NMR reveals two-step association of Congo Red to amyloid β in low-molecular-weight aggregates

Marie Ø Pedersen; Katrine Mikkelsen; Manja A Behrens; Jan S Pedersen; Jan Johannes Enghild; Troels Skrydstrup; Anders Malmendal; Niels Christian Nielsen

doi:10.1021/jp108035y

NMR reveals two-step association of Congo Red to amyloid β in low-molecular-weight aggregates

Marie Ø Pedersen, Katrine Mikkelsen, Manja A Behrens, Jan S Pedersen, Jan Johannes Enghild, Troels Skrydstrup, Anders Malmendal, Niels Christian Nielsen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

Aggregation of the Amyloid β peptide into amyloid fibrils is closely related to development of Alzheimer's disease. Many small aromatic compounds have been found to act as inhibitors of fibril formation, and have inspired the search for new drug candidates. However, the detailed mechanisms of inhibition are largely unknown. In this study, we have examined in detail the binding of the fibril-formation inhibitor Congo Red (CR) to monomeric Aβ(1-40) using a combination of 1D, 2D, saturation transfer difference, and diffusion NMR, as well as dynamic light scattering experiments. Our results show that CR binds to the fibril forming stretches of Aβ(1-40) monomers, and that complex formation occurs in two steps: An initial 1:1 CR:Aβ(1-40) complex is formed by a relatively strong interaction (K(d) ≈ 5 μM), and a 2:1 complex is formed by binding another CR molecule in a subsequent weaker binding step (K(d) ≈ 300 μM). The size of these complexes is comparable to that of Aβ(1-40) alone. The existence of two different complexes might explain the contradictory reports regarding the inhibitory effects of CR on the fibril-formation process.

Original language	English
Journal	Journal of Physical Chemistry Part B: Condensed Matter, Materials, Surfaces, Interfaces & Biophysical
Volume	114
Issue	48
Pages (from-to)	16003-16010
Number of pages	8
ISSN	1520-6106
DOIs	https://doi.org/10.1021/jp108035y
Publication status	Published - Nov 2010

Keywords

Amyloid beta-Peptides
Congo Red
Diffusion
Light
Magnetic Resonance Spectroscopy
Molecular Structure
Molecular Weight
Peptide Fragments
Scattering, Radiation

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10.1021/jp108035y

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Pedersen, M. Ø., Mikkelsen, K., Behrens, M. A., Pedersen, J. S., Enghild, J. J., Skrydstrup, T., Malmendal, A., & Nielsen, N. C. (2010). NMR reveals two-step association of Congo Red to amyloid β in low-molecular-weight aggregates. Journal of Physical Chemistry Part B: Condensed Matter, Materials, Surfaces, Interfaces & Biophysical, 114(48), 16003-16010. https://doi.org/10.1021/jp108035y

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abstract = "Aggregation of the Amyloid β peptide into amyloid fibrils is closely related to development of Alzheimer's disease. Many small aromatic compounds have been found to act as inhibitors of fibril formation, and have inspired the search for new drug candidates. However, the detailed mechanisms of inhibition are largely unknown. In this study, we have examined in detail the binding of the fibril-formation inhibitor Congo Red (CR) to monomeric Aβ(1-40) using a combination of 1D, 2D, saturation transfer difference, and diffusion NMR, as well as dynamic light scattering experiments. Our results show that CR binds to the fibril forming stretches of Aβ(1-40) monomers, and that complex formation occurs in two steps: An initial 1:1 CR:Aβ(1-40) complex is formed by a relatively strong interaction (K(d) ≈ 5 μM), and a 2:1 complex is formed by binding another CR molecule in a subsequent weaker binding step (K(d) ≈ 300 μM). The size of these complexes is comparable to that of Aβ(1-40) alone. The existence of two different complexes might explain the contradictory reports regarding the inhibitory effects of CR on the fibril-formation process.",

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author = "Pedersen, {Marie {\O}} and Katrine Mikkelsen and Behrens, {Manja A} and Pedersen, {Jan S} and Enghild, {Jan Johannes} and Troels Skrydstrup and Anders Malmendal and Nielsen, {Niels Christian}",

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Pedersen, MØ, Mikkelsen, K, Behrens, MA, Pedersen, JS , Enghild, JJ , Skrydstrup, T, Malmendal, A & Nielsen, NC 2010, 'NMR reveals two-step association of Congo Red to amyloid β in low-molecular-weight aggregates', Journal of Physical Chemistry Part B: Condensed Matter, Materials, Surfaces, Interfaces & Biophysical, vol. 114, no. 48, pp. 16003-16010. https://doi.org/10.1021/jp108035y

NMR reveals two-step association of Congo Red to amyloid β in low-molecular-weight aggregates. / Pedersen, Marie Ø; Mikkelsen, Katrine; Behrens, Manja A et al.
In: Journal of Physical Chemistry Part B: Condensed Matter, Materials, Surfaces, Interfaces & Biophysical, Vol. 114, No. 48, 11.2010, p. 16003-16010.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - NMR reveals two-step association of Congo Red to amyloid β in low-molecular-weight aggregates

AU - Pedersen, Marie Ø

AU - Mikkelsen, Katrine

AU - Behrens, Manja A

AU - Pedersen, Jan S

AU - Enghild, Jan Johannes

AU - Skrydstrup, Troels

AU - Malmendal, Anders

AU - Nielsen, Niels Christian

PY - 2010/11

Y1 - 2010/11

N2 - Aggregation of the Amyloid β peptide into amyloid fibrils is closely related to development of Alzheimer's disease. Many small aromatic compounds have been found to act as inhibitors of fibril formation, and have inspired the search for new drug candidates. However, the detailed mechanisms of inhibition are largely unknown. In this study, we have examined in detail the binding of the fibril-formation inhibitor Congo Red (CR) to monomeric Aβ(1-40) using a combination of 1D, 2D, saturation transfer difference, and diffusion NMR, as well as dynamic light scattering experiments. Our results show that CR binds to the fibril forming stretches of Aβ(1-40) monomers, and that complex formation occurs in two steps: An initial 1:1 CR:Aβ(1-40) complex is formed by a relatively strong interaction (K(d) ≈ 5 μM), and a 2:1 complex is formed by binding another CR molecule in a subsequent weaker binding step (K(d) ≈ 300 μM). The size of these complexes is comparable to that of Aβ(1-40) alone. The existence of two different complexes might explain the contradictory reports regarding the inhibitory effects of CR on the fibril-formation process.

AB - Aggregation of the Amyloid β peptide into amyloid fibrils is closely related to development of Alzheimer's disease. Many small aromatic compounds have been found to act as inhibitors of fibril formation, and have inspired the search for new drug candidates. However, the detailed mechanisms of inhibition are largely unknown. In this study, we have examined in detail the binding of the fibril-formation inhibitor Congo Red (CR) to monomeric Aβ(1-40) using a combination of 1D, 2D, saturation transfer difference, and diffusion NMR, as well as dynamic light scattering experiments. Our results show that CR binds to the fibril forming stretches of Aβ(1-40) monomers, and that complex formation occurs in two steps: An initial 1:1 CR:Aβ(1-40) complex is formed by a relatively strong interaction (K(d) ≈ 5 μM), and a 2:1 complex is formed by binding another CR molecule in a subsequent weaker binding step (K(d) ≈ 300 μM). The size of these complexes is comparable to that of Aβ(1-40) alone. The existence of two different complexes might explain the contradictory reports regarding the inhibitory effects of CR on the fibril-formation process.

KW - Amyloid beta-Peptides

KW - Congo Red

KW - Diffusion

KW - Light

KW - Magnetic Resonance Spectroscopy

KW - Molecular Structure

KW - Molecular Weight

KW - Peptide Fragments

KW - Scattering, Radiation

U2 - 10.1021/jp108035y

DO - 10.1021/jp108035y

M3 - Journal article

C2 - 21077638

SN - 1520-6106

VL - 114

SP - 16003

EP - 16010

JO - Journal of Physical Chemistry Part B: Condensed Matter, Materials, Surfaces, Interfaces & Biophysical

JF - Journal of Physical Chemistry Part B: Condensed Matter, Materials, Surfaces, Interfaces & Biophysical

IS - 48

ER -

NMR reveals two-step association of Congo Red to amyloid β in low-molecular-weight aggregates

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Keywords

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