td-5108 and Nerve-Degeneration

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.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Cell Survival; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Male; Mice; Mice, Transgenic; Nerve Degeneration; Neurons; Neuroprotective Agents; Peptide Fragments; Piperidines; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Synaptic Transmission; Treatment Outcome