5-HT4 Receptor Agonists for the Treatment of Alzheimer’s Dsease

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.