The serotonin 5-HT4 receptor and the amyloid precursor protein processing

A large body of evidence supports a major role for the serotonin 5-HT4 receptor in learning and memory and it is suggested that 5-HT4 agonists may be beneficial for memory disorders such as Alzheimer's disease (AD). The 5-HT4 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-HT4 receptor, h5-HT4(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-HT4(g) receptor isoform as well as the human APP695. The 5-HT4 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-HT4 antagonist, GR113808. Furthermore, 5-HT4 ligands enhance sAPPalpha secretion via cAMP-dependent and PKA-independent signalling pathways indicating there are alternative pathways by which the h5-HT4 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-HT4 receptor as a novel target for the treatment of AD. (C) 2002 Elsevier Science Inc. All rights reserved.