ABSTRACT Alzheimer’s disease (AD) is a progressive neurological disorder primarily affecting new memory formation as well as retrieval of previously acquired memories. According to World Health Organization, current global population suffering from cognitive impairment is estimated to 37 million. The number is projected to double in next one and half decade. Half of the population afflicted with dementia is represented by AD patients. Current therapies, which provide marginal symptomatic relief to AD patients, are effective only in half of the patient population. In depth understanding of the molecular mechanism of the disease is urgently required to develop more effective therapies. Therapies in clinical development may either offer symptomatic relief to patients or provide pure disease modifications, thus limiting benefit to patients. 5-HT4 receptor agonists offer an attractive option for the treatment of AD patients. Activation of 5- HT4 receptor under preclinical conditions is demonstrated to improve neurotransmission and enhance the release of acetylcholine resulting in the memory formation. In various cell based and animal models, partial 5-HT4 receptor agonists are demonstrated to promote the release of soluble amyloid precursor protein alpha and block the release of amyloid beta peptide offering suitable candidates as disease modification agents. Remarkably, 5-HT4 receptor agonists are also reported to induce neurogenesis in hippocampus as well as enteric system through the activation of cyclic AMP response element binding protein in rodents. Taken together, 5-HT4 agonists address all major facets of Alzheimer’s disease and may provide therapeutic potential for other neurological disorders.
Cite this paper
nullI. Ahmad and R. Nirogi, "5-HT4 Receptor Agonists for the Treatment of Alzheimer’s Dsease," Neuroscience and Medicine, Vol. 2 No. 2, 2011, pp. 87-92. doi: 10.4236/nm.2011.22013.
 C. Gerald, N. Adham, H.-T. Kao, M. A. Olsen, T. M. Laz, L. E. Schechter, J. A. Bard, P. J.-J. Vaysse, P. R. Hartig, T. A. Branchek and R. L. Weinshank, “The 5-HT4 receptor: molecular cloning and pharmacological characterization of two splice variants,” The EMBO Journal, vol. 14, no. 12, 15 June 1995, pp. 2806-2815.
 [H. S. Kim, “5-hydroxytryptamine4 receptor agonists and colonic motility,” Journal of Smooth Muscle Research, vol. 45, no. 1, 2009, pp. 25-29.
 G. J. Sanger, “Translating 5-HT receptor pharmacology,” Neurogastroenterology Motility, vol. 21, no. 12, December 2009, pp. 1235-1238.
 J. Tack, “Prucalopride: a new drug for the treatment of chronic constipation,” Expert Review in Gastroenterology and Hepatology, vol. 3, no. 4, August 2009, pp. 337-343.
 M. V. King, C. A. Marsden and K. C. Fone, “A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory,” Trends in Pharmacological Sciences, vol. 29, no. 9, September 2008, pp. 482-492.
 G. Perez-Garcia and A. Menesses, “A. Memory formation, amnesia, improved memory and reversed amnesia: 5-HT role,” Behavioural Brain Research, vol. 195, no. 1, 16 December 2008, pp. 195: 17-29.
 S. J. Robert and F. Lezoualc’h, “Distinct functional effects of human 5-HT4 receptor isoforms on beta-amyloid secretion,” Neurodegenerative Diseases, vol. 5, no. 3-4, March 2008, pp. 163-165.
 I. M. Coupar, P. V. Desmond and H. R. Irving, “Human 5-HT4 and 5-HT7 receptor splice variants: are they important,” Current Neuropharmacology, vol. 5, no. 4, December 2007, pp. 224-231.
 M. Langlois and R. Fischmeister, “5-HT4 receptor ligands: applications and new prospects,” Journal of Medicinal Chemistry, vol. 46, no. 3, 30 January 2003, pp. 319-344.
 A. Pindon, G. V. Hecke, P. V. Gompel, A. S. Lesage, J. E. Leysen and M. Jurzak, “Differences in signal transduction of two 5-HT4 receptor splice variants: compound specificity and dual coupling with G?s and G?i/o-proteins,” Molecular Pharmacology, vol. 61, no. 1, January 2002, pp. 85-96.
 P. C. Moser, O. E. Bergis, S. Jegham, A. Lochead, E. Duconseille, J.-P. Terranova, D. Caille, I. Berque-Bestel, F. Lezoualc’h, R. Fischmeister, A. Dumuis, J. Bockaert, P. George, P. Soubrie and B. Scatton, “SL65.0155, a novel 5-hydroxytryptamine 4 receptor partial agonist with potent cognition-enhancing properties,” Journal of Pharmacology and Experimental Therapeutics, vol. 302, no. 2, August 2002, pp. 731-741.
 J.-H. Han, S. A. Kushner, A. P. Yiu, C. J. Cole, A. Matynia, R. A. Brown, R. L. Neve, J. F. Guzowski, A. J. Silva and S. A. Josselyn, “Neuronal competition and selection during memory formation,” Science, vol. 316, no. 5823, 20 April 2007, pp. 457-460.
 M. Xia, R. Huang, V. Guo, N. Southall, M.-H. Cho, J. Inglese, C. P. Austin and M. Nirenberg, “Identification of compounds that potentiate CREB signaling as possible enhancers of long-term potentiation,” Proceedings of National Academy of Science USA, vol. 106, no. 7, 17 February 2009, pp. 2412-2417.
 V. Micale, G. M. Leggio, C. Mazzola and F. Drago, “Cognitive effects of SL65.0155, a serotonin 5-HT4 receptor partial agonist , in animal models of amnesia,” Brain Research, vol. 1121, no. 1, 22 November 2006, pp. 207-215.
 C. Hille, S. Bate, J. Davis and M. I. Gonzalez, “5-HT4 receptor agonism in the five-choice serial reaction time task,” Behavioural Brain Research, vol. 195, no. 1, 16 December 2008, pp. 180-186.
 M. Matsumoto, H. Togashi, K. Mori, K.-I. Ueno, S. Ohashi, T. Kojima and M. Yoshioka, “Evidence for involvement of central 5-HT4 receptors in cholinergic function associated with cognitive processes: behavioral, electrophysiological, and neurochemical studies,” Journal of Pharmacology and Experimental Therapeutics, vol. 296, no. 3, March 2001, pp. 676-682.
 E. G. Mohler, S. Shacham, S. Noiman, F. Lezoualc’h, S. Robert, M. Gastineau, J. Rutkowski, Y. Marantz, A. Dumuis, J. Bockaert, P. E. Gold and M. E. Ragozzino, “VRX-03011, a novel 5-HT4 agonist, enhances memory and hippocampal acetylcholine efflux,” Neuropharmacology, vol 53, no. 4, September 2007, pp. 563-573.
 F. Shen, J. A. M. Smith, R. Chang, D. L. Bourdet, P. R. Tsuruda, G. P. Obedencio and D. T. Beattie, “5-HT4 receptor agonist mediated enhancement of cognitive function in vivo and amyloid precursor protein processing in vitro: A pharmacodynamic and pharmacokinetic assessment,” Neuropharmacology doi:10.1016/j.neuropharm.2011.02.026
 A. Kulla and D. Manahan-Vaughan, “Modulation by serotonin 5-HT4 receptors of long-term potentiation and depotentiation in the dentate gyrus of freely moving rats,” Cerebral Cortex, vol. 12, no.2, February 2002, pp. 150-162.
 S. A. Small and K. Duff, “Linking A? and Tau in late-onset Alzheimer’s disease: a dual pathway hypothesis,” Neuron, vol. 60, no. 4, 26 November 2008, pp. 534-542.
 E. R. L. C. Vardy , A. J. Catto and N. M. Hooper, “Proteolytic mechanisms in amyloid-? metabolism: therapeutic implications for Alzheimer’s disease,” Trends in Molecular Medicine, vol. 11, no. 10, October 2005, pp. 464-472.
 J. Nunan and D. H. Small, “Regulation of APP cleavage by ?-, ?- and ?-secretases,” FEBS Letters, vol. 483, no. 1, 13 October 2000, pp. 6-10.
 W.-L. Wu and L. Zhang, “?-Secretase inhibitors for the treatment of Alzheimer’s Disease,” Drug Development Research, vol. 70, no. 2, March 2009 pp. 94-100.
 S. J. Stachel, “Progress toward the development of a viable BACE-1 inhibitor,” Drug Development Research, vol 70, no. 2, March 2009 pp. 101-110.
 M. L. Hemming, J. E. Elias, S. P. Gygi and D. J. Selkoe, “Proteomic profiling of ?-secretase substrates and mapping of substrate requirements,” PLoS Biology, vol. 6, no. 10, October 2008, pp. 2314-2328.
 S. J. Robert, J. L. Zugaza, R. Fischmeister, A. M. Gardiers and F. Lezoualc’h, “The human serotonin 5-HT4 receptor regulates secretion of non-amyloidogenic precursor protein, Journal of Biological Chemistry, vol. 276, no. 48, 30 November 2001, pp. 44881-44888.
 M. Cachard-Chastel, F. Lezoualc’h, I. Dewachter, C. Delomenie, S. Croes, S. Devijver, M. Langlois, F. V. Leuven, S. Sicsic and A. M. Gardier, “5-HT4 receptor agonists increase sAPP? levels in the cortex and hippocampus of male C57BL/6j mice,” British Journal of Pharmacology, vol. 150, no. 7, April 2007, pp. 883-892.
 S. Cho and Y. Hu, “Activation of 5-HT4 receptors inhibits secretion of ?-amyloid peptides and increases neuronal survival, Experimental Neurology, vol. 203, no. 1, January 2007, pp. 274-278.
 S. Robert, M. Maillet, E. Morel, J.-M. Launay, R. Fischmeister, L. Mercken and F. Lezoualc’h, “Regulation of the amyloid precursor protein ectodomain shedding by the 5-HT4 receptor and epac,” FEBS Letters, vol. 579, no. 5, 14 February 2005, pp. 1136-1142.
 R. M. Eglen, D. W. Bonhaus, L. G. Johnson, E. Leung and R. D. Clark, “Pharmacological characterization of two novel and potent 5-HT4 receptor agonists, RS 67333 and RS 67506, in vitro and in vivo,” British Journal of Pharmacology, vol. 115, no. , 1995, pp. 1387-1392.
 M.-T. Liu, Y.-H. Kuan, J. Wang, R. Hen and M.D. Gershon, “5-HT4 receptor mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice,” Journal of Neuroscience, vol. 29, no. 31, 5 August 2009, pp. 9683-9699.
 G. Lucas, V. V. Rymar, J. Du, O. Mnie-Filali, C. Bisgaard, S. Manta, L. Lambas-Senas, O. Wiborg, N. Haddjeri, G. Pineyro, A. F. Sadikot and G. Debonnel, “Serotonin4 (5-HT4) receptor agonists are putative antidepressants with a rapid onset of action,” Neuron, vol. 55, no. 5, 6 September 2007; 55: 712-725.