The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Inhibition of ${\beta}-amyloid_{1-40}$ Peptide Aggregation and Neurotoxicity by Citrate

  • Park, Yong-Hoon (Inam Neuroscience Research Center College of Medicine, Wonkwang University) ;
  • Kim, Young-Jin (Department of Neurology, Sanbon Medical Center, College of Medicine, Wonkwang University) ;
  • Son, Il-Hong (Inam Neuroscience Research Center College of Medicine, Wonkwang University) ;
  • Yang, Hyun-Duk (Inam Neuroscience Research Center College of Medicine, Wonkwang University)
  • Published : 2009.08.31
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Abstract

The accumulation of ${\beta}$-amyloid (A${\beta}$) aggregates is a characteristic of Alzheimer's disease (AD). Furthermore, these aggregates have neurotoxic effects on cells, and thus, molecules that inhibit A${\beta}$ aggregate formation could be valuable therapeutics for AD. It is well known that aggregation of A${\beta}$ depends on its hydrophobicity, and thus, in order to increase the hydrophilicity of A${\beta}$, we considered using citrate, an anionic surfactant with three carboxylic acid groups. We hypothesized that citrate could reduce hydrophobicity and increase hydrophilicity of A${\beta}_{1-40}$ molecules via hydrophilic/electrostatic interactions. We found that citrate significantly inhibited A${\beta}_{1-40}$ aggregation and significantly protected SH-SY5Y cell line against A${\beta}_{1-40}$ aggregates-induced neurotoxicity. In details, we examined the effects of citrate on A${\beta}_{1-40}$ aggregation and on A${\beta}_{1-40}$ aggregates-induced cytotoxicity, cell viability, and apoptosis. Th-T assays showed that citrate significantly inhibited A${\beta}_{1-40}$ aggregation in a concentration-dependent manner (Th-T intensity: from 91.3% in 0.01 mM citrate to 82.1% in 1.0 mM citrate vs. 100.0% in A${\beta}_{1-40}$ alone). In cytotoxicity and viability assays, citrate reduced the toxicity of A${\beta}_{1-40}$ in a concentration-dependent manner, in which the cytotoxicity decreased from 107.5 to 102.3% as compared with A${\beta}_{1-40}$ aggregates alone treated cells (127.3%) and the cell viability increased from 84.6 to 93.8% as compared with the A${\beta}_{1-40}$ aggregates alone treated cells (65.3%). Furthermore, Hoechst 33342 staining showed that citrate (1.0 mM) suppressed A${\beta}_{1-40}$ aggregates-induced apoptosis in the cells. This study suggests that citrate can inhibit A${\beta}_{1-40}$ aggregation and protect neurons from the apoptotic effects of A${\beta}_{1-40}$ aggregates. Accordingly, our findings suggest that citrate administration should be viewed as a novel neuroprotective strategy for AD.

Keywords

References

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