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Experimental Genetics Group
Br J Pharmacol. 2007 Apr;150(7):883-92. Cachard-Chastel M1,2, Lezoualc'h F2,3, Dewachter I4, Deloménie C2, Croes S4, Devijver H4, Langlois M5, Van Leuven F4, Sicsic S2,5, Gardier AM1,2. 1EA3544, Sérotonine et Neuropharmacologie, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry cedex, France. 2IFR-141, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry cedex, France. 3INSERM, U769, Signalisation et Physiopathologie Cardiaque, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry cedex, France. 4Experimental Genetics Group, K.U.Leuven, Leuven, Belgium. 5BIOCIS, Labaratoire de Reconnaissance Moléculaire et Synthèse, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry cedex, France. A strategy to treat Alzheimer's disease (AD) is to increase the soluble form of amyloid precursor protein (sAPPalpha), a promnesic protein, in the brain. Because strong evidence supports beneficial effects of 5-hydroxytryptamine 5-HT(4) receptor agonists in memory and learning, we investigated the role of 5-HT(4) 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-HT(4) receptor agonists and, up to 240 min later, the hippocampus and cortex were analysed by Western blot for sAPPalpha determination. KEY RESULTS: Prucalopride (5 or 10 mg kg(-1)) significantly increased sAPPalpha 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-HT(4) receptor antagonist, GR125487 (1 mg kg(-1), s.c.) inhibited prucalopride induced- increase in sAPPalpha levels. In addition, levels of sAPPalpha were increased by ML10302 only at 20 mg kg(-1) and was limited to the cortex. Also, prucalopride increased sAPPalpha 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 sAPPalpha levels in the cortex and hippocampus. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that the 5-HT(4) receptor plays a key role in the non-amyloidogenic pathway of APP metabolism in vivo and give support to the beneficial use of 5-HT(4) agonists for AD treatment.  FULL TEXT |
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