Role of amyloid-beta glycine 33 in oligomerization, toxicity, and neuronal plasticity

Anja Harmeier, Christian Wozny, Benjamin R Rost, Lisa-Marie Munter, Haiqing Hua, Oleg Georgiev, Michael Beyermann, Peter W. Hildebrand, Christoph Weise, Walter Schaffner, Dietmar Schmitz, Gerd Multhaup

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

The aggregation of the amyloid-beta (Abeta) peptide plays a pivotal role in the pathogenesis of Alzheimer's disease, as soluble oligomers are intimately linked to neuronal toxicity and inhibition of hippocampal long-term potentiation (LTP). In the C-terminal region of Abeta there are three consecutive GxxxG dimerization motifs, which we could previously demonstrate to play a critical role in the generation of Abeta. Here, we show that glycine 33 (G33) of the central GxxxG interaction motif within the hydrophobic Abeta sequence is important for the aggregation dynamics of the peptide. Abeta peptides with alanine or isoleucine substitutions of G33 displayed an increased propensity to form higher oligomers, which we could attribute to conformational changes. Importantly, the oligomers of G33 variants were much less toxic than Abeta(42) wild type (WT), in vitro and in vivo. Also, whereas Abeta(42) WT is known to inhibit LTP, Abeta(42) G33 variants had lost the potential to inhibit LTP. Our findings reveal that conformational changes induced by G33 substitutions unlink toxicity and oligomerization of Abeta on the molecular level and suggest that G33 is the key amino acid in the toxic activity of Abeta. Thus, a specific toxic conformation of Abeta exists, which represents a promising target for therapeutic interventions.

LanguageEnglish
Pages7582-7590
Number of pages9
JournalJournal of Neuroscience
Volume29
Issue number23
DOIs
Publication statusPublished - 10 Jun 2009

Fingerprint

Neuronal Plasticity
Amyloid
Glycine
Long-Term Potentiation
Poisons
Amyloid beta-Peptides
Isoleucine
Dimerization
Alanine
Alzheimer Disease
Amino Acids
Peptides

Keywords

  • amino acid motifs
  • amino acid sequence
  • amino acid substitution
  • amyloid beta-peptides
  • animals
  • cell death
  • cell line, tumor
  • cells, cultured
  • Drosophila melanogaster
  • excitatory postsynaptic potentials
  • eye
  • glycine
  • hippocampus
  • humans
  • hydrophobic and hydrophilic interactions
  • long-term potentiation
  • models, molecular
  • molecular sequence data
  • mutation, missense
  • neuronal plasticity
  • neurons
  • peptide fragments
  • protein conformation
  • protein multimerization
  • rats
  • rats, wistar

Cite this

Harmeier, A., Wozny, C., Rost, B. R., Munter, L-M., Hua, H., Georgiev, O., ... Multhaup, G. (2009). Role of amyloid-beta glycine 33 in oligomerization, toxicity, and neuronal plasticity. Journal of Neuroscience, 29(23), 7582-7590. https://doi.org/10.1523/JNEUROSCI.1336-09.2009
Harmeier, Anja ; Wozny, Christian ; Rost, Benjamin R ; Munter, Lisa-Marie ; Hua, Haiqing ; Georgiev, Oleg ; Beyermann, Michael ; Hildebrand, Peter W. ; Weise, Christoph ; Schaffner, Walter ; Schmitz, Dietmar ; Multhaup, Gerd. / Role of amyloid-beta glycine 33 in oligomerization, toxicity, and neuronal plasticity. In: Journal of Neuroscience. 2009 ; Vol. 29, No. 23. pp. 7582-7590.
@article{23fc1b1fba874b17b0302aad57aeee6b,
title = "Role of amyloid-beta glycine 33 in oligomerization, toxicity, and neuronal plasticity",
abstract = "The aggregation of the amyloid-beta (Abeta) peptide plays a pivotal role in the pathogenesis of Alzheimer's disease, as soluble oligomers are intimately linked to neuronal toxicity and inhibition of hippocampal long-term potentiation (LTP). In the C-terminal region of Abeta there are three consecutive GxxxG dimerization motifs, which we could previously demonstrate to play a critical role in the generation of Abeta. Here, we show that glycine 33 (G33) of the central GxxxG interaction motif within the hydrophobic Abeta sequence is important for the aggregation dynamics of the peptide. Abeta peptides with alanine or isoleucine substitutions of G33 displayed an increased propensity to form higher oligomers, which we could attribute to conformational changes. Importantly, the oligomers of G33 variants were much less toxic than Abeta(42) wild type (WT), in vitro and in vivo. Also, whereas Abeta(42) WT is known to inhibit LTP, Abeta(42) G33 variants had lost the potential to inhibit LTP. Our findings reveal that conformational changes induced by G33 substitutions unlink toxicity and oligomerization of Abeta on the molecular level and suggest that G33 is the key amino acid in the toxic activity of Abeta. Thus, a specific toxic conformation of Abeta exists, which represents a promising target for therapeutic interventions.",
keywords = "amino acid motifs, amino acid sequence, amino acid substitution, amyloid beta-peptides, animals, cell death, cell line, tumor, cells, cultured, Drosophila melanogaster, excitatory postsynaptic potentials, eye, glycine, hippocampus, humans, hydrophobic and hydrophilic interactions, long-term potentiation, models, molecular, molecular sequence data, mutation, missense, neuronal plasticity, neurons, peptide fragments, protein conformation, protein multimerization, rats, rats, wistar",
author = "Anja Harmeier and Christian Wozny and Rost, {Benjamin R} and Lisa-Marie Munter and Haiqing Hua and Oleg Georgiev and Michael Beyermann and Hildebrand, {Peter W.} and Christoph Weise and Walter Schaffner and Dietmar Schmitz and Gerd Multhaup",
year = "2009",
month = "6",
day = "10",
doi = "10.1523/JNEUROSCI.1336-09.2009",
language = "English",
volume = "29",
pages = "7582--7590",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "23",

}

Harmeier, A, Wozny, C, Rost, BR, Munter, L-M, Hua, H, Georgiev, O, Beyermann, M, Hildebrand, PW, Weise, C, Schaffner, W, Schmitz, D & Multhaup, G 2009, 'Role of amyloid-beta glycine 33 in oligomerization, toxicity, and neuronal plasticity' Journal of Neuroscience, vol. 29, no. 23, pp. 7582-7590. https://doi.org/10.1523/JNEUROSCI.1336-09.2009

Role of amyloid-beta glycine 33 in oligomerization, toxicity, and neuronal plasticity. / Harmeier, Anja; Wozny, Christian; Rost, Benjamin R; Munter, Lisa-Marie; Hua, Haiqing; Georgiev, Oleg; Beyermann, Michael; Hildebrand, Peter W.; Weise, Christoph; Schaffner, Walter; Schmitz, Dietmar; Multhaup, Gerd.

In: Journal of Neuroscience, Vol. 29, No. 23, 10.06.2009, p. 7582-7590.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Role of amyloid-beta glycine 33 in oligomerization, toxicity, and neuronal plasticity

AU - Harmeier, Anja

AU - Wozny, Christian

AU - Rost, Benjamin R

AU - Munter, Lisa-Marie

AU - Hua, Haiqing

AU - Georgiev, Oleg

AU - Beyermann, Michael

AU - Hildebrand, Peter W.

AU - Weise, Christoph

AU - Schaffner, Walter

AU - Schmitz, Dietmar

AU - Multhaup, Gerd

PY - 2009/6/10

Y1 - 2009/6/10

N2 - The aggregation of the amyloid-beta (Abeta) peptide plays a pivotal role in the pathogenesis of Alzheimer's disease, as soluble oligomers are intimately linked to neuronal toxicity and inhibition of hippocampal long-term potentiation (LTP). In the C-terminal region of Abeta there are three consecutive GxxxG dimerization motifs, which we could previously demonstrate to play a critical role in the generation of Abeta. Here, we show that glycine 33 (G33) of the central GxxxG interaction motif within the hydrophobic Abeta sequence is important for the aggregation dynamics of the peptide. Abeta peptides with alanine or isoleucine substitutions of G33 displayed an increased propensity to form higher oligomers, which we could attribute to conformational changes. Importantly, the oligomers of G33 variants were much less toxic than Abeta(42) wild type (WT), in vitro and in vivo. Also, whereas Abeta(42) WT is known to inhibit LTP, Abeta(42) G33 variants had lost the potential to inhibit LTP. Our findings reveal that conformational changes induced by G33 substitutions unlink toxicity and oligomerization of Abeta on the molecular level and suggest that G33 is the key amino acid in the toxic activity of Abeta. Thus, a specific toxic conformation of Abeta exists, which represents a promising target for therapeutic interventions.

AB - The aggregation of the amyloid-beta (Abeta) peptide plays a pivotal role in the pathogenesis of Alzheimer's disease, as soluble oligomers are intimately linked to neuronal toxicity and inhibition of hippocampal long-term potentiation (LTP). In the C-terminal region of Abeta there are three consecutive GxxxG dimerization motifs, which we could previously demonstrate to play a critical role in the generation of Abeta. Here, we show that glycine 33 (G33) of the central GxxxG interaction motif within the hydrophobic Abeta sequence is important for the aggregation dynamics of the peptide. Abeta peptides with alanine or isoleucine substitutions of G33 displayed an increased propensity to form higher oligomers, which we could attribute to conformational changes. Importantly, the oligomers of G33 variants were much less toxic than Abeta(42) wild type (WT), in vitro and in vivo. Also, whereas Abeta(42) WT is known to inhibit LTP, Abeta(42) G33 variants had lost the potential to inhibit LTP. Our findings reveal that conformational changes induced by G33 substitutions unlink toxicity and oligomerization of Abeta on the molecular level and suggest that G33 is the key amino acid in the toxic activity of Abeta. Thus, a specific toxic conformation of Abeta exists, which represents a promising target for therapeutic interventions.

KW - amino acid motifs

KW - amino acid sequence

KW - amino acid substitution

KW - amyloid beta-peptides

KW - animals

KW - cell death

KW - cell line, tumor

KW - cells, cultured

KW - Drosophila melanogaster

KW - excitatory postsynaptic potentials

KW - eye

KW - glycine

KW - hippocampus

KW - humans

KW - hydrophobic and hydrophilic interactions

KW - long-term potentiation

KW - models, molecular

KW - molecular sequence data

KW - mutation, missense

KW - neuronal plasticity

KW - neurons

KW - peptide fragments

KW - protein conformation

KW - protein multimerization

KW - rats

KW - rats, wistar

UR - http://www.jneurosci.org/

U2 - 10.1523/JNEUROSCI.1336-09.2009

DO - 10.1523/JNEUROSCI.1336-09.2009

M3 - Article

VL - 29

SP - 7582

EP - 7590

JO - Journal of Neuroscience

T2 - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 23

ER -