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P4‐309: Peass(3‐42) Increases Aggregation Propensity of ass(1‐42) by Accelerating Primary and Secondary Pathways
Author(s) -
Dammers Christina,
Buell Alexander,
Schwarten Melanie,
Willbold Dieter
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.07.052
Subject(s) - monomer , kinetics , fibril , chemistry , thioflavin , protein aggregation , biophysics , amyloid (mycology) , peptide , amyloid fibril , biochemistry , amyloid β , biology , organic chemistry , polymer , medicine , inorganic chemistry , physics , disease , pathology , quantum mechanics , alzheimer's disease
Background: A variety of amyloid-b (Ab) peptides differing in length and modification have been discovered with pyroglutamate-modified Ab variants (pEAb) as a significant proportion. pEAb was shown to be more likely to form b-sheet structures and to have a dramatically enhanced aggregation propensity compared to non-modified Ab, suggesting its role in inducing and facilitating Ab oligomerization and accumulation. Despite this potential importance, pEAb aggregationmechanism and the influence on the kinetics of other Ab variants have not yet been elucidated. Methods:Aggregation kinetics of recombinant pEAb(3-42) and Ab(1-42) monomers were analysed at various concentrations and mixing ratios by thioflavin-T assays. Both seeded and nonseeded experiments were performed, in order to be able to investigate the effects of monomeric and aggregated pEAb on the aggregation of Ab(1-42), and vice versa. Results:pEAb(3-42) was found to aggregate much faster than Ab(1-42) and critical concentrations above which aggregation was observed were drastically decreased by one order of magnitude. Mixtures of both peptides, at concentrations where either species alone did not display aggregation, were found to form amyloid fibrils. The addition of pEAb(3-42) monomers and fibrils was shown to notably accelerate Ab(1-42) aggregation. In contrast, the aggregation kinetics of pEAb(3-42) was slowed down in the presence of monomers as well as fibrils of Ab(1-42). Conclusions:We elucidated the co-aggregation mechanism of Ab(1-42) with themore toxic and aggregation prone variant pEAb(3-42). The presence of small amounts of pEAb(3-42) monomers increases primary nucleation of Ab(1-42) fibrils and serve as a highly catalytic surface for secondary nucleation and elongation of non-truncated Ab species. Ab(1-42) monomers drastically decelerate pEAb(3-42) primary and secondary nucleation but do not decrease pEAb(3-42) elongation rate. Ab(1-42) fibrils are not suitable as templates for the addition of monomeric pEAb(3-42). In fact, high concentrations of fibrillary Ab(1-42) can prevent pEAb(3-42) aggregation, presumably due to non-reactive binding of pEAb monomer to Ab(1-42) fibril surfaces. In concentrations where both species do not aggregate as homofibrils, mixtures of pEAb(3-42) and Ab(1-42) display aggregation suggesting crossprimary nucleation. Thus, pEAb(3-42) catalyzes aggregating of Ab(1-42) affecting all reaction processes while Ab(1-42) dramatically slows down pEAb(3-42) primary nucleation and secondary pathways by non-reactive surface binding.