S 24795 Limits β-Amyloid–α7 Nicotinic Receptor Interaction and Reduces Alzheimer's Disease-Like Pathologies

BackgroundBeta-amyloid (Aβ) enables Alzheimer's disease (AD) plaque and neurofibrillary pathogenesis. Soluble Aβ promotes intraneuronal Aβ aggregates and τ phosphorylation by interacting with α7 nicotinic receptors (α7nAChRs). The current study assessed whether the novel α7nAChR partial agonist 2-(2-(4-bromophenyl)-2-oxoethyl)-1-methyl pyridinium (S 24795) could reduce AD-like pathologies by interfering with Aβ–α7nAChR interaction.MethodsWe compared the in vitro effect of S 24795, memantine, galantamine, and Aβ12-28 on Aβ42–α7nAChR interaction in rat hippocampal synaptosomes. We further evaluated the effect of S 24795 on Aβ42-induced τ phosphorylation with rat hippocampal synaptosomes in vitro. Effects of S 24795 on Aβ42 immunostaining, Aβ42–α7nAChR interaction, and/or Aβ42-mediated reduction of calcium (Ca2+) influx through α7nAChR and N-methyl-d-aspartate receptor (NMDAR) were assessed in Aβ42-incubated organotypic brain slices and intracerebroventricularly (ICV) Aβ42-injected mouse brain.ResultsPreincubation with S 24795 in vitro reduces Aβ42–α7nAChR interaction and Aβ42-induced τ phosphorylation. In organotypic brain slice cultures and in an ICV Aβ42 injection in vivo model, S 24795 reduces Aβ42–α7nAChR association and Aβ42 immunostaining. S 24795 also normalizes Ca2+ fluxes through both α7nAChR and NMDAR channels in Aβ42-infused mouse brains and Aβ42-exposed organotypic cortical slices. Unlike S 24795 and Aβ12-28, galantamine or memantine minimally affect Aβ42–α7nAChR coupling and Aβ42-mediated reduction of α7nAChR- and NMDAR-mediated Ca2+ influx.InterpretationDrugs like S 24795 that disrupt Aβ42–α7nAChR interaction might alleviate Aβ42-mediated synaptic dysfunction and block AD-like pathologies.