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N-Terminal Extensions Retard Aβ42 Fibril Formation but Allow Cross-Seeding and Coaggregation with Aβ42.

Szczepankiewicz, Olga LU ; Linse, Björn; Meisl, Georg; Thulin, Eva LU ; Frohm, Birgitta LU ; Sala Frigerio, Carlo; Colvin, Michael T; Jacavone, Angela C; Griffin, Robert G and Knowles, Tuomas, et al. (2015) In Journal of the American Chemical Society 137(46). p.14673-14685
Abstract
Amyloid β-protein (Aβ) sequence length variants with varying aggregation propensity coexist in vivo, where coaggregation and cross-catalysis phenomena may affect the aggregation process. Until recently, naturally occurring amyloid β-protein (Aβ) variants were believed to begin at or after the canonical β-secretase cleavage site within the amyloid β-protein precursor. However, N-terminally extended forms of Aβ (NTE-Aβ) were recently discovered and may contribute to Alzheimer's disease. Here, we have used thioflavin T fluorescence to study the aggregation kinetics of Aβ42 variants with N-terminal extensions of 5-40 residues, and transmission electron microscopy to analyze the end states. We find that all variants form amyloid fibrils of... (More)
Amyloid β-protein (Aβ) sequence length variants with varying aggregation propensity coexist in vivo, where coaggregation and cross-catalysis phenomena may affect the aggregation process. Until recently, naturally occurring amyloid β-protein (Aβ) variants were believed to begin at or after the canonical β-secretase cleavage site within the amyloid β-protein precursor. However, N-terminally extended forms of Aβ (NTE-Aβ) were recently discovered and may contribute to Alzheimer's disease. Here, we have used thioflavin T fluorescence to study the aggregation kinetics of Aβ42 variants with N-terminal extensions of 5-40 residues, and transmission electron microscopy to analyze the end states. We find that all variants form amyloid fibrils of similar morphology as Aβ42, but the half-time of aggregation (t1/2) increases exponentially with extension length. Monte Carlo simulations of model peptides suggest that the retardation is due to an underlying general physicochemical effect involving reduced frequency of productive molecular encounters. Indeed, global kinetic analyses reveal that NTE-Aβ42s form fibrils via the same mechanism as Aβ42, but all microscopic rate constants (primary and secondary nucleation, elongation) are reduced for the N-terminally extended variants. Still, Aβ42 and NTE-Aβ42 coaggregate to form mixed fibrils and fibrils of either Aβ42 or NTE-Aβ42 catalyze aggregation of all monomers. NTE-Aβ42 monomers display reduced aggregation rate with all kinds of seeds implying that extended termini interfere with the ability of monomers to nucleate or elongate. Cross-seeding or coaggregation may therefore represent an important contribution in the in vivo formation of assemblies believed to be important in disease. (Less)
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Journal of the American Chemical Society
volume
137
issue
46
pages
14673 - 14685
publisher
The American Chemical Society
external identifiers
  • pmid:26535489
  • wos:000366004700020
  • scopus:84948799632
ISSN
1520-5126
DOI
10.1021/jacs.5b07849
language
English
LU publication?
yes
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b8440c56-26d8-45aa-8ce0-141a738bebb4 (old id 8243162)
date added to LUP
2015-12-08 10:16:09
date last changed
2017-11-12 03:09:02
@article{b8440c56-26d8-45aa-8ce0-141a738bebb4,
  abstract     = {Amyloid β-protein (Aβ) sequence length variants with varying aggregation propensity coexist in vivo, where coaggregation and cross-catalysis phenomena may affect the aggregation process. Until recently, naturally occurring amyloid β-protein (Aβ) variants were believed to begin at or after the canonical β-secretase cleavage site within the amyloid β-protein precursor. However, N-terminally extended forms of Aβ (NTE-Aβ) were recently discovered and may contribute to Alzheimer's disease. Here, we have used thioflavin T fluorescence to study the aggregation kinetics of Aβ42 variants with N-terminal extensions of 5-40 residues, and transmission electron microscopy to analyze the end states. We find that all variants form amyloid fibrils of similar morphology as Aβ42, but the half-time of aggregation (t1/2) increases exponentially with extension length. Monte Carlo simulations of model peptides suggest that the retardation is due to an underlying general physicochemical effect involving reduced frequency of productive molecular encounters. Indeed, global kinetic analyses reveal that NTE-Aβ42s form fibrils via the same mechanism as Aβ42, but all microscopic rate constants (primary and secondary nucleation, elongation) are reduced for the N-terminally extended variants. Still, Aβ42 and NTE-Aβ42 coaggregate to form mixed fibrils and fibrils of either Aβ42 or NTE-Aβ42 catalyze aggregation of all monomers. NTE-Aβ42 monomers display reduced aggregation rate with all kinds of seeds implying that extended termini interfere with the ability of monomers to nucleate or elongate. Cross-seeding or coaggregation may therefore represent an important contribution in the in vivo formation of assemblies believed to be important in disease.},
  author       = {Szczepankiewicz, Olga and Linse, Björn and Meisl, Georg and Thulin, Eva and Frohm, Birgitta and Sala Frigerio, Carlo and Colvin, Michael T and Jacavone, Angela C and Griffin, Robert G and Knowles, Tuomas and Walsh, Dominic M and Linse, Sara},
  issn         = {1520-5126},
  language     = {eng},
  number       = {46},
  pages        = {14673--14685},
  publisher    = {The American Chemical Society},
  series       = {Journal of the American Chemical Society},
  title        = {N-Terminal Extensions Retard Aβ42 Fibril Formation but Allow Cross-Seeding and Coaggregation with Aβ42.},
  url          = {http://dx.doi.org/10.1021/jacs.5b07849},
  volume       = {137},
  year         = {2015},
}