Effects of secondary metabolite extract from Phomopsis occulta on β-amyloid aggregation

PLoS One. 2014 Oct 2;9(10):e109438. doi: 10.1371/journal.pone.0109438. eCollection 2014.

Abstract

Inhibition of β-amyloid (Aβ) aggregation is an attractive therapeutic and preventive strategy for the discovery of disease-modifying agents in Alzheimer's disease (AD). Phomopsis occulta is a new, salt-tolerant fungus isolated from mangrove Pongamia pinnata (L.) Pierre. We report here the inhibitory effects of secondary metabolites from Ph. occulta on the aggregation of Aβ42. It was found that mycelia extracts (MEs) from Ph. occulta cultured with 0, 2, and 3 M NaCl exhibited inhibitory activity in an E. coli model of Aβ aggregation. A water-soluble fraction, ME0-W-F1, composed of mainly small peptides, was able to reduce aggregation of an Aβ42-EGFP fusion protein and an early onset familial mutation Aβ42E22G-mCherry fusion protein in transfected HEK293 cells. ME0-W-F1 also antagonized the cytotoxicity of Aβ42 in the neural cell line SH-SY5Y in dose-dependent manner. Moreover, SDS-PAGE and FT-IR analysis confirmed an inhibitory effect of ME0-W-F1 on the aggregation of Aβ42 in vitro. ME0-W-F1 blocked the conformational transition of Aβ42 from α-helix/random coil to β-sheet, and thereby inhibited formation of Aβ42 tetramers and high molecular weight oligomers. ME0-W-F1 and other water-soluble secondary metabolites from Ph. occulta therefore represent new candidate natural products against aggregation of Aβ42, and illustrate the potential of salt tolerant fungi from mangrove as resources for the treatment of AD and other diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism*
  • Biological Products / chemistry
  • Biological Products / isolation & purification
  • Biological Products / pharmacology*
  • Cell Line
  • Fungi / chemistry*
  • HEK293 Cells
  • Humans
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism*
  • Peptides / chemistry
  • Peptides / isolation & purification
  • Peptides / pharmacology*
  • Protein Aggregates / drug effects*
  • Protein Structure, Secondary / drug effects

Substances

  • Amyloid beta-Peptides
  • Biological Products
  • Peptide Fragments
  • Peptides
  • Protein Aggregates
  • amyloid beta-protein (1-42)

Grants and funding

Work in China was supported by Shenzhen City, China (Grant No. JCYJ2012061408533365, http://www.szsti.gov.cn/, YZ). Work in Cambridge was funded by the European Research Council (Advanced Investigator Grant 233232, http://erc.europa.eu/, AT) and an anonymous donation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter the authors′ adherence to PLOS ONE policies on sharing data and materials.