Chronic 5-HT₄ receptor activation decreases Aβ production and deposition in hAPP/PS1 mice

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.