5‐HT4 receptor agonists increase sAPPα levels in the cortex and hippocampus of male C57BL/6j mice

Background and purpose: A strategy to treat Alzheimer's disease (AD) is to increase the soluble form of amyloid precursor protein (sAPPα), a promnesic protein, in the brain. Because strong evidence supports beneficial effects of 5‐hydroxytryptamine 5‐HT4 receptor agonists in memory and learning, we investigated the role of 5‐HT4 receptors on APP processing in 8 weeks‐old male C57BL/6j mice. Experimental approach: Mice were given, subcutaneously, prucalopride or ML 10302 (s.c.), two highly selective 5‐HT4 receptor agonists and, up to 240 min later, the hippocampus and cortex were analysed by Western blot for sAPPα determination. Key results: Prucalopride (5 or 10 mg kg‐1) significantly increased sAPPα levels in the hippocampus and cortex, but did not modify the expression level of APP mRNA as detected by quantitative RT‐PCR. A selective 5‐HT4 receptor antagonist, GR125487 (1 mg kg‐1, s.c.) inhibited prucalopride induced‐ increase in sAPPα levels. In addition, levels of sAPPα were increased by ML10302 only at 20 mg kg‐1 and was limited to the cortex. Also, prucalopride increased sAPPα levels in the cortex of a transgenic mouse model of AD, expressing the London mutation of APP. Furthermore, the combined injection of a selective acetylcholinesterase inhibitor, donepezil and prucalopride induced a synergic increase in sAPPα levels in the cortex and hippocampus. Conclusions and implications: Our results demonstrate that the 5‐HT4 receptor plays a key role in the non‐amyloidogenic pathway of APP metabolism in vivo and give support to the beneficial use of 5‐HT4 agonists for AD treatment. British Journal of Pharmacology (2007) 150, 883–892. doi:10.1038/sj.bjp.0707178