Inhibiting Aβ toxicity in Alzheimer's disease by a pyridine amine derivative

Eur J Med Chem. 2019 Apr 15:168:330-339. doi: 10.1016/j.ejmech.2019.02.052. Epub 2019 Feb 20.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder with no radical therapy. Aggregation of amyloid β-peptide (Aβ) induced by various factors is associated with pathogenesis of AD. A pyridine amine derivative, 3-bis(pyridin-2-ylmethyl)aminomethyl-5-hydroxybenzyltriphenylphosphonium bromide (PAT), is synthesized. The inhibition of self- and metal-induced Aβ aggregation by PAT is confirmed by thioflavine T fluorescence, circular dichroism spectroscopy, and TEM. Western blot, RT-PCR and fluorescence imaging indicate that PAT can alleviate the Aβ-induced paralysis, reduce the production of ROS, and protect the mitochondrial function in transgenic C. elegans. Genetic analyses indicate that heat shock protein is involved in the alleviation of Aβ toxicity. PAT also inhibits the activity of acetylcholinesterase in C. elegans. Morris water maze test shows that the memory and cognitive ability of APP/PS1 AD model mice are significantly improved by PAT. Both in vitro and in vivo studies demonstrate that PAT is effective in counteracting Aβ toxicity and ameliorating cognitive functions in AD mice, and therefore a potential lead compound of anti-AD drugs.

Keywords: Alzheimer's disease; Amyloid-β peptide; Anti-AD drug; Caenorhabditis elegans; Heat shock protein.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amines / chemical synthesis
  • Amines / chemistry
  • Amines / pharmacology*
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Mice
  • Mice, Transgenic
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • PC12 Cells
  • Protein Aggregates / drug effects
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Rats
  • Reactive Oxygen Species / analysis
  • Reactive Oxygen Species / metabolism
  • Structure-Activity Relationship

Substances

  • Amines
  • Amyloid beta-Peptides
  • Neuroprotective Agents
  • Protein Aggregates
  • Pyridines
  • Reactive Oxygen Species
  • pyridine