Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio.

Inna Kuperstein; Kerensa Broersen; Iryna Benilova; J. Rozenski; Wim Jonckheere; Maja Debulpaep; Annelies Vandersteen; Ine Segers-Nolten; Kees Van Der Werf; Vinod Subramaniam; Dries Braeken; Geert Callewaert; Carmen Bartic; D'hooge Rudi; Ivo Cristiano Martins; Frederic Rousseau; Joost Schymkowitz; Bart Destrooper

Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio.

Inna Kuperstein, Kerensa Broersen, Iryna Benilova, J. Rozenski, Wim Jonckheere, Maja Debulpaep, Annelies Vandersteen, Ine Segers-Nolten, Kees Van Der Werf, Vinod Subramaniam, Dries Braeken, Geert Callewaert, Carmen Bartic, D'hooge Rudi, Ivo Cristiano Martins, Frederic Rousseau, Joost Schymkowitz, Bart Destrooper

Department of Bio-engineering Sciences

Research output: Contribution to journal › Article › peer-review

459 Citations (Scopus)

Abstract

The amyloid peptides Ab40 and Ab42 of Alzheimer's disease are thought to contribute differentially to the disease process. Although Ab42 seems more pathogenic than Ab40, the reason for this is not well understood. We show here that small alterations in the Ab42:Ab40 ratio dramatically affect the biophysical and biological properties of the Ab mixtures reflected in their aggregation kinetics, the morphology of the resulting amyloid fibrils and synaptic function tested in vitro and in vivo. A minor
increase in the Ab42:Ab40 ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these Ab species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of Ab peptides is more crucial than the absolute amounts of peptides for the induction of neurotoxic conformations has important
implications for anti-amyloid therapy. Our work also suggests the dynamic nature of the equilibrium between toxic and non-toxic intermediates.

Original language	English
Pages (from-to)	3408-3420
Number of pages	13
Journal	EMBO Journal
Volume	29
Issue number	19
Publication status	Published - 3 Sept 2010

Keywords

Alzheimer's disease
beta-amyloid peptides
microelectrode array
neurotoxicity
oligomer

Cite this

Kuperstein, I., Broersen, K., Benilova, I., Rozenski, J., Jonckheere, W., Debulpaep, M., Vandersteen, A., Segers-Nolten, I., Van Der Werf, K., Subramaniam, V., Braeken, D., Callewaert, G., Bartic, C., Rudi, D., Martins, I. C., Rousseau, F., Schymkowitz, J., & Destrooper, B. (2010). Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio. EMBO Journal, 29(19), 3408-3420.

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title = "Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio.",

abstract = "The amyloid peptides Ab40 and Ab42 of Alzheimer's disease are thought to contribute differentially to the disease process. Although Ab42 seems more pathogenic than Ab40, the reason for this is not well understood. We show here that small alterations in the Ab42:Ab40 ratio dramatically affect the biophysical and biological properties of the Ab mixtures reflected in their aggregation kinetics, the morphology of the resulting amyloid fibrils and synaptic function tested in vitro and in vivo. A minor increase in the Ab42:Ab40 ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these Ab species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of Ab peptides is more crucial than the absolute amounts of peptides for the induction of neurotoxic conformations has important implications for anti-amyloid therapy. Our work also suggests the dynamic nature of the equilibrium between toxic and non-toxic intermediates.",

keywords = "Alzheimer's disease, beta-amyloid peptides, microelectrode array, neurotoxicity, oligomer",

author = "Inna Kuperstein and Kerensa Broersen and Iryna Benilova and J. Rozenski and Wim Jonckheere and Maja Debulpaep and Annelies Vandersteen and Ine Segers-Nolten and {Van Der Werf}, Kees and Vinod Subramaniam and Dries Braeken and Geert Callewaert and Carmen Bartic and D'hooge Rudi and Martins, {Ivo Cristiano} and Frederic Rousseau and Joost Schymkowitz and Bart Destrooper",

year = "2010",

month = sep,

day = "3",

language = "English",

volume = "29",

pages = "3408--3420",

journal = "EMBO Journal",

issn = "0261-4189",

publisher = "Nature Publishing Group",

number = "19",

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Kuperstein, I, Broersen, K, Benilova, I, Rozenski, J, Jonckheere, W , Debulpaep, M, Vandersteen, A, Segers-Nolten, I, Van Der Werf, K, Subramaniam, V, Braeken, D, Callewaert, G, Bartic, C, Rudi, D, Martins, IC, Rousseau, F, Schymkowitz, J & Destrooper, B 2010, 'Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio.', EMBO Journal, vol. 29, no. 19, pp. 3408-3420.

TY - JOUR

T1 - Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio.

AU - Kuperstein, Inna

AU - Broersen, Kerensa

AU - Benilova, Iryna

AU - Rozenski, J.

AU - Jonckheere, Wim

AU - Debulpaep, Maja

AU - Vandersteen, Annelies

AU - Segers-Nolten, Ine

AU - Van Der Werf, Kees

AU - Subramaniam, Vinod

AU - Braeken, Dries

AU - Callewaert, Geert

AU - Bartic, Carmen

AU - Rudi, D'hooge

AU - Martins, Ivo Cristiano

AU - Rousseau, Frederic

AU - Schymkowitz, Joost

AU - Destrooper, Bart

PY - 2010/9/3

Y1 - 2010/9/3

N2 - The amyloid peptides Ab40 and Ab42 of Alzheimer's disease are thought to contribute differentially to the disease process. Although Ab42 seems more pathogenic than Ab40, the reason for this is not well understood. We show here that small alterations in the Ab42:Ab40 ratio dramatically affect the biophysical and biological properties of the Ab mixtures reflected in their aggregation kinetics, the morphology of the resulting amyloid fibrils and synaptic function tested in vitro and in vivo. A minor increase in the Ab42:Ab40 ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these Ab species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of Ab peptides is more crucial than the absolute amounts of peptides for the induction of neurotoxic conformations has important implications for anti-amyloid therapy. Our work also suggests the dynamic nature of the equilibrium between toxic and non-toxic intermediates.

AB - The amyloid peptides Ab40 and Ab42 of Alzheimer's disease are thought to contribute differentially to the disease process. Although Ab42 seems more pathogenic than Ab40, the reason for this is not well understood. We show here that small alterations in the Ab42:Ab40 ratio dramatically affect the biophysical and biological properties of the Ab mixtures reflected in their aggregation kinetics, the morphology of the resulting amyloid fibrils and synaptic function tested in vitro and in vivo. A minor increase in the Ab42:Ab40 ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these Ab species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of Ab peptides is more crucial than the absolute amounts of peptides for the induction of neurotoxic conformations has important implications for anti-amyloid therapy. Our work also suggests the dynamic nature of the equilibrium between toxic and non-toxic intermediates.

KW - Alzheimer's disease

KW - beta-amyloid peptides

KW - microelectrode array

KW - neurotoxicity

KW - oligomer

M3 - Article

SN - 0261-4189

VL - 29

SP - 3408

EP - 3420

JO - EMBO Journal

JF - EMBO Journal

IS - 19

ER -

Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio.

Abstract

Keywords

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