Title: Chronic 5-HT4 receptor activation decreases Aβ production and deposition in hAPP/PS1 mice
Authors: Tesseur, Ina ×
Pimenova, Anna
Lo, Adrian
Ciesielska, M.
Lichtenthaler, S.F.
De Maeyer, J.H.
Schuurkes, J.A.
D'Hooge, Rudi
De Strooper, Bart #
Issue Date: 2013
Publisher: Elsevier
Series Title: Neurobiology of Aging vol:34 issue:7 pages:1779-1789
Article number: 10.1016/j.neurobiolaging.2013.01.020
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.
ISSN: 0197-4580
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Biological Psychology
Department of Human Genetics - miscellaneous
Laboratory for the Research of Neurodegenerative Diseases
× corresponding author
# (joint) last author

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