Activation of 5-HT4 receptors inhibits secretion of beta-amyloid peptides and increases neuronal survival.
Activation of 5-HT4 receptors has been shown to improve memory processes in preclinical cognition models, suggesting potential utility of 5-HT4 agonists for the symptomatic treatment of Alzheimer's disease (AD). Recent studies have shown that 5-HT4 agonists also increase the secretion of the non-amyloidogenic soluble amyloid precursor protein-alpha (sAPPalpha). In the present study, we demonstrated that a selective 5-HT4 partial agonist, RS67333, inhibited the generation of beta-amyloid peptide (Abeta) in primary cortical cultures of Tg2576 transgenic mice expressing human APP(K670N/M671L). Furthermore, treatments with RS67333 selectively increased the survival of transgenic neurons in a dose-dependent manner, which was inhibited by 5-HT4 antagonists. These and previous data collectively suggest that the 5-HT4 receptor may be an effective therapeutic target for AD, providing both symptomatic improvements and neuroprotection.
Cho
Seongeun
S
Neuroscience Discovery Research, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. chos1@wyeth.com
Hu
Yun
Y
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000814:Aniline Compounds; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010880:Piperidines; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D044422:Receptors, Serotonin, 5-HT4; C107826:RS 67333; D012701:Serotonin