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

Background: Beta-amyloid (A beta) enables Alzheimer's disease (AD) plaque and neurofibrillary pathogenesis. Soluble A beta promotes intraneuronal A beta aggregates and tau phosphorylation by interacting with alpha 7 nicotinic receptors (alpha 7nAChRs). The current study assessed whether the novel alpha 7nAChR partial agonist 2-(2-(4-bromophenyl)-2-oxoethyl)-1-methyl pyridinium (S 24795) could reduce AD-like pathologies by interfering with A beta-alpha 7nAChR interaction. Methods: We compared the in vitro effect of S 24795, memantine, galantamine, and A beta(12-28) on A beta(42)-alpha 7nAChR interaction in rat hippocampal synaptosomes. We further evaluated the effect of S 24795 on A beta(42)-induced tau phosphorylation with rat hippocampal synaptosomes in vitro. Effects of S 24795 on A beta(42) immunostaining, A beta(42)-alpha 7nAChR interaction, and/or A beta(42)-mediated reduction of calcium (Ca(2+)) influx through alpha 7nAChR and N-methyl-D-aspartate receptor (NMDAR) were assessed in A beta(42)-incubated organotypic brain slices and intracerebroventricularly (ICV) A beta(42)-injected mouse brain. Results: Preincubation with S 24795 in vitro reduces A beta(42)-alpha 7nAChR interaction and A beta(42)-induced tau phosphorylation. In organotypic brain slice cultures and in an ICV A beta(42) injection in vivo model, S 24795 reduces A beta(42)-alpha 7nAChR association and A beta(42) immunostaining. S 24795 also normalizes Ca(2+) fluxes through both alpha 7nAChR and NMDAR channels in A beta(42)-infused mouse brains and A beta(42)-exposed organotypic cortical slices. Unlike S 24795 and A beta(12-28), galantamine or memantine minimally affect A beta(42)-alpha 7nAChR coupling and A beta(42)-mediated reduction of alpha 7nAChR- and NMDAR-mediated Ca(2+) influx. Interpretation: Drugs like S 24795 that disrupt A beta 42-alpha 7nAChR interaction might alleviate A beta(42)-mediated synaptic dysfunction and block AD-like pathologies.