The serotonin 5-HT4 receptor and the amyloid precursor protein processing.
A large body of evidence supports a major role for the serotonin 5-HT(4) receptor in learning and memory and it is suggested that 5-HT(4) agonists may be beneficial for memory disorders such as Alzheimer's disease (AD). The 5-HT(4) receptors are members of the G protein-coupled receptor superfamily and are positively coupled to adenylyl cyclase. In this communication we show that a neuronal isoform of the human 5-HT(4) receptor, h5-HT(4(g)) regulates the metabolism of the amyloid precursor protein (APP695). This process is observed in Chinese hamster ovary (CHO) cells stably coexpressing the neuronal h5-HT(4(g)) receptor isoform as well as the human APP695. The 5-HT(4) agonists strongly stimulate the release of the non-amyloidogenic soluble amyloid precursor protein sAPPalpha as detected by immunoblot. Prucalopride was more potent than serotonin (5-HT) with regard to enhanced of sAPPalpha secretion. This process was blocked by a selective 5-HT(4) antagonist, GR113808. Furthermore, 5-HT(4) ligands enhance sAPPalpha secretion via cAMP-dependent and PKA-independent signalling pathways indicating there are alternative pathways by which the h5-HT(4) receptor via cAMP regulates APP metabolism. Because the alpha-cleavage event may preclude the formation of amyloidogenic peptides, and secreted sAPPalpha has putative neuroprotective and enhancing-memory properties, our present data suggest the 5-HT(4) receptor as a novel target for the treatment of AD.
Lezoualc'h
Frank
F
Cardiologie Cellulaire et Moléculaire INSERM U-446, Faculté de Pharmacie, Institut de Signalisation et Innovation Thérapeutique (IFR-75), Université Paris-Sud, F-9229, Châtenay-Malabry, France. frank.lezoualch@cep.u-psud.fr
Robert
Sylvain J
SJ
D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D003071:Cognition / Q000502:physiology; D006224:Cricetinae; D006801:Humans; D008969:Molecular Sequence Data; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4