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

• Published in: Biological psychiatry (1969) 2010, Vol.67 (6), p.522-530
• Main Authors: Wang, Hoau-Yan, Bakshi, Kalindi, Shen, Changpeng, Frankfurt, Maya, Trocmé-Thibierge, Caryn, Morain, Philippe
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Alzheimer's disease; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Medical sciences; Neurology; nicotinic receptor agonist; NMDA receptor; Organic mental disorders. Neuropsychology; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; synaptic dysfunction; α7 nicotinic acetylcholine receptor; β-amyloid
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2009.09.031

Background Beta-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. Methods We 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. Results Preincubation 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. Interpretation Drugs like S 24795 that disrupt Aβ42 –α7nAChR interaction might alleviate Aβ42 -mediated synaptic dysfunction and block AD-like pathologies.