S 24795 Limits beta-amyloid-alpha7 Nicotinic Receptor Interaction and Reduces Alzheimer's Disease-Like Pathologies

Biol Psychiatry. 2010 Mar 15;67(6):522-30. doi: 10.1016/j.biopsych.2009.09.031. Epub 2009 Nov 22.

Abstract

Background: Beta-amyloid (Abeta) enables Alzheimer's disease (AD) plaque and neurofibrillary pathogenesis. Soluble Abeta promotes intraneuronal Abeta aggregates and tau phosphorylation by interacting with alpha7 nicotinic receptors (alpha7nAChRs). The current study assessed whether the novel alpha7nAChR partial agonist 2-(2-(4-bromophenyl)-2-oxoethyl)-1-methyl pyridinium (S 24795) could reduce AD-like pathologies by interfering with Abeta-alpha7nAChR interaction.

Methods: We compared the in vitro effect of S 24795, memantine, galantamine, and Abeta(12-28) on Abeta(42)-alpha7nAChR interaction in rat hippocampal synaptosomes. We further evaluated the effect of S 24795 on Abeta(42)-induced tau phosphorylation with rat hippocampal synaptosomes in vitro. Effects of S 24795 on Abeta(42) immunostaining, Abeta(42)-alpha7nAChR interaction, and/or Abeta(42)-mediated reduction of calcium (Ca(2+)) influx through alpha7nAChR and N-methyl-d-aspartate receptor (NMDAR) were assessed in Abeta(42)-incubated organotypic brain slices and intracerebroventricularly (ICV) Abeta(42)-injected mouse brain.

Results: Preincubation with S 24795 in vitro reduces Abeta(42)-alpha7nAChR interaction and Abeta(42)-induced tau phosphorylation. In organotypic brain slice cultures and in an ICV Abeta(42) injection in vivo model, S 24795 reduces Abeta(42)-alpha7nAChR association and Abeta(42) immunostaining. S 24795 also normalizes Ca(2+) fluxes through both alpha7nAChR and NMDAR channels in Abeta(42)-infused mouse brains and Abeta(42)-exposed organotypic cortical slices. Unlike S 24795 and Abeta(12-28), galantamine or memantine minimally affect Abeta(42)-alpha7nAChR coupling and Abeta(42)-mediated reduction of alpha7nAChR- and NMDAR-mediated Ca(2+) influx.

Interpretation: Drugs like S 24795 that disrupt Abeta(42)-alpha7nAChR interaction might alleviate Abeta(42)-mediated synaptic dysfunction and block AD-like pathologies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / chemically induced
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Calcium / metabolism
  • Cholinergic Agonists / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agonists / pharmacology
  • Frontal Lobe / drug effects
  • Frontal Lobe / ultrastructure
  • Hippocampus / drug effects*
  • Hippocampus / ultrastructure
  • Immunoprecipitation / methods
  • Injections, Intraventricular / methods
  • Male
  • Mice
  • Mice, Inbred C57BL
  • N-Methylaspartate / pharmacology
  • Organ Culture Techniques
  • Peptide Fragments
  • Phosphorylation / drug effects
  • Pyridinium Compounds / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, Nicotinic / metabolism*
  • Synaptosomes / drug effects*
  • Synaptosomes / metabolism
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • Amyloid beta-Peptides
  • Cholinergic Agonists
  • Chrna7 protein, mouse
  • Chrna7 protein, rat
  • Excitatory Amino Acid Agonists
  • Peptide Fragments
  • Pyridinium Compounds
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Nicotinic
  • S 24795
  • alpha7 Nicotinic Acetylcholine Receptor
  • amyloid beta-protein (1-42)
  • N-Methylaspartate
  • Calcium