Quantification of the Concentration of A beta 42 Propagons during the Lag Phase by an Amyloid Chain Reaction Assay

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Standard

Quantification of the Concentration of A beta 42 Propagons during the Lag Phase by an Amyloid Chain Reaction Assay. / Arosio, Paolo; Cukalevski, Risto; Frohm, Birgitta; Knowles, Tuomas P. J.; Linse, Sara.

I: Journal of the American Chemical Society, Vol. 136, Nr. 1, 2014, s. 219-225.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

APA

CBE

MLA

Vancouver

Author

Arosio, Paolo ; Cukalevski, Risto ; Frohm, Birgitta ; Knowles, Tuomas P. J. ; Linse, Sara. / Quantification of the Concentration of A beta 42 Propagons during the Lag Phase by an Amyloid Chain Reaction Assay. I: Journal of the American Chemical Society. 2014 ; Vol. 136, Nr. 1. s. 219-225.

RIS

TY - JOUR

T1 - Quantification of the Concentration of A beta 42 Propagons during the Lag Phase by an Amyloid Chain Reaction Assay

AU - Arosio, Paolo

AU - Cukalevski, Risto

AU - Frohm, Birgitta

AU - Knowles, Tuomas P. J.

AU - Linse, Sara

PY - 2014

Y1 - 2014

N2 - The aggregation of the amyloid beta peptide, A beta 42, implicated in Alzheimer's disease, is characterized by a lag phase followed by a rapid growth phase. Conventional methods to study this reaction are not sensitive to events taking place early in the lag phase promoting the assumption that only monomeric or oligomeric species are present at early stages and that the lag time is defined by the primary nucleation rate only. Here we exploit the high sensitivity of chemical chain reactions to the reagent composition to develop an assay which improves by 2 orders of magnitude the detection limit of conventional bulk techniques and allows the concentration of fibrillar A beta 42 propagons to be detected and quantified even during the lag time. The method relies on the chain reaction multiplication of a small number of initial fibrils by secondary nucleation on the fibril surface in the presence of monomeric peptides, allowing the quantification of the number of initial propagons by comparing the multiplication reaction kinetics with controlled seeding data. The quantitative results of the chain reaction assay are confirmed by qualitative transmission electron microscopy analysis. The results demonstrate the nonlinearity of the aggregation process which involves both primary and secondary nucleation events even at the early stages of the reaction during the lag-phase.

AB - The aggregation of the amyloid beta peptide, A beta 42, implicated in Alzheimer's disease, is characterized by a lag phase followed by a rapid growth phase. Conventional methods to study this reaction are not sensitive to events taking place early in the lag phase promoting the assumption that only monomeric or oligomeric species are present at early stages and that the lag time is defined by the primary nucleation rate only. Here we exploit the high sensitivity of chemical chain reactions to the reagent composition to develop an assay which improves by 2 orders of magnitude the detection limit of conventional bulk techniques and allows the concentration of fibrillar A beta 42 propagons to be detected and quantified even during the lag time. The method relies on the chain reaction multiplication of a small number of initial fibrils by secondary nucleation on the fibril surface in the presence of monomeric peptides, allowing the quantification of the number of initial propagons by comparing the multiplication reaction kinetics with controlled seeding data. The quantitative results of the chain reaction assay are confirmed by qualitative transmission electron microscopy analysis. The results demonstrate the nonlinearity of the aggregation process which involves both primary and secondary nucleation events even at the early stages of the reaction during the lag-phase.

U2 - 10.1021/ja408765u

DO - 10.1021/ja408765u

M3 - Article

VL - 136

SP - 219

EP - 225

JO - Journal of the American Chemical Society

T2 - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 1520-5126

IS - 1

ER -