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

Lowering the production and accumulation of A beta has been explored as treatment for Alzheimer's disease (AD), because A beta 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 alpha-secretase processing, which increases sAPP alpha and reduces A beta, 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 sAPP alpha 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 A beta in hippocampus, but the potential mechanisms underlying these observations seem to be complex. We found no evidence for direct alpha-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. (C) 2013 Elsevier Inc. All rights reserved.