polypeptides exist as mixtures with variations in sequence length or post-translational modifications; in particular amyloid β (Aβ) peptides of variable length coexist in the central nervous system and possess a propensity to aggregate in Alzheimer's disease and related dementias. Here we have probed the co-aggregation and cross-seeding behavior of the two principal forms of Aβ, Aβ40 and Aβ42 that differ by two hydrophobic residues at the C-terminus. We find, using isotope-labeling, mass spectrometry and electron microscopy that they separate preferentially into homomolecular pure Aβ42 and Aβ40 structures during fibril formation from mixed solutions of both peptides. Although mixed fibrils are not formed, the kinetics of amyloid formation of one peptide is affected by the presence of the other form. In particular monomeric Aβ42 accelerates strongly the aggregation of Aβ40 in a concentration-dependent manner. Whereas the aggregation of each peptide is catalyzed by low concentrations of preformed fibrils of the same peptide, we observe a comparably insignificant effect when Aβ42 fibrils are added to Aβ40 monomer or vice versa. Therefore we conclude that fibril-catalysed nucleus formation and elongation are highly sequence specific events but Aβ40 and Aβ42 interact during primary nucleation. These results provide a molecular level description of homomolecular and heteromolecular aggregation steps in mixtures of polypeptide sequence variants.

Graphical abstract: The Aβ40 and Aβ42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation

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Publication details

The article was received on 18 Aug 2014, accepted on 30 Apr 2015 and first published on 08 May 2015


Article type: Edge Article
DOI: 10.1039/C4SC02517B
Citation: Chem. Sci., 2015,6, 4215-4233
  • Open access: Creative Commons BY license
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    The Aβ40 and Aβ42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation

    R. Cukalevski, X. Yang, G. Meisl, U. Weininger, K. Bernfur, B. Frohm, T. P. J. Knowles and S. Linse, Chem. Sci., 2015, 6, 4215
    DOI: 10.1039/C4SC02517B

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