| First Author | Tesseur I | Year | 2013 |
| Journal | Neurobiol Aging | Volume | 34 |
| Issue | 7 | Pages | 1779-89 |
| PubMed ID | 23474291 | Mgi Jnum | J:211746 |
| Mgi Id | MGI:5576112 | Doi | 10.1016/j.neurobiolaging.2013.01.020 |
| Citation | Tesseur I, et al. (2013) Chronic 5-HT4 receptor activation decreases Abeta production and deposition in hAPP/PS1 mice. Neurobiol Aging 34(7):1779-89 |
| abstractText | Lowering the production and accumulation of Abeta has been explored as treatment for Alzheimer's disease (AD), because Abeta 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 sAPPalpha and reduces Abeta, 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 sAPPalpha 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 Abeta 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. |
