Protein/peptide self-assembly into amyloid structures associates with major neurodegenerative disorders such as Alzheimer's disease (AD). Soluble assemblies (oligomers) of the Aβ peptide and their aggregates are perceived as neurotoxic species in AD. While screening for synthetic cleavage agents that could break down such aberrant assemblies through hydrolysis, we observed that the assemblies of Aβ oligopeptides, containing the nucleation sequence Aβ14-24 (H14QKLVFFAEDV24), could act as cleavage agents by themselves. Autohydrolysis showed a common fragment fingerprint among various mutated Aβ14-24 oligopeptides, Aβ12-25-Gly and Aβ1-28, and full-length Aβ1-40/42, under physiologically relevant conditions. Primary endoproteolytic autocleavage at the Gln15-Lys16, Lys16-Leu17 and Phe19-Phe20 positions was followed by subsequent exopeptidase self-processing of the fragments. Control experiments with homologous d-amino acid enantiomers Aβ12-25-Gly and Aβ16-25-Gly showed the same autocleavage pattern under similar reaction conditions. The autohydrolytic cascade reaction (ACR) was resilient to a broad range of conditions (20-37 °C, 10-150 μM peptide concentration at pH 7.0-7.8). Evidently, assemblies of the primary autocleavage fragments acted as structural/compositional templates (autocatalysts) for self-propagating autohydrolytic processing at the Aβ16-21 nucleation site, showing the potential for cross-catalytic seeding of the ACR in larger Aβ isoforms (Aβ1-28 and Aβ1-40/42). This result may shed new light on Aβ behaviour in solution and might be useful in the development of intervention strategies to decompose or inhibit neurotoxic Aβ assemblies in AD.
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