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

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

SUBMITTER: Dammers C 

PROVIDER: S-EPMC5612032 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature