End Cannabinoids and Their Effect on Alzheimer’s disease

Alzheimer’s is a type and the most common kind of dementia. The progressive form of brain disorder is irreversible and destroys critical functions such as the thinking skills and gradually tends to destroy an individual’s ability to execute simple and normal tasks. The symptoms of Alzheimer’s commonly appear in individuals who are in the mdi 60s of age. The estimates of the prevalence of this disease vary with various places. However, the prevalence in America is estimated to be more than five million. Currently, Alzheimer’s is ranked sixth in the US as the leading cause of death. The most recent estimates have also indicated that the disease might have moved a notch higher to rank third in the killer diseases lead by heart disease and cancer more so for the older people. Alzheimer’s causes dementia mostly in older people. It results in the loss of cognitive functioning commonly referred to as thinking, reasoning and remembering. It also affects the patient’s behavioral abilities to the extreme extent of interfering with their daily lives and activities. Dementia as caused by Alzheimer’s varies in its severity right from its mild stage as it starts to affect the victim’s functioning up to the highest stage of severity whereby the victim has to solely depend on another individual to execute the basic activities of their lives (Passmore, 2008). Although an increasing age is the greatest risk of Alzheimer’s, it has not been found to be a normal part of an individual’s ageing. 

The disease was named after Dr. Alois Alzheimer. The Dr. in the year 1906, noticed that there changes in a woman’s brain tissue whose death was caused by some unusual mental illness. The symptoms exhibited by the illness included an unpredictable behavior, language problems and loss of memory. Dr. Alzheimer examined the woman’s brain after she had died and noticed there were some abnormal clumps which are in modern technology referred to as amyloid plaques. He also noticed several tangled bundlers of fiber that are currently referred to as neurofibrillary. 

Effects and Diagnosis

Alzheimer’s affects an individual in almost all aspects of their lives. This is based on the fact that they are rendered unable to carry out the normal activities. The loss of memory and inability to reason negatively affects their social connections as well as the ability to do any kind of work either to earn or for individual purposes. For the diagnosis of Alzheimer’s, doctors use a series of tools and methods that help them to determine whether an individual with memory issues may possibly have Alzheimer’s dementia (Passmore , 2008). This is because Alzheimer is not the only cause of dementia but the most common especially in older people. Dementia may however have been caused by another cause or factor. There are various activities that a doctor may implement in diagnosing Alzheimer’s. They may ask an individual, their family member or friends some relevant questions regarding their overall health which include their medical history and the ability to perform daily activities. Questions are also asked regarding behavior and personality to identify any suggestive changes that may relate to Alzheimer’s. The doctors also conduct tests involving memory effectiveness, language, attention and problem solving skills in the individuals. The tests are carried out alongside other standard medical tests which involve urine and blood tests that are aimed at identifying the other possible causes of the problem they exhibit. Advanced tests include the scanning of the brain such as the MRI (magnetic resonance imaging), positron emission tomography (PET) and CT (computed tomography) (Lyketsos , 2011) as an extensive way of ruling out the availability of other causes for the disease’ symptoms (Reisberg, Doody, Stöffler, Schmitt, Ferris, Möbius, 2003). To effective monitor the development or changes of the individual’s memory and the relevant cognitive functions in them.

Prevention and cure of Alzheimer’s

While there has not yet been concluded and verified preventive measure of the disease, suggestions have been given of how individuals can minimize the risk factors and decrease the chances of the disease. There are various factors that are associated with the prevention of the factors that are said to facilitate the development of the disease which involve mitigating the possibility of the occurrence of the risk factors. The factors help in reducing the risk of the dangerous cognitive decline thus reducing the risk of the disease (Passmore, 2008). As a result, individuals have continuously been advised to lead healthy lifestyles which include eating healthy, engaging in physical activities, maintaining healthy wait and not smoking. It is believed that making healthy choices helps to minimize the possibilities of getting various chronic diseases such as heart diseases and heart attack thus leading to the assumption that healthy living would have the same effect on Alzheimer’s. Alzheimer’s is yet to have a known cure. Research has only intensified the hopes that with time, there may be some mechanisms that will enable the slowing down or preventing the devastating disease, Alzheimer’s. 

Endocannabinoid system has gradually merged as an effective drug target for various immune-mediated of the central nervous system illnesses. There has been rapidly growing evidence that suggests endocannabinoid intervention would have particular relevance to the disease. This study presents a review of the physiology of endocannabinoid and examines the evidence that proves it as a potential target Alzheimer’s disease (Passmore, 2008). To begin with, endocannabinoid (eCB) system has various lipid signaling molecules binding to a minimum of two of the G-protein-couples receptors (GPCRs) while it also impacts both the cognition and immunity. Alzheimer’s disease (AD) as a neurodegenerative cognitive disorder has an inflammatory component as well as agents that influence immunity. The GPCR also have a history of ‘drugable’ as well as the capability to manipulate endocannabinoid tone while acting directly at the receptors that are demonstrated with various agents both in animal models and cell culture. They suggest that the potential effectiveness of a novel drug in the disease (Pardon et al, 2009). The recent experiments that have been carried out have suggested that there is a crucial role played by eCB system in the AD pathophysiology therefore motivating treatment based on the potential for cannabinoid interventions.

The Aspects of the molecular mechanisms (endocannabinoid)

An active compound in marijuana referred to as tetrahydrocannabinol (THC) was found to have a positive effect in promoting the removal of the toxic clumps of the amyloid beta protein found in the brain. The clumps are thought and said to kick start or facilitate the initial development of Alzheimer’s disease (AD). Studies carried out in previous researches revealed that there was evidence of the said protective effects of cannabinoids such as THC particularly on patients who had neurodegenerative diseases. Several other studies have also revealed the evidence that cannabinoids may tend to be neuroprotective against the known symptoms of the disease. A study was collected to test the available effects to THC on the human neurons that were grown in a lab and that mimic the same effects of AD. THC is a special little compound ad is responsible for a majority of the psychological effects of marijuana which includes the high aspect (Pardon et al, 2009). It is equally said to have effective natural pain relieving elements and has been termed as an efficient treatment for the symptoms of almost all diseases including chronic pains, chemotherapy, stroke and post- traumatic stress disorders. 

THC has been depicted as such an amazing agent medically whereby researchers have worked hard and are still working hard on the breeding of a genetically modified yeast that will produce it in an even more efficient manner than it does to generate synthetic versions. This compound works by travelling through an individual’s lungs to their bloodstream after which it attaches to the two types of receptors referred to as the cannabinoid receptor 1 (CB1) and also the cannabinoid receptor 2 (CB2) that are located on the cell surface of the body (Jeremy, 2016). While in the brain, the two receptors are significantly concentrated in the neurons that are associates with memory, thinking coordination, pleasure, time reception while it also binds with another class of lipid molecules known as endocannabinoids which the body produces during regular physical activities that tend to promote the cell-to –cell signaling in the human brain.

The compound THC is also in a position to bind them the same way the receptors do. The moment they do, they then immediately start to mess with an individual’s ability of the brain to communicate with the brain itself. This is both good and dangerous since while an individual might tend to forget something critical or suddenly become incapable to swing a baseball bat that have been swinging all along, they may feel amazing and have the desire and appetite to consume all the snacks available. Through research, studies have suggested that by binding to the receptors, THC may be having other significant effects on ageing brains based on the fact that it seems to help an individual’s body to clear out toxic accumulations such referred to as plaques of the amyloid beta. It has not been entirely confirmed what the cause of Alzheimer’s disease is although it is thought to generate from the build-up of two lesions namely amyloid plaques as well as neurofibrillary tangles.

Amyloid plaques often position themselves between the neurons in form of dense clusters of beta amyloid molecules which is a viscous kind of protein and tens to easily clump together. The neurofibrillary tangles on the other hand are caused by the tau proteins, defective and which again form some thick and insoluble mass of the body neurons. It has not yet been made clear why the lesions begin to appear in the brain although several studies have sought to link inflammation of the brain tissues to that proliferation of the neurofibrillary tangles and. Consequently, finding something that eases the brain and also encourage one’s body to clear the lesions at the same time would be the first critical step towards finding the first successful and effective treatment on land. THC is also found to inhibit the systematic formation of the amyloid plaques by way of blocking that enzyme in the human brain that tends to produce them. Further studies have proven that THC is also capable of eliminating the dangerous inflammatory response that is derived from the nerve cells thus ensuring their continued survival. 

Inflammation occurring in the brain is one key ingredient of the damage associated with the killer disease AD. However, it has often been depicted the response comes from the immune-like cells found in human brain and not actually the claimed nerve cells. After the identification of the process of molecular basis of the inflammatory response to the amyloid beta, it was discovered that compounds that resembled THC made by the nerve cells themselves can be involved in preventing the same cells from dying. With experiments carried out with mice that were infected with Alzhemer’s, it was found out that a drug candidate developed by a certain lab called J147 could also effectively remove that amyloid beta from nerve cells and also reduce inflammatory response in the brain and also from the nerve cells. Additionally, J147 also improved memory while preventing brain damage that could have been caused by the disease (Jeremy, 2016). It was the research with J147 that resulted in the discovery that endocannabinoids was also capable of removing amyloid beta and at the same time reduce the unnecessary inflammation.

Endocannabinoids belong to a family of the lipid messengers engaging cell surface receptors which are the targets of the compound tetrahydrocannabino (THC) which is the active principle in cannabis, popularly known as marijuana. These are normally generated on demand following a cleavage by the membrane precursors already in a variety of the short ranged signaling process. It is in the human brain where they unite with CB1, the cannabinoid receptors and axon terminals so as to control the channel activity ion and the neurotransmitter release (Pardon et al, 2009). The ability of the endocannbinoids to modulate their synaptic effectiveness is related with a broad range of functional consequences which also provides a series of unique therapeutic possibilities.

The dedicated cannabinoid receptor CB1 discovery was much of a surprise to the research community considering that the only recognizable ligand for this receptor when its discovery was made was an active component of marijuana. The discovery together with the surprise resulted in deeper investigations in an attempt to identify endogenous ligands which is the second cannabinoid receptor CB2. The investigations also involved the eCB metabolizing and synthesizing enzymes as well as a reuptake means of transport (Aso and Ferrer, 2014). Following these investigations, endogenous cannabinoids were found to be signaling biolipids that included N- arachidonoylethanolamide (AEA) and the 2-arachidonoylglycerol (2-AG) which was the most studied. 

Cannabinoids and Memory

Human beings and marijuana have a rich history together that dates back thousand years ago when it was first discovered and out to use by the Chinese and Indian civilizations for various purposes such as industrial, medicinal and religious purposes. In the modern world, the use of this plant has yielded controversy based on its ingredients and effects. Its common active ingredient whose effect is under debate being the tetrahydrocannabinol (THC) and the effect it would have on the human body. There were later discoveries made about receptors in both humans and animals that found out they bind THC and other cannabinoids, some of which were endogenous. This has led to the interesting new knowledge regarding the physiology of animal systems.

The receptors along other endogenous agonists have been found in various types of animal species that range from leeches, mollusks and mammals including the human beings. These agonists and receptors have also been found to be similar across the various species. Receptors are abundant in human brain and are particularly in plenty in the hippocampus which is the region of the human brain that is responsible for various types of learning and memory. This confirms the popularly known side effect of ingesting or smoking marijuana has been the disruption of both the short term and the working memory. The two types of memories are mediated by the hippocampus. The recent research on cannabinoids has proven that endocannabinoid system in the neurons is an integral component found in the operation and the regulation of the learning memory. The understanding of the role of the receptors alongside their agonists in the neural signaling may tend to uncover a variety of the secrets regarding how animals get to learn. Researchers found out that the human body has an endocannabinoid system and that THC effects are most likely caused by the disruption of the naturally occurring system (Aso and Ferrer, 2014) following the realization, the receptors were then found in both the vertebrate and invertebrate species. The CB1 and Cb2 receptors were also found to demonstrate significant differences in their affinity for ligands, structure as well as their distribution in the human body. The receptor CB1 will commonly be found in the PNS/CNS and may also be found along the CB2 in the body organs such as in the sperms, immune system cells, heart, liver and spleen. The study also revealed that cannabinoids can affect several systems in the human body although they are particularly more prevalent around the nervous system.

There are various properly replicated experiments that have been carried out on the impact of THC on memory and learning to facilitate a clear understanding of cannabinoids in the processes. These studies most of them in humans have indicated that THC impairs an individual’s short term memory as well as their working memory which occur in the hippocampus. More evident also proved that the compound THC impairs the spatial working memory in animals such as mice while performing some maze tasks (Koppel and Davies, 2008). In all the studies that have been conducted from time to time, it has been found out that the exogenous cannabinoids disrupt both learning and memory.

Therapeutics Associated With Signaling Mechanism of Alzheimer’s

Currently, it is only the symptomatic therapies for the disease that are available. This means that they do not necessarily capable of acting on the evolution of this disease. The drugs that have been approved by FDA (US Food and Drug Administration) for Alezheimer’s treatment and modulate neurotransmitters which are either the glutamate or acetylcholine. The standard medical treatment that is approved for AD includes the partial N-methyl-D-aspartate (NMDA) antagonist and cholinesterase inhibitors. The limited effectiveness of the available therapies against the disease has yielded the intensive need for efforts that are devoted to the development of new agents that will help to prevent and retard the disease process. A variety of therapeutic interventions have previously been applied including the targeting of the endogenous cannabionoid systems as one potential therapeutic approach to the treatment of Alzheimer ’s disease (AD). Interventions applied in the care, treatment as well as the support for people suffering from the disease can either be pharmacological where drugs are used or non-pharmacological where no drugs are used. 

The non-pharmacological intervention involves both behavioral and environmental modification. This involves therapies such as the cognitive stimulation therapy (CST) that is normally used to support the people with mild AD. During the therapy, an individual is usually invited to participate in set therapeutic sessions with trained practitioners who are skilled and who specialize in such care. Each of the sessions comprise of various themed activities that are designed to engage the patients and stimulate them. The therapy is underpinned by critical and key principles of the individual’s respect, inclusion, involvement and use of reminiscence (Aso and Ferrer, 2014). Physical exercises are also part of the non-pharmacological therapy whereby an individual especially those who do not have cognitive impairments benefits from the physical engagements.

Clinical Trials for Future Drugs

Over the last 3 decades, medical researchers have made impressive progress in their attempt to understand the healthy brain functions and what happens with the AD disease. Targets have also been made for the coming generation drug therapies that are currently under investigations. They include;

Beta-Amyloid

This is said to be the key component of plaques which is a hallmark for Alzheimer’s brain abnormality. Medical professionals and scientists have had a detailed understanding of the protein fragment and how it is normally clipped from the parent compound known as the Amyloid Precursor Protein (APP) by the two enzymes gamma-secretase and beta-secretase forming the beta-amyloid protein found in the abnormally high levels in brains of people with AD. The researchers are hence trying to develop medications that are aimed at handling almost every point of in the amyloid processing. It involves the blocking activity of the beta-secreatse enzyme thus preventing beta-amyloid fragments from managing to clump into plaques. They have gone ahead and used antibodies against the beta-amyloid so as to clear them from the brain (Aso and Ferrer, 2014). Other efforts being made by researchers include drugs that target the tau protein, Inflammation, beta secrate and receptors.

Molecular components, cellular systems and preclinical rodents for endocannabinoids

AEA and the 2-AG tend to be synthesized from the lipid precursors that are normally derived from some enzymatic cleavage of the cell membrane component that is found in the neurons and also in the immune competent cells. In their response to neural membrane depolarization and the immune cell activation, they then get released whereby they act the receptors CB1 and CB2. AEA and 2-AG are degraded by intracellular enzymes of the fatty acid hydrolase (FAAH) as well as the monoacylblyerol respectively.Both receptors, CB1 and CB2 are GPCRs and consist of significant homology. The two receptors diverge in their specificity and function of cellular expression. Normally, the CB1 receptor gets expressed in the brain more so in the cerebral cortex, basal ganglia, hippocampus and cerebellum as well as in the peripheral neural tissue. This occurs both in the sensory nerve fibers and also in the autonomic nervous systems. The activation of presynaptic CB1 receptor then results in the attenuation of the calcium and also causes subsequent inhibition of the release of neurotransmitters (GABA, serotonin and glutamate). It also leads to the stimulation of various protein kinases and the opening of some potassium channels. Evidence has been found that cannabinoids are in a suitable position to inhibit activities of the nigrostriatal dopaminergic neurons which is probably meant to generate catalepsy at relatively high doses. CB1 receptor actively contributes in a majority of the cell maintenance functions besides participating to the particular role it does in the consolidation of memory.

The receptor CB2 has been expressed in various immune cells such as the B lymphocytes, macrophages, monocytes, natural killer cells, T cells and polymorphonuclear neutrophil. This fact has led to its strong reputation of being a peripheral receptor. At the same time, it has been densely expressed by the activation of microgalia located in the central nervous system (CNS). While it may not be true under the entire available conditions, there is a wealth of prove suggesting that the stimulation of immune cells with the cannabinoids has a general immunosuppressive effect. The simulation of these cultured microglial cells with the lipopolysaccharide as well as the anti-CD40 antibodies and tend to induce an increased expression of CB2 receptor. This suggests that there is a feedback inhibition function for the CB2 receptor (Lyketsos, 2011). Particularly, cannabinoids are found to have been demonstrating as suppressing a production of various pro-inflammatory cytokines in the human cell cultures as well as in the animal models as medicated by the CB2 receptors. The role of the receptor CB2 as the feedback-inhibitor of the immune responsiveness in CNS is analogous to its function at the periphery was also demonstrated in the culture for human fetal astrocytes whereby a cannabionoid was indicated to decrease the production of the tumor necrosis factor (TNF-a) as well as the several chemokines that follow the interleukin stimulation. The effect was however reversed by the CB2 antagonist. The impact of cannabionids on cytokines was equally confirmed in two separate studies whereby marijuana smoking was linked to the inhibition of cytokine production as well as the antimicrobial activity of the pulmonary alveolar macrophages.

In a cultured microglial cell, the CB2 receptor stimulation was shown to suppress TNF- and also the nitric oxide production. At the same time, in an activated microglia, an innate immune cell of a central nervous system that responds to the neuronal damage. CB2 receptors have also been localized to a leading edge of a lamellipodia. They have also been identified as having the ability to regulate other cells migration that is triggered by the active production of 2-AG. Essentially, the experiments carried out have provided that there is the evidence of 2-AG capacity to trigger and induce migration through the CB2 receptor and in a series of cell types among them dendritic cells, B cells as well as eiosinophils that establishes its functionality as the chemotactic agent Cannabioids that acts through the CB2 receptor stimulation equally have proliferative impacts on various cells among them microglia (Bisogno and Di Marzo, 2010). Compiled together, this illustrates that the eCBs functions in a rather complex manner instead of an anti-inflammatory or pro-inflammatory manner through directing and also attenuating the body’s immune response. 

The 2-AG and endogenous cannabinoids and amide have the affinity for the two receptors CB1 and CB2. Evidence has proven that there are low levels of a constitutive production of AEA more so in the CNS and also in the periphery. The evidence of a constitutive production is primarily identified in CNS. Generally, the production of eCBs is highly required as stimulated by the membrane depolarization in the neurons and immune cell activation. ECBs concentration is increased as a response to the traumatic or otherwise the pathogenic events that lead majority to the speculations of regulatory or other compensatory mechanisms in the production. Most important to the immune modulation which is the production of eCB is the stimulation by the activation of immune cells that include dendritic cells and macrophages while the stimulated immune cells on the other hand tend to have a reduced expression of eCB degrading enzymes. Ever since the discovery and the partial function of the receptor subtypes of the eCB system, there have been various agents that have been developed targeting the system that include both the receptor agonists and antagonists of various levels of the receptor specificity and the molecules that block the eCB reuptake and increase the local eCB tone via inhibition of their enzymatic degradation (Bisogno and Di Marzo, 2010). The molecules can then form the foundation for new drugs that are aimed at altering eCB physiology in diseases such as cognition and immunity diseases.

The eCB systems intervention has demonstrated some treatment potential in several rodent models of various neurological disorders available in the anti-inflammatory, anti-nociceptive and neuroprotective capacities. In an experiment, some mice were subjected to a closed head injury that developed some elevated concentrations of the 2A-G in the traumatized hemispheres where the administration of 2-AG to the mice after a close head injury was found to reduce infarct volume, brain edema as well as the hippocampal cell death as compared to the uninjured mice. This suggested an effective role of eCB in CNS. In another experimental autoimmune encephalomyelitis (EAE), an animal model for the multiple sclerosis (MS) and a basal of 1.3-2 fold increased in an anandamide and 1.4-1.8 fold increased in 2-AGwas also demonstrated in the CNS (Katz, Jeste, Mintzer, Clyde, Napolitano, Brecher and Rasmussen, 2000).The cannabinomimetic compounds have since been demonstrated as having the ability and capacity to reduce both tremor and spasticity in the mice used for the experiment.

Potential Impact of Endocannabinoids on the Alzheimer’s related Cognition

There are numerous negative effects of marijuana on memory and earning that have properly been established. The effects are perceived as secondary to the CB1 receptor stimulation. Both acute and chronic uses of marijuana are said to impair immediate recall, memory retrieval and short-term memory. The CB1is consistent with this and its localization has revealed that there are abundant expressions in basal ganglia, cerebellum, cerebral cortex and hippocampus. The memory impairment that that is induced by marijuana is similar to the one identified in Alzheimer’s disease, a disease of the hippocampal degeneration and stimulates investigations into the actual and real functions of the eCB physiology more so in the normative hippocampal functioning. In a human context the density of receptor expression tends to be the highest in the frontal and temporal lobes as well as asymmetric with intensified receptor on the side of the left hemisphere which suggests a relationship with both the memory system and language.

The psychoactive element components of marijuana has been found to have an impact on memory some that some have been found and confirmed in both the monkeys and rodents thus employing various out coming measures that include the radial maze and other instrumental cases on discriminatory tasks. The administration of low doses of THC has also been proven to impair spatial memories more so in the young healthy adults. The effects of the THC that acts at the CB1 receptor are clearly established but the significance of endogenous cannabinoids to memory and learning are not clear yet. 

The 2-AG and AEA have both been identified as brains natural ligands. Vitro experiments indicate that endogenous cannabinoids facilitates changes in the neural activities that are linked to memory an play an important role in the long term synaptic plasticity that suggests that eCBs demonstrate a potentially positive effect in cognition. In a vivo experiment, the mice might have been equivocal whereby reports of impaired and enhanced memory performance null mutant. In a human being, there is a triple repeat of the polymorphism gene of CB1 that is associated with hebephrenic (Bisogno and Di Marzo, 2010). This is a cognitive impaired phenotype of schizophrenia The CB1 receptors in hippocampus and neocortex have distinctly be expresses by the GABAergic interneurons while interacting with the eCBs that are produced in post-synaptic neurons which happens in a retrograde manner with the resultant suppression of inhibition that is depolarization-induced. 

Generally, the modulation of inhibition has effects on the long-term potentiation. Modulation of inhibitions in general has effects on long term potentiation, (LTP) at the excitatory synapses. The hippocampus on the other hand plays an integral role in the memory’s anatomy. The physiology argues for the eCB mediated cognition enhancement. Oxidative stress and inflammation hare acceptable as critical risk factors for the development of Alzheimer’s disease (AD). Interventions like cananbinoids that attenuate the risks short of arresting microglial activity and also have innate neuroprotective benefits that are attractive as effective potential preventative treatments of the disease, Alzheimer’s (Bisogno and Di Marzo, 2010). However, there are many crucial studies about reconciling the role played by eCB systems to have not yet been provided in literature.

References

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