title: Effect of alanine replacement of l17 and f19 on the aggregation and neurotoxicity of arctic-type aβ40.
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.
authors: Structural Biology Program, National Yang-Ming University, Taipei, Taiwan, ROC. chen15@mmc.edu.tw
authors: Yi-Ru
authors: YR
authors: Chen
authors: Hsien-bin
authors: HB
authors: Huang
authors: Chi-Jen
authors: CJ
authors: Lo
authors: Chih-Ching
authors: CC
authors: Wang
authors: Li-Kang
authors: LK
authors: Ho
authors: Hsin-Tzu
authors: HT
authors: Liu
authors: Ming-Shi
authors: MS
authors: Shiao
authors: Ta-Hsien
authors: TH
authors: Lin
authors: Yi-Cheng
authors: YC
authors: Chen
mesh_terms: D000409:Alanine; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D009154:Mutation; D009498:Neurotoxins / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity*; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity*; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); D000409:Alanine
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