title: Chronic 5-HT4 receptor activation decreases Aβ production and deposition in hAPP/PS1 mice.
abstract: Lowering the production and accumulation of Aβ has been explored as treatment for Alzheimer's disease (AD), because Aβ is postulated to play an important role in the pathogenesis of AD. 5-HT4 receptors are an interesting drug target in this regard, as their activation might stimulate α-secretase processing, which increases sAPPα and reduces Aβ, at least according to the central dogma in APP processing. Here we describe a novel high-affinity 5-HT4 receptor agonist SSP-002392 that, in cultured human neuroblastoma cells, potently increases the levels of cAMP and sAPPα at 100-fold lower concentrations than the effective concentrations of prucalopride, a known selective 5-HT4 receptor agonist. Chronic administration of this compound in a hAPP/PS1 mouse model of Alzheimer's disease decreased soluble and insoluble Aβ in hippocampus, but the potential mechanisms underlying these observations seem to be complex. We found no evidence for direct α-secretase stimulation in the brain in vivo, but observed decreased APP and BACE-1 expression and elevated astroglia and microglia responses. Taken together these results provide support for a potential disease-modifying aspect when stimulating central 5-HT4 receptors; however, the complexity of the phenomena warrants further research.
authors.affiliation: Center for Human Genetics, Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven, Leuven, Belgium ina.tesseur@med.kuleuven.be
authors.forename: Ina
authors.initials: I
authors.lastname: Tesseur
authors.forename: Anna A
authors.initials: AA
authors.lastname: Pimenova
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Lo
authors.forename: Marta
authors.initials: M
authors.lastname: Ciesielska
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.forename: Joris H
authors.initials: JH
authors.lastname: De Maeyer
authors.forename: Jan A J
authors.initials: JA
authors.lastname: Schuurkes
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics*; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4