Molecular plasticity regulates oligomerization and cytotoxicity of the multi-peptide length Abeta pool

A. Vandersteen, M.F. Masman, G. de Baets, W. Jonckheere, Kees van der Werf, S.J. Marrink, J. Rozenski, I. Benilova, B. De Strooper, Vinod Subramaniam, J. Schymkowitz, F. Rousseau, Kerensa Broersen

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22 Citations (Scopus)

Abstract

Current therapeutic approaches under development for Alzheimer disease, including γ-secretase modulating therapy, aim at increasing the production of Aβ1–38 and Aβ1–40 at the cost of longer Aβ peptides. Here, we consider the aggregation of Aβ1–38 and Aβ1–43 in addition to Aβ1–40 and Aβ1–42, in particular their behavior in mixtures representing the complex in vivo Aβ pool. We demonstrate that Aβ1–38 and Aβ1–43 aggregate similar to Aβ1–40 and Aβ1–42, respectively, but display a variation in the kinetics of assembly and toxicity due to differences in short timescale conformational plasticity. In biologically relevant mixtures of Aβ, Aβ1–38 and Aβ1–43 significantly affect the behaviors of Aβ1–40 and Aβ1–42. The short timescale conformational flexibility of Aβ1–38 is suggested to be responsible for enhancing toxicity of Aβ1–40 while exerting a cyto-protective effect on Aβ1–42. Our results indicate that the complex in vivo Aβ peptide array and variations thereof is critical in Alzheimer disease, which can influence the selection of current and new therapeutic strategies
Original languageEnglish
Article number36732
Pages (from-to)36732-36743
JournalJournal of biological chemistry
Volume287
Issue number44
DOIs
Publication statusPublished - 19 Sep 2012

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Oligomerization
Cytotoxicity
Plasticity
Toxicity
Amyloid Precursor Protein Secretases
Peptides
Alzheimer Disease
Complex Mixtures
Agglomeration
Kinetics
Therapeutics

Keywords

  • METIS-288675
  • IR-81968

Cite this

Vandersteen, A., Masman, M. F., de Baets, G., Jonckheere, W., van der Werf, K., Marrink, S. J., ... Broersen, K. (2012). Molecular plasticity regulates oligomerization and cytotoxicity of the multi-peptide length Abeta pool. Journal of biological chemistry, 287(44), 36732-36743. [36732]. https://doi.org/10.1074/jbc.M112.394635
Vandersteen, A. ; Masman, M.F. ; de Baets, G. ; Jonckheere, W. ; van der Werf, Kees ; Marrink, S.J. ; Rozenski, J. ; Benilova, I. ; De Strooper, B. ; Subramaniam, Vinod ; Schymkowitz, J. ; Rousseau, F. ; Broersen, Kerensa. / Molecular plasticity regulates oligomerization and cytotoxicity of the multi-peptide length Abeta pool. In: Journal of biological chemistry. 2012 ; Vol. 287, No. 44. pp. 36732-36743.
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abstract = "Current therapeutic approaches under development for Alzheimer disease, including γ-secretase modulating therapy, aim at increasing the production of Aβ1–38 and Aβ1–40 at the cost of longer Aβ peptides. Here, we consider the aggregation of Aβ1–38 and Aβ1–43 in addition to Aβ1–40 and Aβ1–42, in particular their behavior in mixtures representing the complex in vivo Aβ pool. We demonstrate that Aβ1–38 and Aβ1–43 aggregate similar to Aβ1–40 and Aβ1–42, respectively, but display a variation in the kinetics of assembly and toxicity due to differences in short timescale conformational plasticity. In biologically relevant mixtures of Aβ, Aβ1–38 and Aβ1–43 significantly affect the behaviors of Aβ1–40 and Aβ1–42. The short timescale conformational flexibility of Aβ1–38 is suggested to be responsible for enhancing toxicity of Aβ1–40 while exerting a cyto-protective effect on Aβ1–42. Our results indicate that the complex in vivo Aβ peptide array and variations thereof is critical in Alzheimer disease, which can influence the selection of current and new therapeutic strategies",
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author = "A. Vandersteen and M.F. Masman and {de Baets}, G. and W. Jonckheere and {van der Werf}, Kees and S.J. Marrink and J. Rozenski and I. Benilova and {De Strooper}, B. and Vinod Subramaniam and J. Schymkowitz and F. Rousseau and Kerensa Broersen",
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Vandersteen, A, Masman, MF, de Baets, G, Jonckheere, W, van der Werf, K, Marrink, SJ, Rozenski, J, Benilova, I, De Strooper, B, Subramaniam, V, Schymkowitz, J, Rousseau, F & Broersen, K 2012, 'Molecular plasticity regulates oligomerization and cytotoxicity of the multi-peptide length Abeta pool' Journal of biological chemistry, vol. 287, no. 44, 36732, pp. 36732-36743. https://doi.org/10.1074/jbc.M112.394635

Molecular plasticity regulates oligomerization and cytotoxicity of the multi-peptide length Abeta pool. / Vandersteen, A.; Masman, M.F.; de Baets, G.; Jonckheere, W.; van der Werf, Kees; Marrink, S.J.; Rozenski, J.; Benilova, I.; De Strooper, B.; Subramaniam, Vinod; Schymkowitz, J.; Rousseau, F.; Broersen, Kerensa.

In: Journal of biological chemistry, Vol. 287, No. 44, 36732, 19.09.2012, p. 36732-36743.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Molecular plasticity regulates oligomerization and cytotoxicity of the multi-peptide length Abeta pool

AU - Vandersteen, A.

AU - Masman, M.F.

AU - de Baets, G.

AU - Jonckheere, W.

AU - van der Werf, Kees

AU - Marrink, S.J.

AU - Rozenski, J.

AU - Benilova, I.

AU - De Strooper, B.

AU - Subramaniam, Vinod

AU - Schymkowitz, J.

AU - Rousseau, F.

AU - Broersen, Kerensa

PY - 2012/9/19

Y1 - 2012/9/19

N2 - Current therapeutic approaches under development for Alzheimer disease, including γ-secretase modulating therapy, aim at increasing the production of Aβ1–38 and Aβ1–40 at the cost of longer Aβ peptides. Here, we consider the aggregation of Aβ1–38 and Aβ1–43 in addition to Aβ1–40 and Aβ1–42, in particular their behavior in mixtures representing the complex in vivo Aβ pool. We demonstrate that Aβ1–38 and Aβ1–43 aggregate similar to Aβ1–40 and Aβ1–42, respectively, but display a variation in the kinetics of assembly and toxicity due to differences in short timescale conformational plasticity. In biologically relevant mixtures of Aβ, Aβ1–38 and Aβ1–43 significantly affect the behaviors of Aβ1–40 and Aβ1–42. The short timescale conformational flexibility of Aβ1–38 is suggested to be responsible for enhancing toxicity of Aβ1–40 while exerting a cyto-protective effect on Aβ1–42. Our results indicate that the complex in vivo Aβ peptide array and variations thereof is critical in Alzheimer disease, which can influence the selection of current and new therapeutic strategies

AB - Current therapeutic approaches under development for Alzheimer disease, including γ-secretase modulating therapy, aim at increasing the production of Aβ1–38 and Aβ1–40 at the cost of longer Aβ peptides. Here, we consider the aggregation of Aβ1–38 and Aβ1–43 in addition to Aβ1–40 and Aβ1–42, in particular their behavior in mixtures representing the complex in vivo Aβ pool. We demonstrate that Aβ1–38 and Aβ1–43 aggregate similar to Aβ1–40 and Aβ1–42, respectively, but display a variation in the kinetics of assembly and toxicity due to differences in short timescale conformational plasticity. In biologically relevant mixtures of Aβ, Aβ1–38 and Aβ1–43 significantly affect the behaviors of Aβ1–40 and Aβ1–42. The short timescale conformational flexibility of Aβ1–38 is suggested to be responsible for enhancing toxicity of Aβ1–40 while exerting a cyto-protective effect on Aβ1–42. Our results indicate that the complex in vivo Aβ peptide array and variations thereof is critical in Alzheimer disease, which can influence the selection of current and new therapeutic strategies

KW - METIS-288675

KW - IR-81968

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DO - 10.1074/jbc.M112.394635

M3 - Article

VL - 287

SP - 36732

EP - 36743

JO - Journal of biological chemistry

JF - Journal of biological chemistry

SN - 0021-9258

IS - 44

M1 - 36732

ER -

Vandersteen A, Masman MF, de Baets G, Jonckheere W, van der Werf K, Marrink SJ et al. Molecular plasticity regulates oligomerization and cytotoxicity of the multi-peptide length Abeta pool. Journal of biological chemistry. 2012 Sep 19;287(44):36732-36743. 36732. https://doi.org/10.1074/jbc.M112.394635