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.
MeSH terms
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Alzheimer Disease / drug therapy
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Alzheimer Disease / metabolism
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Alzheimer Disease / physiopathology
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Amyloid beta-Peptides / antagonists & inhibitors*
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism
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Aniline Compounds / pharmacology
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Aniline Compounds / therapeutic use
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Animals
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Cerebral Cortex / drug effects*
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Cerebral Cortex / metabolism
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Cerebral Cortex / physiopathology
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Female
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Humans
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Male
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Mice
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Mice, Transgenic
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Nerve Degeneration / drug therapy
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Nerve Degeneration / physiopathology
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Nerve Degeneration / prevention & control
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Neurons / drug effects*
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Neurons / metabolism
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Neuroprotective Agents / pharmacology*
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Neuroprotective Agents / therapeutic use
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Peptide Fragments / antagonists & inhibitors
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Peptide Fragments / metabolism
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Piperidines / pharmacology
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Piperidines / therapeutic use
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Receptors, Serotonin, 5-HT4 / metabolism
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Serotonin / metabolism
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Serotonin 5-HT4 Receptor Agonists*
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Serotonin Receptor Agonists / pharmacology*
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Serotonin Receptor Agonists / therapeutic use
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology
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Treatment Outcome
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Aniline Compounds
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Neuroprotective Agents
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Peptide Fragments
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Piperidines
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Serotonin 5-HT4 Receptor Agonists
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Serotonin Receptor Agonists
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amyloid beta-protein (1-40)
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amyloid beta-protein (1-42)
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Receptors, Serotonin, 5-HT4
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RS 67333
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Serotonin