s-24795 and Disease-Models--Animal

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

Topics: alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Amyloid beta-Peptides; Animals; Calcium; Cholinergic Agonists; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Frontal Lobe; Hippocampus; Immunoprecipitation; Injections, Intraventricular; Male; Mice; Mice, Inbred C57BL; N-Methylaspartate; Organ Culture Techniques; Peptide Fragments; Phosphorylation; Pyridinium Compounds; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Synaptosomes

The comparative effects of a newly described specific alpha7 nAChR partial agonist, S 24795, and a cholinesterase inhibitor, donepezil, currently used as a symptomatic Alzheimer's disease treatment were studied in two mouse models of aging-related memory deficits.. We employed radial arm-maze paradigms assessing short-term working memory (STWM, experiment A) and mnemonic flexibility, a cardinal property of long-term declarative (LTDM, experiment B). Both compounds were administered daily at 0.3 and 1 mg/kg subcutaneously (~3 weeks).. In the STWM experiment, vehicle-treated aged mice displayed a severe and persistent deficit in the retention of successive arm visits in comparison to younger controls. S 24795 at 1 mg/kg (trends at 0.3 mg/kg) and donepezil at 0.3 mg/kg (but not 1 mg/kg) exerted beneficial effects on this deficit: The performance of aged mice treated with these drugs remarkably increased across the testing days and almost reached young adult performance level. In the critical test trials of memory flexibility (i.e., LTDM), in experiment B, S 24795 at 1 mg/kg (trends at 0.3 mg/kg) and donepezil at the dose of 1 mg/kg (but not 0.3 mg/kg) improved aged mice performance.. This preclinical demonstration that S 24795 restored specific age-related memory deficits with as much efficacy as donepezil adds to recent literature in highlighting the potential interest of an alpha7 nAChR drug as a symptomatic AD therapeutic.

Topics: Aging; alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Animals; Choice Behavior; Cholinesterase Inhibitors; Discrimination Learning; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Indans; Inhibition, Psychological; Injections, Subcutaneous; Maze Learning; Memory, Short-Term; Mice; Mice, Inbred C57BL; Nicotinic Agonists; Nootropic Agents; Piperidines; Pyridinium Compounds; Receptors, Nicotinic; Retention, Psychology