Pyroglutamate-modified Aβ(3-42) affects aggregation kinetics of Aβ(1-42) by accelerating primary and secondary pathways

摘要: The aggregation into amyloid fibrils of amyloid-β (Aβ) peptides is a hallmark Alzheimer's disease. A variety Aβ have been discovered in vivo, with pyroglutamate-modified (pEAβ) forming significant proportion. pEAβ mainly localized the core plaques, suggesting possible role inducing and facilitating oligomerization accumulation. Despite this potential importance, mechanism its influence on kinetics other variants not yet elucidated. Here we show that pEAβ(3-42) forms much faster than Aβ(1-42) critical concentration above which was observed drastically decreased by one order magnitude compared to Aβ(1-42). We elucidated co-aggregation pEAβ(3-42). At concentrations at both species do aggregate as homofibrils, mixtures aggregate, formation mixed nuclei. presence monomers increases rate primary nucleation serve highly efficient templates for elongation catalytic surfaces secondary On hand, addition decelerates while altering rate. In addition, even moderate fibrillar prevent aggregation, likely due non-reactive binding fibrils. Thus, accelerates affecting all individual reaction steps process dramatically slows down