Alzheimers disease is a progressive neurological disorder affecting formation of new memory as well as retrieval of previously acquired memories. Around 37 million of the current global population has been estimated to be suffering from this disease. The problem with the current therapies is that they provide symptomatic relief only in half of the population suffering form the disease. The 5-hT4 receptor agonist offers an attractive option for the treatment of AD patients. Under the pre-clinical conditions, activation of 5-hT4 receptor was observed to increase the release of acetylcholine and improve the neurotransmission 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.
CAUSES OF Alzheimer's disease:
1. Cholinergic hypothesis:
This hypothesis proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine.. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid, leading to generalised neuroinflammation.
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2. Amyloid hypothesis:
This hypothesis postulated that amyloid beta (Aβ) deposits are the fundamental cause of the disease. The presence of the gene for the amyloid beta precursor protein (APP) on chromosome 21, alon with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost exhibit AD by 40 years of age. Also APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain..
3. Tau hypothesis:
In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.
4. Herpes simplex virus type 1 has also been proposed to play a causative role in people carrying the susceptible versions of the apoE gene.
5. Another theory also states the age-related myelin breakdown releases iron, wic causes further damage. . Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as amyloid-beta and tau.
6. Oxidative stress and dyshomeostasis of biometal (biology) metabolism may be significant in the formation of the pathology.
AD is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. Due to this, atrophy of the affected regions, which include degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. Advanced studies like MRI and PET of AD patients when compared with healthy older adults, showed reductions in the size of specific brain regions.
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD. Plaques are dense, mostly insoluble deposits of amyloid-beta peptide and cellular material outside and around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of aging, the brains of people with AD have a greater number of them in specific brain regions such as the temporal lobe. Lewy bodies are not rare in the brains of people with AD.
Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 39-43 amino acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival and post-injury repair. In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques
CHARACTERISTICS OF ALZHEIMER'S DISEASE
The disease course is divided into four stages, with progressive patterns of cognitive and functional impairments.
The most noticeable characteristic is memory loss, which tells us difficulty in remembering learned facts which are recent and inability to acquire new knowledge. Some problems also arise with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships) can also be symptomatic of the early stages of AD. Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease. The preclinical stage of the disease has also been termed mild cognitive impairment, but whether this term corresponds to a different diagnostic stage or identifies the first step of AD is a matter of dispute.
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The following impairments are observed which gradually increase with the progression of the disease- executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems. AD does not affect all memory capacities equally. Older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat) are affected to a lesser degree than new facts or memories. While performing fine motor tasks such as writing, drawing or dressing, certain movement coordination and planning difficulties (apraxia) may be present but they are commonly unnoticed. 
Progressive deterioration eventually hinders independence; with subjects being unable to perform most common activities of daily living. Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated as time passes and AD progresses, so the risk of falling increases. During this phase, memory problems worsen, and the person may fail to recognise close relatives. Long-term memory, which was previously intact, becomes impaired.
Behavioural and neuropsychiatric changes become more prevalent. Common manifestations are wandering, irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. Sundowning can also appear. Approximately 30% of people with AD develop illusionary misidentifications and other delusional symptoms. Subjects also lose insight of their disease process and limitations (anosognosia). Urinary incontinence can develop. These symptoms create stress for relatives and caretakers, which can be reduced by moving the person from home care to other long-term care facilities.
During this last stage of AD, the person is completely dependent upon caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common results. People with AD will ultimately not be able to perform even the simplest tasks without assistance. Muscle mass and mobility deteriorate to the point where they are bedridden, and they lose the ability to feed themselves. AD is a terminal illness, with the cause of death typically being an external factor, such as infection of pressure ulcers or pneumonia, not the disease itself.
1. Cholinesterase inhibitors (Aricept, Cognex, Exelon, Razadyne). Cholinesterase inhibitors curb the breakdown of acetylcholine, a chemical in the brain important for memory and learning. These types of medications help increase the levels of acetylcholine in the brain. These drugs may slow the progression of symptoms for about half of people taking them for a limited time, on average 6 to 12 months.
Aricept is the only treatment approved by the FDA for all stages of Alzheimer's disease: mild, moderate, and severe. It is available as tablets to swallow or tablets to dissolve in the mouth. Cognex was the first of these drugs to be FDA approved, but it is used less commonly than the other medications. Exelon is approved for use in mild to moderate Alzheimer's dementia and is available as a skin patch, capsules, and liquid form. Razadyne (formerly Reminyl) is also approved for mild to moderate Alzheimer's dementia and is available as an extended-release capsule, immediate-release tablet, and liquid forms. Common side effects are usually mild for these medications and include diarrhea, vomiting, nausea, fatigue, insomnia, loss of appetite, and weight loss. Cognex use may cause liver damage, so your doctor will need to perform tests to monitor liver function.
2. Namenda. Namenda is approved to treat moderate-to-severe Alzheimer's disease. Namenda works by a different mechanism than other Alzheimer's treatments; it is thought to play a protective role in the brain by regulating the activity of a different brain chemical called glutamate. Glutamate also plays a role in learning and memory. Brain cells in people with Alzheimer's disease release too much glutamate. Namenda helps regulate glutamate activity. Namenda is the only drug for Alzheimer's that works this way. It may improve mental function and performance of daily activities for some people. Namenda may have increased benefit when used with Aricept, Exelon, Razadyne, or Cognex. Side effects of Namenda include tiredness, dizziness, confusion, constipation, and headache.
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Donazepil marketed under the brand name of Aricept is a centrally acting Acetylcholine esterase inhibitor. Rivastigmine sold under the brand name of Exelon and Razadyne act in the same way as that of donazepil.
Memantamine and Namenda act on the glutametargic system by blocking the NMDA receptor.
The ideal treatment of Alzheimer's disease includes:
1. Normalization of memory
2. Reestablishment of synaptic work
3. Removal of amyloidal deposits in the brain
4. Inhibition of neuronal death
The following are the tools under investigation for improving AD affected targets:
1. Antibodies against A-beta
2. Antibodies against tau
3. Inhibitors of A-beta generating enzymes
4. Anti-inflammatory biological
NEW TARGETS FOR TREATNENT OF ALZHEIMERS DISEASE
New Targets improving neuro-protection and synaptic plasticity
Neuronal cell adhesion molecules (CAMs)
Receptor tyrosine kinases
The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors (GPCRs) and ligand-gated ion channels (LGICs) found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.
The serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine / norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P, among others. The serotonin receptors influence various biological and neurological processes such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. The serotonin receptors are the target of a variety of pharmaceutical and illicit drugs, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic agents, antimigraine agents, hallucinogens, and entactogens.
A brief explanation about the different kinds of Serotonin receptors:
Decreasing cellular levels of cAMP
Increasing cellular levels of IP3 and DAG.
Ligand-gated Na+ and K+ cation channel
Depolarizing plasma membrane
Increasing cellular levels of cAMP
Decreasing cellular levels of cAMP
Increasing cellular levels of cAMP
Increasing cellular levels of cAMP
ROLE OF 5HT-4 RECEPTORS IN ALZHEIMER'S DISEASE:
5-HT4 receptor is a G protein coupled receptor (GPCR) which belongs to serotonin receptor family and is coupled to G protein containing Gαs sub-unit. 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 signalling 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.
A larger number of 5-HT4 receptor splice variants were identified both in human and rodents with no significant splice specific tissue expression . All the identified human splice variants exhibited identical amino acid sequence up to Leucine 358 with differences emerging in the short carboxyl terminal tail . Such an observation lead to the conclusion that ligand binding properties of various receptor isoforms may not differ, as entire extracellular and transmembrane domain remained conserved across various receptor subtypes.
Positive impact of cAMP in acquisition and consolidation of memory is well accepted. Activation of CREB protein by cAMP dependent protein kinase is an important mediator of memory formation . A number of signalling pathways leading to cAMP accumulation in neurons are being explored as possible candidates for therapeutic interventions of cognitive deficits associated with various neurological disorders.
5-HT4 receptor is expressed at high level in limbic system of CNS. The receptor is coupled to G protein containing Gαs subunit. Thus, activation of the receptor by an agonist leads to cAMP formation which through CREB phosphorylation is proposed to help in new memory formation. CREB mediated memory formation is likely mediated through the expression of brain derived neurotrophic factor (BDNF) and other trophic and procognitive factors. In addition, activation of the 5-HT4 receptor is proposed to facilitate the release of various neurotransmitters by blocking potassium channels and subsequent mobilization of calcium ions. .
In order to better understand the mode of action of 5-HT4 receptor agonists leading to memory formation, specific and targeted studies were conducted using various neurochemistry and electrophysiology based approaches. Role of 5-HT4 receptor in synaptic plasticity was demonstrated in freely moving rats with implanted microelectrodes. Activation of the receptor by specific agonist led to neurotransmission in hippocampus.. As mentioned earlier, activation of 5-HT4 receptor leads to the release of various neurotransmitters mediated through calcium influx, as a result of blockade of potassium channels. A 5-HT4 receptor agonist, methoxytryptamine was reported to increase the level of acetylcholine in prefrontal cortex of rats.. One of the mechanistic roles of extracellular acetylcholine is to enhance cholinergic neurotransmission which plays central role in memory formation. Thus, 5-HT4 receptors may improve memory formation by enhancing the synaptic release of acetylcholine in the brain which would in turn enhance the cholinergic transmission.
A major proposed advantage of using 5-HT4 receptor agonist for the treatment of AD patients is its ability to shift the equilibrium of amyloid precursor protein (APP) processing from amyloidogenic to non-amyloidogenic form . Aβ peptide either in soluble oligomer or aggregated multimer format in the brain is a major contributing factor of AD pathology . The peptide is generated by the action of beta and gamma secretases which either produce 42 or 40 amino acid peptides. Both these peptides are amyloidogenic and implicated in the progression of the disease with 42 amino acid peptide having higher potential to aggregate. Another enzyme reported to cleave APP within the amyloidogenic peptide sequence is less known alpha secretase. Activation of the alpha secretase pathway is shown to shift the balance of APP cleavage from amyloidogenic to non- amyloidogenic form. The first product of alpha secretase pathway is soluble APP alpha (sAPPα) protein. sAPPα acts as a neurotrophic factor and helps in neuronal survival. The protein gets further cleaved by other proteases and eliminated.
Major efforts to develop disease modifying drugs for AD treatment focused on identifying potent and selective inhibitors of beta or gamma secretases . The blockade of these enzymes would not only prevent generation of amyloidogenic form of the peptide but may also shift the equilibrium of APP processing towards alpha secretase pathway. Highly involved effort for the identification of potent and selective beta secretase inhibitors was hampered due to large and complex substrate binding pocket of the enzyme . In addition, compounds which demonstrated acceptable in vitro properties exhibited poor pharmacokinetic and brain penetration profile. Development of gamma-secretase inhibitor was more successful with molecules reaching up to phase III of clinical development. As gamma secretase was reported to cleave other critical signaling proteins, development of compounds which block the APP processing activity without affecting the critically required enzyme action on other substrates had offered initial challenge which was overcome with smart chemistry efforts.
One of the most remarkable features of 5-HT4 receptor agonists is their ability to induce neurogenesis in hippo-campus as well as enteric system in rodents. This feature of 5-HT4 receptor agonists truly offers disease modifying potential, as the compounds may be able to replace the degenerated cells by inducing production of new neurons. A number of 5-HT4 receptor agonists are reported to induce the survival of enteric neurons and induce the neurite outgrowth under culture conditions which can be blocked by 5-HT4 receptor specific antagonist. In the same study, incorporation of bromo-de-oxyuridine was reported in vivo in enteric cells expressing neuronal markers upon treatment with 5-HT4 receptor agonists. Mouse model with targeted disruption of 5-HT4 gene was explored to investigate any role of the receptor in neurogenesis. While the number of neurons in the enteric system were comparable between wild type and gene knockout mice at birth, the number of neurons declined over a period of time in the mutant mice . Above observations strongly support the role of 5-HT4 receptor and its agonists in neurogenesis in brain and peripheral tissues.
Figure . A cartoon representation of 5-HT4 receptor activation leading to various cellular events. Activation of 5- -HT4 receptor leads to acetylcholine release, which coupled with the release of BDNF, may help in memory formation. The activation of the receptor is also reported to enhance the release of sAPPα, which along with BDNF-induced neurogenesis offers disease modifying potential for AD patients.
ADVANTAGES OF 5-HT4 RECEPTORS OVER OTHER DRUGS FOR TREATMENT OF ALZHEIMER'S DISEASE:
The ability of 5-HT4 receptor agonists to increase acetylcholine (ACh) release and reduce cognitive impairment in both animals and humans has been demonstrated. In addition, 5-HT4 receptor agonist modulation of levels of the amyloid precursor protein (APP) derived peptides, soluble amyloid precursor protein (sAPPα) and amyloid beta protein (Aβ) in the CNS has been reported.
Due to increased efficacy and reduced potency and side effects of the 5-HT4 receptors and the selectivity of drugs for the receptors make them a potential target for cognition enhancement.
Pharmacokinetic data indicated that the CNS penetration for all three 5-HT(4) receptor agonists was relatively low..