Activation of 5-HT4 receptors inhibits secretion of beta-amyloid peptides and increases neuronal survival.

Abstract

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.

• Authors: Seongeun Cho, Yun Hu
• Journal: Experimental neurology (Exp Neurol) Vol. 203 Issue 1 Pg. 274-8 (Jan 2007) ISSN: 0014-4886 [Print] United States
• PMID: 16978609 (Publication Type: Journal Article)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Aniline Compounds
• Neuroprotective Agents
• Peptide Fragments
• Piperidines
• Serotonin 5-HT4 Receptor Agonists
• Serotonin Receptor Agonists
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)
• Receptors, Serotonin, 5-HT4
• RS 67333
• Serotonin

Topics

• Alzheimer Disease (drug therapy, metabolism, physiopathology)
• Amyloid beta-Peptides (antagonists & inhibitors, metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Aniline Compounds (pharmacology, therapeutic use)
• Animals
• Cell Survival (drug effects, physiology)
• Cells, Cultured
• Cerebral Cortex (drug effects, metabolism, physiopathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Humans
• Male
• Mice
• Mice, Transgenic
• Nerve Degeneration (drug therapy, physiopathology, prevention & control)
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Peptide Fragments (antagonists & inhibitors, metabolism)
• Piperidines (pharmacology, therapeutic use)
• Receptors, Serotonin, 5-HT4 (metabolism)
• Serotonin (metabolism)
• Serotonin 5-HT4 Receptor Agonists
• Serotonin Receptor Agonists (pharmacology, therapeutic use)
• Synaptic Transmission (drug effects, physiology)
• Treatment Outcome