Journal Article

FZJ-2017-05969

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Pyroglutamate-modified Aβ(3-42) affects aggregation kinetics of Aβ(1-42) by accelerating primary and secondary pathways

Dammers, C.FZJ* ; Schwarten, M.FZJ* ; Buell, A. K. ; Willbold, D. (Corresponding author)FZJ*

2017
RSC Cambridge

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Please use a persistent id in citations: http://hdl.handle.net/2128/15146  doi:10.1039/C6SC04797A

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

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Contributing Institute(s):

1. Strukturbiochemie (ICS-6)

Research Program(s):

1. 553 - Physical Basis of Diseases (POF3-553) (POF3-553)

Appears in the scientific report 2017

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Database coverage:
; ; ; Current Contents - Physical, Chemical and Earth Sciences ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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