The potential of synthetic indolylquinoline derivatives for Aβ aggregation reduction by chemical chaperone activity

Neuropharmacology. 2016 Feb;101:309-19. doi: 10.1016/j.neuropharm.2015.09.005. Epub 2015 Sep 8.

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia associated with progressive cognitive decline and memory loss. Extracellular β-amyloid (Aβ) is a major constituent of senile plaques, one of the pathological hallmarks of AD. Aβ deposition causes neuronal death via a number of possible mechanisms such as increasing oxidative stress. Therefore therapeutic approaches to identify novel Aβ aggregate reducers could be effective for AD treatment. Using a Trx-His-Aβ biochemical assay, we screened 11 synthetic indolylquinoline compounds, and found NC009-1, -2, -6 and -7 displaying potential to reduce Aβ aggregation. Treating Tet-On Aβ-GFP 293 cells with these compounds reduced Aβ aggregation and reactive oxygen species. These compounds also promoted neurite outgrowth in Tet-On Aβ-GFP SH-SY5Y cells. Furthermore, treatment with above compounds improved neuronal cell viability, neurite outgrowth, and synaptophysin expression level in mouse hippocampal primary culture under oligomeric Aβ-induced cytotoxicity. Moreover, the tested NC009-1 significantly ameliorated Aβ-induced inhibition of hippocampal long-term potentiation in mouse hippocampal slices. Our results demonstrate how synthetic indolylquinoline compounds are likely to work as chemical chaperones in Aβ-aggregation reduction and neuroprotection, providing insight into the possible applications of indolylquinoline compounds in AD treatment.

Keywords: Alzheimer's disease; Aβ aggregation; Synthetic indolylquinoline derivatives; Therapeutics.

MeSH terms

  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Cell Survival
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Embryo, Mammalian
  • Female
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hippocampus / cytology
  • Humans
  • In Vitro Techniques
  • Long-Term Potentiation / drug effects*
  • Long-Term Potentiation / genetics
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / physiology
  • Neuroprotective Agents / pharmacology*
  • Patch-Clamp Techniques
  • Peptide Fragments / pharmacology
  • Quinolines / pharmacology*
  • Reactive Oxygen Species
  • Transfection

Substances

  • Amyloid beta-Peptides
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Peptide Fragments
  • Quinolines
  • Reactive Oxygen Species
  • amyloid beta-protein (1-42)
  • Green Fluorescent Proteins
  • quinoline