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Magnetic resonance imaging and spectroscopy will ultimately be a powerful tool to measure the effects of these neuroprotective approaches. Abstract Hyperammonemia can be caused by various acquired or inherited disorders such as urea cycle defects. Publication types Research Support, Non-U. Gov't Review. We also hypothesize how ammonia may be linked to AD.
Additionally, we discuss the evidence that support the hypothesis that ammonia is a key factor contributing to AD progression. Lastly, we summarize the old and new experimental evidence that focuses on energy metabolism, mitochondrial function, inflammatory responses, excitatory glutamatergic, and GABAergic neurotransmission, and memory in support of our ammonia-related hypotheses of AD.
All living organisms produce ammonia as a byproduct of cellular metabolism. At high concentrations, ammonia is toxic and causes deleterious effects to the cell Cooper and Plum, Effects include disruption of cellular energy metabolism, mitochondrial dysfunction, modulation of inflammatory responses, and neurotransmission in neurons.
Existing evidence suggests that accumulation of ammonia in the brain affects neuronal function and may lead to several neurological abnormalities. Therefore, ammonia could be a causative factor for Alzheimer disease AD and may be involved in the progression of the disease. In , Seiler for the first time published his hypothesis about a linkage between ammonia and AD Seiler, However, since then, few research undertakings have directly shown a pathophysiological role of ammonia within the AD brain.
In this review, toxicity and transport of various forms of ammonia are briefly described. AD—related factors are also highlighted and then built upon to discuss the contribution of ammonia to AD. In mammalian brains, ammonia is derived mostly from the metabolism of the putative neurotransmitters glutamate and aspartate, and monoamines.
In the brain, ammonia derives from two main pathways; endogenous and exogenous sources Figure 1 ; Seiler, , ; O'Donnell, Endogenous sources of brain ammonia involve: hydrolysis of proteins; degradation of amino acids e. One endogenous source comes from abnormalities in glucose metabolism which results in excessive ammonia concentrations within the cerebral cortex Hoyer et al.
Aside from liver dysfunction, ammonia also could be generated from the deficiency of brain metabolism or detoxification processes resulting from the major reduction in the activity of glutamine synthesis Suarez et al. Another source of brain ammonia is adenosinemonophosphate AMP deaminase, which regulates the purine nucleotides and converts AMP to inosine monophosphate and ammonia.
In , Sims and colleagues found that the activity of adenosinemonophosphate AMP deaminase is approximately 2-folds greater in AD brains compared with control individuals Sims et al. These outcomes led to the assumption that over-activity of AMP deaminase could be a source of elevated ammonia levels during deficient glucose metabolism in AD Sims et al.
Further, monoamine oxidase MAO could be involved, to a lower extent, in the process of ammonia production due to degradation of neurotransmitters and non-transmitter monoamines. Figure 1. Diagrammatic representation of sources, transport and metabolism of ammonia in the brain.
Exogenous sources produce large quantities of ammonia in the gastrointestinal tract, resulting from bacterial degradation of urea and deamination of amino acids Marcaggi and Coles, Urea cycle failure and deficient hepatic urea formation, inborn errors of metabolism, bacterial infection in the gut are major causes of accumulation of ammonia in the brain Figure 2. Additionally, some studies suggest that excessive ammonia levels in mammals have been related to AD due to toxic accumulation of glutamine in astrocytes, what leads to cell swelling and finally cell death Butterworth, However, evidence for a role for ammonia in the pathology of AD is still not concrete.
Figure 2. Scheme diagram representing possible consequences of chronic hyperammonemia, presumed to lead to progressive impairment of astrocytes and neuronal damage as well as mitochondrial malfunction.
Ammonia is the major end product of cellular amino acid metabolism Wright, Ammonia is a highly toxic material in animals at even sub-millimolar concentrations Marcaida et al.
Ammonia is a weak base with a pK of 9. This occur since NH 3 can alter the intraorganelle pH away from the optimal necessary pH for normal operation Seglen, This competition affects neuronal excitability and membrane potential in mammalian neurons Cooper and Plum, It has also been demonstrated that high ammonia concentrations can depolarize hippocampal neurons Bosoi and Rose, Elevated ammonia also causes major damage in the CNS, including changes in blood-brain barrier BBB morphology Laursen and Diemer, , modification in astrocyte and neuron morphology Gregorios et al.
In addition, elevated ammonia levels in mammals have been related to AD due to toxic accumulation of glutamine in astrocytes, which leads to cell swelling and ultimately cell death Butterworth, In microglia and astroglioma cell-lines, ammonia affects major functional activities such as phagocytosis and endocytosis.
In addition, ammonia modifies the secretion of cytokines and elevates the activity of lysosomal hydrolases Atanassov et al. Further, ammonium ions inhibit important enzymes involved in protein metabolism, such as alpha-ketoglutarate dehydrogenase and isocitrate dehydrogenase, which ultimately leads to free radical generation Cooper and Plum, Moreover, elevated ammonia concentration reduces the activity of the antioxidant enzymes, and results in inhibition of mitochondrial electron transport chain ETC Murthy et al.
In rat brain it has been shown that high ammonia concentrations interact with mitochondria and inhibit complexes I—IV of the ETC Veauvy et al. Marcaida and coworkers found evidence that ammonia toxicity is mediated by excessive activation of N -methyl-D-aspartate NMDA -type glutamate receptors in the brain. In most species, including mammals, the ammonia concentration of body fluids is typically low ca.
Concentrations exceeding 1 mM are usually toxic to mammalian cells Hrnjez et al. Because of its toxicity an effective ammonia detoxification or excretion system is crucial to maintain cellular and body fluid ammonia levels within a tolerable range to ensure normal systemic functions.
To protect the brain from ammonia-induced stress, understanding the specific role of ammonia transporters, which are putatively involved in the ammonia transport system, is critical. It has been shown that total ammonia levels in erythrocytes are greater than three times as compared to plasma ammonia levels Huizenga et al. The RhAG erythroid- Rh complex may play a role in keeping the total blood ammonia level low by transporting ammonia inside the red blood cells RBCs Huang et al.
In mammals, RhAG is located in erythrocytes and erythropoietic tissues Nakada et al. The RhBG and RhCG Non-erythroid Rh proteins have been distributed in various organs such as brain, kidney, liver, and skin, more specifically in locations where ammonia production and excretion is crucial Liu et al.
Gene expression of the Rh proteins from the brain of rainbow trout, Oncorhynchus mykiss, was significantly up-regulated upon ammonia-induced stress Nawata and Wood, This suggests that the brain Rh proteins contribute at least partially to the ammonia excretion process. However, the debate regarding transport specificity of members of the Rh family is ongoing. Recently, the X-ray crystallographic analysis on RhCG revealed that monomers of Rh proteins contain a hydrophobic pore element, while the protein form in a trimeric complex promotes the passage of gas form of ammonia NH 3 Gruswitz et al.
Furthermore, topological analyses indicated that the structures of the 12 transmembrane TM domains are conserved in all Rh proteins Huang and Peng, Sequence alignment analyses of Rh proteins among mammals, fish, crustaceans, nematodes and insects suggested that Rh proteins are phylogenetically related and most likely share a conserved ammonia transport function Weihrauch et al.
Aquaporins AQPs are membrane proteins that operate as channels for the transport of water. However, in a rat model of acute liver failure, the protein expression level of AQP-4 significantly increased, which appeared to precede the onset of astrocyte swelling. Therefore, astrocytes may respond to elevated blood ammonia concentrations by an alteration in expression levels of AQP-4 Rao et al. Moreover, it was shown that knocking out the AQP-4 gene in cultured astrocytes is capable of preventing ammonia-induced cell swelling Rama Rao et al.
This transporter localized at high expression levels in brain tissues, which may reveal a particular role in neural tissues beyond its housekeeping roles. All cells actively regulate their intracellular pH and NHE is potentially involved in acid-base regulation.
For example, NHE-1 is highly expressed in neurons and astrocytes to contribute in cellular pH regulation and cell volume Pizzonia et al. In addition to cellular pH regulation, NHEs would promote an acidification across lipid bilayers and thereby assist ammonia trapping as suggested in the proximal tubule Hamm and Simon, However, whether transporting protons could assist ammonia trapping for mammalian astrocytes is not completely understood.
These processes are in favor of maintaining cellular osmolality and energizing various sodium dependent transporters such as NKA Hu and Kaplan, ; Kaplan, The involvement of the NKA in ammonia transport processes has been shown in many species and various tissues, including the mammalian astrocytes. Protein and mRNA expression analyses from ammonia-induced astrocyte cultures indicated that NKA was up-regulated in response to high ammonia concentrations, suggesting an important role of NKA in an ammonia transport mechanism Xue et al.
Additionally, blocking NKA by using a ouabain inhibitor leads to reduce ammonium-induced astrocytic swelling, suggesting NKA is involved in ammonia homeostasis and cell swelling Dai et al. Two isoforms of NKCC 1 and 2 have been identified in several cells and tissues.
These studies highlight the role of NKCC in ammonia homeostasis and astrocyte swelling. Overall, dysregulation of the nitrogen transport system due to ammonia toxicity and any changes in ammonia transporter expression and function could affect brain ammonia homeostasis and function, which may lead to severe neuronal damage in the AD brain.
As mentioned above, changes in the expression of ammonia transporters most likely play a critical role in ammonia homeostasis and cell swelling; however, a possible link between the altered ammonia transporter function and AD is still missing.
Therefore, more studies will be needed to investigate details regarding the mechanisms involved in the transport of toxic ammonia in the AD vs. Elucidation of clinical pathological mechanisms related to the ammonia transport system may provide common links to the etiology of AD. Together these insights are crucial for developing therapeutic drugs to modify dangerous ammonia influxes that cause elevated systemic ammonia levels and eventually lethal brain damage in AD.
Currently, AD is the most common progressive neurodegenerative disease in the world Sperling et al. It is clinically characterized by disruption to synaptic plasticity, learning, memory, and several other cognitive functions Albert, Besides tau hyperphosphorylation Grundke-Iqbal et al.
The etiology and neuropathogenesis of AD suggest that this disease is complex and is better thought of as a multifactorial neurodegenerative disorder involving various proteins Carreiras et al.
Regarding causative factors in AD, various hypotheses have been proposed including impaired energy metabolism, mitochondrial dysfunction Hoyer, , alterations in neurotransmitter receptors systems such as GABA, glutamate, MAO; Sims et al. Among the neurotoxic agents that have been studied in relation to the pathology of AD, the effect of ammonia, as a potent neurotoxin, has received less attention than it deserves.
In this review several hypotheses are mentioned regarding the etiology of ammonia in AD including deficiency in glycose metabolism, mitochondrial dysfunction, impairment of glut amatergic and GABAergic neurotransmission, dysregulation of inflammatory responses, and memory dysfunction.
Glucose is the main source of energy within the brain and dysfunction of glucose metabolism has critical pathophysiological consequences. Several studies indicate a significant reduction in glycolytic process in brains with dementia Meier-Ruge et al. The dysregulation of glucose metabolism has been demonstrated by comparing the enzymatic activity of glucose transporters Simpson and Davies, , hexokinase Marcus and Freedman, , pyruvate dehydrogenase PDH Bubber et al.
High ammonia concentrations lead to elevated content of astrocytic glutamine with a decrease in glutamate concentration which causes reduction in the activity of the malate-asparate shuttle MAS. Unrelated to MAS activity, high ammonia concentrations in both astrocytes and neurons can inhibit decarboxylation of alpha-ketoglutarate in the TCA cycle, which leads to inhibition of PDH Hertz and Kala, Beside deficiency in glucose metabolism, the functionality of mitochondria is affected in AD brains.
This includes: increases in reactive oxygen species ROS production, disruption in the balance between mitochondrial fission and fusion, changes in mitochondria morphology, mitochondrial enzymatic failure, and a reduced rate of mitochondrial axonal transport Figure 2 ; Zhu et al.
Although, it has been hypothesized that mitochondrial regulation is generally genetically inherent, the activity of mitochondria could be influenced by other neurotoxic factors such as ammonia. Several studies indicate that ammonia compromises various parts of the cellular bioenergetic machinery.
For example, the activity of several ETC enzymes, mitochondrial cytochrome c oxidase, glutathione peroxidase, and superoxidase dismutase are significantly reduced in ammonia-treated brain Kosenko et al.
Existing evidence indicates that energy metabolism is compromised in AD and ammonia is involved in the disruption of energy metabolism i. However, more studies are required to obtain a better understanding of how mitochondria are affected by high ammonia concentrations, how AD vs.
One of the crucial roles of astrocytes is to protect neurons against excitotoxicity by taking up excess ammonia NH 3 and glutamate Glu and converting it into glutamine Gln via adenosine tri-phosphate dependent glutamine synthase GS. Within the liver and neurons, Gln is hydrolyzed via phosphate-dependent glutaminase to Glu and ammonia NH 3 Zielke et al. It has been shown in individuals with HE that there is a lack of balance between excitatory and inhibitory neurotransmission. The major inhibition is due to decreased expression of Glu receptors which leads to reduced glutamatergic tone.
Moreover, the inhibition of glutamate transporters Glt-1 in HE patients results in reductions in Glu re-uptake into astrocytes following excessive extrasynaptic accumulation of Glu Albrecht and Jones, Moreover, abnormal ammonia metabolism in AD brains correlated with decreases of astrocytic GS activity Suarez et al. Changes in the expression level of GS upon an ammonia-induced stress condition may alter astroglial morphology astrocytosis , which can reflect on neuronal function Figure 2.
Consistent with these findings, it is suggested that there is a linkage between impaired ammonia detoxification due to alteration in GS activity and amyloid plaque formation in AD brains Aksenov et al.
Besides the effect of ammonia on glutamatergic tone, ammonia also could alter the gamma-aminobutyric acid GABA system in the brain. GABA is one of the factors that mediate inhibitory neurotransmission. Thus, neurotransmission imbalances caused by ammonia might be responsible for cognitive deficits in AD Seiler, ; Rama Rao et al. However, the mechanisms by which ammonia contributes to the manifestations of AD remain poorly defined.
Elevated brain ammonia is capable of affecting crucial inflammatory processes causing alterations in the release of cytokines and inflammatory proteins by microglia, astroglioma, astrocytes, and neurons Figure 2.
NF-kB is a transcription factor with the critical role in the regulation of inflammatory responses, innate immunity, apopotosis, and mitochondrial dysfunction Barnes and Adcock, ; Henderson et al. This lack of understanding offers potential avenues for further research. Evidence indicates that activation of inflammatory responses is a pathological hallmark of AD.
Memory disruption is one of the major neuropathological hallmarks in AD Albert, The elevation of ammonia concentrations progressively leads to impaired mental status cognitive, spatial learning, and memory dysfunctions. In , Aguilar et al. Other possible mechanisms of the learning deficits produced by high levels of ammonia most likely involve a reduction of the neuronal glutamate-nitric oxide NO -cyclic GMP pathway.
Interestingly, reduction of NO formation correlated with intellectual dysfunction in AD dementia patients, but not in those with vascular dementia Kosenko et al.
In addition, it has been suggested that chronic ammonia exposure affects cognitive function through neurosteroid metabolism. Ammonia impairs the synthesis of neurosteroids, which is believed to be involved in memory impairment.
Also, it has been shown that ammonia impairs long-term potentiation LTP in the hippocampus, which a mechanism is thought critically involved in memory formation. Just over 20 years have passed since the first hypothesis was published suggesting there might be a link between ammonia and AD Seiler, Since then, very few direct investigations have been in favor of a pathophysiological role for ammonia in AD brain.
However, since high brain ammonia concentrations have been detected in AD, characterization of physiological and molecular mechanisms of the ammonia transport system in brain cells of AD vs.
Gaining knowledge on nitrogen transport mechanisms and its regulation in AD will have direct relevance to the medical field. Although, ammonia is not likely a primary cause of AD, it acts as a potent neurotoxin affects various biological pathways such as impairment of energy metabolism, mitochondrial dysfunction, dysregulation of inflammatory response, and memory dysfunction.
Aforementioned factors have also been observed in AD.
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