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.
Highlights
5-HT4 receptor is a G protein coupled receptor (GPCR) which belongs to serotonin receptor family and is coupled to G protein containing G s subunit [1]
Therapies in clinical development may either offer symptomatic relief to patients or provide pure disease modifications, limiting benefit to patients. 5-HT4 receptor agonists offer an attractive option for the treatment of Alzheimer’s disease (AD) patients
A cascade of signaling events result in the phosphorylation of cyclic AMP (cAMP) response element binding protein (CREB) which binds to its response element leading to the expression of a number of genes involved in cell survival
Summary
5-HT4 receptor is a G protein coupled receptor (GPCR) which belongs to serotonin receptor family and is coupled to G protein containing G s subunit [1]. The receptor, upon activation by an agonist, leads to the generation of intracellular cyclic AMP (cAMP) which in turn activates Protein kinase A. A cascade of signaling events result in the phosphorylation of cAMP response element binding protein (CREB) which binds to its response element leading to the expression of a number of genes involved in cell survival. Many excellent review articles were published recently highlighting the role of 5-HT4 receptor agonists for treatment of gastro-intestinal (GI) spectrum of diseases [2,3,4]. We focus on the role of 5-HT4 receptor agonists in the treatment of AD with current understanding of their role in cognitive improvement, disease modification and neurogenesis. We further list enormous challenges that need to be overcome to realize the potential of the target and offer possible future directions that may help in overcoming some of the challenges
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