Cascade autohydrolysis of Alzheimer's Aβ peptides

Research output: Contribution to journalJournal articlepeer-review

Documents

  • Fulltext

    Final published version, 2.29 MB, PDF document

Protein/peptide self-assembly into amyloid structures associates with major neurodegenerative disorders such as Alzheimer's disease (AD). Soluble assemblies (oligomers) of the A beta 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 A beta oligopeptides, containing the nucleation sequence A beta(14-24) (H(14)QKLVFFAEDV(24)), could act as cleavage agents by themselves. Autohydrolysis showed a common fragment fingerprint among various mutated A beta(14-24) oligopeptides, A beta(12-25)-Gly and A beta(1-28), and full-length A beta(1-40/42), under physiologically relevant conditions. Primary endoproteolytic autocleavage at the Gln(15)-Lys(16), Lys(16)-Leu(17) and Phe(19)-Phe(20) positions was followed by subsequent exopeptidase self-processing of the fragments. Control experiments with homologous d-amino acid enantiomers A beta(12-25)-Gly and A beta(16-25)-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 degrees C, 10-150 mu M 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 A beta(16-21) nucleation site, showing the potential for cross-catalytic seeding of the ACR in larger A beta isoforms (A beta(1-28) and A beta(1-40/42)). This result may shed new light on A beta behaviour in solution and might be useful in the development of intervention strategies to decompose or inhibit neurotoxic A beta assemblies in AD.

Original languageEnglish
JournalChemical Science
Volume14
Issue number19
Pages (from-to)4986–4996
Number of pages11
ISSN2041-6520
DOIs
Publication statusPublished - 2023

    Research areas

  • SECONDARY STRUCTURE, COLD DENATURATION, COMMON MECHANISM, ALPHA-SYNUCLEIN, PROTEIN, HYDROLYSIS, DISEASE, OLIGOMERS, NEUROTOXICITY, FRAGMENTS

Number of downloads are based on statistics from Google Scholar and www.ku.dk


No data available

ID: 345431137