Effect of alanine replacement of l17 and f19 on the aggregation and neurotoxicity of arctic-type aβ40

PLoS One. 2013 Apr 25;8(4):e61874. doi: 10.1371/journal.pone.0061874. Print 2013.

Abstract

Alzheimer's disease is the most common form of neurodegenerative disease. Beta-amyloid peptides (Aβ) are responsible for neuronal death both in vitro and in vivo. Previously, L17 and F19 residues were identified as playing key roles in the stabilization of the Aβ40 conformation and in the reduction of its neurotoxicity. In this study, the effects of L17A/F19A mutations on the neurotoxicity of Aβ genetic mutant Arctic-type Aβ40(E22G) were tested. The results showed that compared to Aβ40(E22G), Aβ40(L17A/F19A/E22G) reduced the rate of conformation conversion, aggregation, and cytotoxicity, suggesting that L17 and F19 are critical residues responsible for conformational changes which may trigger the neurotoxic cascade of Aβ. Aβ40(L17A/F19A/E22G) also had decreased damage due to reactive oxygen species. The results are consistent with the discordant helix hypothesis, and confirm that residues 17-25 are in the discordant helix region. Compared to Aβ40(L17A/F19A), reduction in aggregation of Aβ40(L17A/F19A/E22G) was less significantly decreased. This observation provides an explanation based on the discordant helix hypothesis that the mutation of E22 to G22 of Aβ40(E22G) alters the propensity of the discordant helix. Arctic-type Aβ40(E22G) aggregates more severely than wild-type Aβ40, with a consequential increase in toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine*
  • Amino Acid Substitution*
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / toxicity*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Humans
  • Kinetics
  • Mutation
  • Neurotoxins / chemistry*
  • Neurotoxins / genetics
  • Neurotoxins / toxicity*
  • Peptide Fragments / chemistry*
  • Peptide Fragments / genetics
  • Peptide Fragments / toxicity*
  • Protein Multimerization*
  • Protein Stability
  • Protein Structure, Secondary / genetics
  • Reactive Oxygen Species / metabolism

Substances

  • Amyloid beta-Peptides
  • Neurotoxins
  • Peptide Fragments
  • Reactive Oxygen Species
  • amyloid beta-protein (1-40)
  • Alanine

Grants and funding

This work was supported by grants from National Science Council of Taiwan, ROC (NSC96-2311-B-010-010-MY3 and NSC100-2113-M-010-001 to T.H.L. and NSC100-2627-M-715-001 and NSC101-2627-M-715-001 to Y.C.C.), Taipei Veterans General Hospital, Taiwan, Republic of China (V96C1-022, V96S4-002 to T.H.L.) and a grant from Ministry of Education, Aiming for the Top University Plan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.