Dopaminergic Depletion In Brains With Neuropathology And Normal Cognition
Dopamine is a catecholamine neurotransmitter which plays several important roles in the brain acting via 4 distinct pathways, the mesolimbic, mesocortical, nigrostatial and tuberoinfundibular pathways. These pathways are responsible for regulating mood, and aiding cognitive and motor function. Impairment of this system potentially causes depression , memory loss and impaired motor control observed in patients with Alzheimers disease.
Dopamine does not cross the blood brain barrier and is synthesised in two steps from the essential amino acid tyrosine, with the initial conversion of tyrosine to L-DOPA catalysed by tyrosine hydroxylase with the subsequent conversion of L-DOPA to dopamine catalysed by aromatic amino acid decarboxylase . The greatest reduction in dopamine in the MFG was observed in the asymptomatic patients . In the MFG this pathway shows an increase in the abundance of tyrosine and L-DOPA, the precursors of dopamine, followed by a reduction in the abundance of dopamine, suggesting a decrease in the abundance or activity of both TH and AAAD.
In conclusion, our results suggest that abnormalities in dopamine neurotransmission is observed in brains with pathology but no memory problems. Combined therapeutic approaches, especially those affecting the GABAergic and serotonergic system might be useful as adjunctive treatments in AD.
When Theyve Done Their Job
Once a neurotransmitter has completed its task, it is no longer needed. There are three ways that communication with the neurotransmitter can be stopped.
The first is through a process called degradation. This process occurs when an enzyme comes in and changes the composition of the neurotransmitter. When this happens, the receptor no longer recognizes the neurotransmitter and therefore does not interact with it.
The second process is known as diffusion, when the neurotransmitter moves away from the receptor. The third is the reuptake process, which occurs when the neuron that released the neurotransmitter collects it and takes it back up its axon. ;
What Is Alzheimers Disease
Alzheimers disease is a slowly progressing and irreversible disease causing the degeneration of nerve cells in parts of the brain which are important for cognition and memory. It the most common cause of dementia, a general term for loss of memory and other mental abilities severe enough to interfere with daily life. Dementia is estimated to currently affect more than 48 million people worldwide.
Age is the largest risk factor for Alzheimers disease and to date, no available treatments are able to slow down or stop the progression of the disease. Due to increasing life expectancy, Alzheimers disease is viewed as one of the largest healthcare problems of this century, imposing a major economic burden on societies in the Western and developing world.
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Current Status Of Neurotransmitters And Alzheimers Disease
Neurotransmitters play a large role in maintaining synaptic and cognitive functions in mammals, including humans, by sending signals across synapses . Neurotransmitters are usually stored in synaptic vesicles, beneath the membrane in the axon terminal, and are released into the synapse with the appropriate signal from neurons. The released neurotransmitters establish connections through the synaptic cleft and bind to their appropriate receptors.
Neurotransmitters with a known role in AD pathogenesis include acetylcholine, which is synthesized from serine; dopamine, from L-phenyl alanine/L-tyrosine; GABA, from glutamate, a by-product of decarboxylation; serotonin, from L-tryptophan; histaminergic, from L-histidine; and N-methyl-D-aspartate , from D-aspartic acid and arginine. Neurotransmitters without a significant role in AD pathogenesis include glutamate, glycine, norepinephrine, epinephrine, melatonin, gastrin, oxytocin, vasopressin, cholecystokinin, neuropeptide Y, and enkephalins. However, these neurotransmitters may have a role in causing oxidative stress, which is known to be involved in AD pathogenesis.
Fig.1
Neurotransmitters in a healthy synapse and an Alzheimers disease synapse.
Is A Specific Neurotransmitter Altered In Alzheimer’s
Alzheimer disease is a neurodegenerative disorder characterized by memory loss and behavioral and psychological symptoms of dementia. An imbalance of different neurotransmitters glutamate, acetylcholine, dopamine, and serotonin has been proposed as the neurobiological basis of behavioral symptoms in AD.
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Alzheimers disease is a progressive disorder that causes brain cells to waste away and die. Alzheimers disease is the most common cause of dementia a continuous decline in thinking, behavioral and social skills that disrupts a persons ability to function independently.
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What Happens To The Brain In Alzheimer’s Disease
The healthy human brain contains tens of billions of neuronsspecialized cells that process and transmit information via electrical and chemical signals. They send messages between different parts of the brain, and from the brain to the muscles and organs of the body. Alzheimers disease disrupts this communication among neurons, resulting in loss of function and cell death.
Inverse Agonists Of Gabaa Receptor 5 Subunit
GABAA receptor is a pentamer containing various allosteric binding sites. It has been suggested that different subunits of GABAA receptor may exert relatively distinct function. For example, 1 subunit is mainly responsible for the sedative action of diazepam, 2 subunit mediates the anxiolytic-like action, whereas 5 subunit may be associated with cognition and memory . Its reported that 5 subunit deficiency enhanced hippocampus-dependent memory and spatial learning ability in mice . In addition, GABAA receptors containing 5 subunit was found upregulated in the dentate gyrus of 5× FAD mice, and has been suggested to mediate the tonic inhibition in CNS. A series of compounds have been developed, serving as inverse agonists of GABAA receptor 5 subunit, which bind to 5 subunit with much higher affinity than other subunits, but negatively regulate receptor activity.
In the early 2000s, the Merck Sharp and Dohme identified a series of benzothiophene derivatives with a notable binding selectivity for GABAA receptor 5 subunit. Among them the ligands MRK-016, 5IA and 5IA-II, all of which displayed encouraging effect on cognition in animal models. The compound 5IA has further advanced to preclinical and clinical studies .
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A Critical Assessment Of Research On Neurotransmitters In Alzheimers Disease
Article type: Introduction
Authors: Reddy, P. Hemachandraa; b; c; d; e; f; g; *
Affiliations: Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA | Garrison Institute on Aging, South West Campus, Texas Tech University Health Sciences Center, Lubbock, TX, USA | Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, USA | Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, USA | Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX, USA | Department of Speech, Language and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA | Department of Public Health, Graduate School of Biomedical Sciences, Lubbock, TX, USA
Correspondence: Correspondence to: P. Hemachandra Reddy, PhD, Executive Director and Chief Scientific Officer, Mildred and Shirley L. Garrison Chair in Aging, Professor of Cell Biology and Biochemistry, Departments of Neuroscience & Pharmacology and Neurology, Texas Tech University Health Sciences Center, 3601 Fourth Street / MS / 9424 / 4A 124, Lubbock, TX 79430, USA. E-mail: .
Keywords: Amyloid-, cognitive decline, mitochondrial dysfunction, synaptic pathology
DOI: 10.3233/JAD-170256
Journal: Journal of Alzheimer’s Disease, vol. 57, no. 4, pp. 969-974, 2017
Abstract
Which Two Neurotransmitters Have Roles In Appetite Suppression
The two neurotransmitters that play a role in controlling appetite include serotonin and catecholamine. Serotonin can help curb appetite by activating some specific neurons and receptors. This helps to reduce hunger pangs at the same time as blocking certain neurons that cause an increase in appetite. Catecholamines also affect the body’s hunger signals but do so by influencing neurons in the brain that play a role in hunger and satiety.
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What Are The Early Signs And Symptoms Of Alzheimers
Alzheimers is characterized by the progressive loss of memory, cognition, judgment, reasoning, spatial awareness, communication, motor skills, and, eventually, the ability to live independently. Symptoms are easy to miss in the early stages but often include:
- Difficulty completing routine tasks
- Getting loss or losing things
- Missing appointments
- Forgetting recent events or conversations
- Poor judgment, especially with finances
- Difficulty finding words or writing
- Personality changes
Region Specific Analysis In The Asymad Versus Control Group
The abundance of all fifteen metabolites were compared between control and ASYMAD groups . The only neurotransmitter that had an altered abundance was dopamine which was decreased in the MFG . In the ITG aminobutanal and guanosine which are both involved in the metabolism of neurotransmitters were also decreased .
Metabolites significantly increased in abundance and shown as green triangles and metabolites significantly decreased in abundance and shown as red chevrons with the size representing the magnitude of the change. Grey circles represent metabolites that were not significantly associated with disease. A) shifts observed in the cerebellum, B) shifts observed in the inferior temporal gyrus, C) shifts observed in the middle frontal gyrus.
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What Neurotransmitters Play A Role In Alzheimers Disease
Two neurotransmitters involved in memory and learningcalled acetylcholine and glutamateappear to play a role in Alzheimers disease. On the one hand, plaques appear to stimulate the production of chemicals that break down ACH, leading to their depletion. On the other, the progressive death of brain cells triggers the overproduction of glutamate, which overexcites brain cells and eventually kills them.
Causes Of Alzheimers Disease Continued
The AD Brain – Plaques and Tangles
When compared to the brains of people who are aging normally, the brains of people who have AD contain large numbers of plaques, particularly in the hippocampus, the region of the brain that controls memory. In addition, individuals with AD have a significant amount of neurofibrillary tangles spread throughout the brain.
Interestingly, doctors have found some people who showed no symptoms of Alzheimer’s Disease and still had a significant number of plaques and tangles in their brains at autopsy. These people may have developed a so called “cognitive reserve,” or a large number of connections between brain cells due to healthy lifestyle habits and a high level of education which acted like a “buffer” to stave off the symptoms of the disease. Another theory is that plaques and tangles begin to form several years before Alzheimer’s symptoms actually appear, so people who have plaques and tangles but no signs of AD may have died of another cause before living long enough to become cognitively impaired.
Because of this mystery , many scientists believe there is more to Alzheimer’s Disease than abnormal protein accumulations, although these do seem to play a significant role in the development of the disease.
The AD Brain – Free Radicals
The AD Brain – Neurotransmitters
The AD Brain – The Path of Destruction
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Correlation Of Metabolite Abundance And Measures Of Alzheimers Pathology
When examining the relationship between metabolite abundance and measures of pathology and cognitive performance several weak but significant correlations were observed. Of the 15 measured metabolites, all correlated with Braak and CERAD scores in all regions . Correlation analysis to investigate the relationship between metabolite abundance and cognitive performance showed that arginine, aspartate, aminobutanal and guanidobutanoate correlated with MMSE in all regions , GABA, aspartate, tyrosine, DOPA, ornithine, arginine, guanidobutanoate and aminobutanal correlated with Bentons visual retention index and guanidobutanoate correlated with the Boston naming score. Running Title: Neurotransmitter metabolism in Alzheimers brain
Contribution Of Gabaergic Interneurons In Apoe4
Apolipoprotein E4 , the major genetic risk factor for AD, accounts for 6075% of all AD cases, increasing significantly the risk of AD and lowering the age of onset of this disorder . By using mice model knockout of endogenous Apoe and knockin with various human APOE alleles, the neurogenesis was found reduced in both apoE knockout and human apoE4 knockin mice, leading to impaired learning and memory. In apoE4 knockin mice, the GABAergic interneuron number and presynaptic GABAergic input to newly born neurons both decreased, which was associated with increased tau phosphorylation and neurotoxic apoE4 fragments. Treatment with GABAA receptor agonist pentobarbital restored the neurogenesis deficit in apoE4 knockin mice. Consistently, treatment of apoE3 knockin mice with GABAA receptor antagonist picrotoxin decreased the neurogenesis in hippocampus . These findings suggest that the activation of GABAA receptors and GABAergic signaling pathway could be targeted to mitigate the deleterious effects of apoE4 on neurogenesis.
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What Causes Alzheimers Disease
Scientists dont fully know what causes Alzheimers disease but recognize that certain changes in the brain cause the progressive loss of neurons and their connections. This is due in large part to the formation of lesions, called plaques, and twisted protein fibers, called tangles, in the brain. ;These changes may be due to aging-related changes in the brain combined with genetic, environmental, and lifestyle factors the contribute to the onset of the disease.
Introduction Of Alzheimers Disease
Alzheimers disease is the most common age-associated neurodegenerative disorder, which is characterized by the deterioration of memory and cognition. About 10% of the population over the age of 65 and 3050% of the population over the age of 85 suffer from AD . Despite significant research and drug development effort in the past decades, currently there are no effective therapies that can prevent, delay or stop the progression of AD, causing a severe burden for the patients, their families and the society.
A small subset of AD cases result from dominantly inherited genetic mutations in genes encoding the -amyloid precursor protein and presenilins . These AD cases usually develop disease before the age of 60, referring as early-onset familial AD . Sporadic or late-onset AD usually develops the disease later in life, representing the majority of AD cases . The pathological hallmarks of AD include widespread neuronal degeneration, senile plaques and intracellular neurofibrillary tangles .
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Potential Gabaergic Therapies For Ad
Intense therapeutic effort has been taken in the AD field, but the outcomes have been disappointing. As outlined in this review, multiple lines of evidence have strongly suggested that GABAergic neurotransmission plays very important roles in AD pathogenesis. Theres close linkage between GABAergic signaling system and various aspect of AD pathology including A toxicity, tau hyperphosphorylation and apoE4 effect. Accordingly GABAA and GABAB receptor modulators have been investigated in preclinical or clinical tests .
Table 1. Effect of GABAergic chemicals in AD models.
Frontiers In Aging Neuroscience
Case Western Reserve University, United States
Reviewed by
Memorial Sloan Kettering Cancer Center, United States
The editor and reviewers’ affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review.
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Important Questions About Neurotransmitters In Alzheimers Disease
Researchers in AD field are seeking answers to several AD-related questions, including:
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1) Do we need more research on neurotransmitter serotonin involved in depression, anxiety and comorbidity in AD?
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2) Is there a relationship between neurotransmitters and the amyloid hypothesis, which states that, in AD, oligomeric A is the toxic form responsible for synaptic damage?
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3) Also, mitochondrial ATP is essential at synapses, which is where oxidative stress and mitochondrial dysfunction inhibit ATP; to better understand the AD disease process, do we need more research on the relationship between synapses and mitochondria?
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4) Do we need more research on neuron-glia and neuron-astrocyte cross-talk in AD neurons in relation to neurotransmitters?
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5) Do problems in neurotransmitter function actually impact the pathogenesis of AD?
This mini-forum in the Journal of Alzheimers Disease focuses on the relationship between neurotransmitters and AD. It provides timely resources for students, scholars, clinicians, and basic science researchers who are seeking a basic understanding of neurotransmitters in AD.
What Causes Death In People With Alzheimers Disease
The progressive destruction of nerve connections in the brain can eventually disrupt vital functions like swallowing. The majority of Alzheimers death are the result of aspiration pneumonia related to the onset of dysphagia . When this occurs, food or liquid can enter the trachea and cause injury or infection in the lungs that leads to pneumonia.
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Alteration Of Gabaergic Gliotransmission In Ad Mice Models
Its well known that astrocytes are important for uptake and recycling of specific neurotransmitters including GABA and glutamate. In CNS, not only neurons, but also astrocytes were found to be able to produce and release GABA, activating GABAA and GABAB receptors in nearby neurons . Recently, several studies indicate that astrocytes activated by A could release GABA and participate in AD pathology .
In APP/PS1 and 5× FAD mice, significantly more astrocytes were found activated in hippocampus. Normally astrocytes in wild type mice show minimal GABA immunoreactivity. While in AD mice models, reactive astrocytes were found to abundantly produce and release inhibitory GABA gliotransmitter. As a consequence, HPLC analysis with collected interstitial fluid samples from dentate gyrus revealed significantly elevated GABA level in APP/PS1 mice than wild-type littermates . In the hippocampus of 5× FAD, the GABA, glutamate and GAD immunostaining intensity were dramatically elevated in astrocytes . In the synaptosomes isolated from cortex of aged APP/PS1 mice with high amyloid load, the protein level of GAD was found significantly higher than in wild type control and plaque-free region cerebellum. Further study revealed that the increased GAD activity was localized in isolated glial synaptosome, rather than neuronal synaptosome, suggesting that in APP/PS1 transgenic mice, A plaques stimulate the astrocytic GABA synthesis and release .
What Are The Symptoms Of Alzheimers Disease
Early symptoms of Alzheimers disease include short-term memory loss, as well as mood and behavior changes. As the disease progresses, Alzheimers patients gradually lose cognitive function and require assistance in performing daily activities. At an advanced stage, they need constant assistance due to more serious memory loss and difficulties with speaking, walking and swallowing.
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