Regulation of the frontocortical sodium pump by Na+ in Alzheimer’s disease: difference from the age-matched control but similarity to the rat model (original) (raw)
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Cl−-ATPase and Na+/K+-ATPase activities in Alzheimer's disease brains
Neuroscience Letters, 1998
The enzyme activities and the protein levels of Cl −-ATPase and Na + /K +-ATPase were examined in Alzheimer's disease (AD) brains. Cl −-ATPase and Na + /K +-ATPase activities in AD brains (n = 13) were significantly lower than those in age-matched control brains (n = 12). In contrast, there was no significant difference in anion-insensitive Mg 2 +-ATPase activity between the two groups. Western blot analysis revealed that the protein levels of Cl −-ATPase, Na + /K +-ATPase and neuron specific Na + /K +-ATPase a3 isoform were also significantly reduced in AD brains, while the amount of protein disulfide isomerase, one of the house keeping membrane proteins, was not different between the two groups. The data first demonstrated that Cl −-ATPase and Na + /K +-ATPase are selectively impaired in AD brains, which may reduce the gradients of Na + , K + and Cl − across the cell membranes to cause excitotoxic cellular response and the resulting neuronal death.
Brain Na(+), K(+)-ATPase Activity In Aging and Disease
International journal of biomedical science : IJBS, 2014
Na(+)/K(+) pump or sodium- and potassium-activated adenosine 5'-triphosphatase (Na(+), K(+)-ATPase), its enzymatic version, is a crucial protein responsible for the electrochemical gradient across the cell membranes. It is an ion transporter, which in addition to exchange cations, is the ligand for cardenolides. This enzyme regulates the entry of K(+) with the exit of Na(+) from cells, being the responsible for Na(+)/K(+) equilibrium maintenance through neuronal membranes. This transport system couples the hydrolysis of one molecule of ATP to exchange three sodium ions for two potassium ions, thus maintaining the normal gradient of these cations in animal cells. Oxidative metabolism is very active in brain, where large amounts of chemical energy as ATP molecules are consumed, mostly required for the maintenance of the ionic gradients that underlie resting and action potentials which are involved in nerve impulse propagation, neurotransmitter release and cation homeostasis. Prote...
Direct interaction of beta-amyloid with Na,K-ATPase as a putative regulator of the enzyme function
By maintaining the Na + and K + transmembrane gradient mammalian Na,K-ATPase acts as a key regulator of neuronal electrotonic properties. Na,K-ATPase has an important role in synaptic transmission and memory formation. Accumulation of beta-amyloid (Aβ) at the early stages of Alzheimer's disease is accompanied by reduction of Na,K-ATPase functional activity. The molecular mechanism behind this phenomenon is not known. Here we show that the monomeric Aβ(1-42) forms a tight (K d of 3 μM), enthalpy-driven equimolar complex with α1β1 Na,K-ATPase. The complex formation results in dose-dependent inhibition of the enzyme hydrolytic activity. The binding site of Aβ(1-42) is localized in the " gap " between the alpha-and beta-subunits of Na,K-ATPase, disrupting the enzyme functionality by preventing the subunits from shifting towards each other. Interaction of Na,K-ATPase with exogenous Aβ(1-42) leads to a pronounced decrease of the enzyme transport and hydrolytic activity and Src-kinase activation in neuroblastoma cells SH-SY5Y. This interaction allows regulation of Na,K-ATPase activity by short-term increase of the Aβ(1-42) level. However prolonged increase of Aβ(1-42) level under pathological conditions could lead to chronical inhibition of Na,K-ATPase and disruption of neuronal function. Taken together, our data suggest the role of beta-amyloid as a novel physiological regulator of Na,K-ATPase. Na,K-ATPase creates the Na + and K + transmembrane gradient vital for all animal cells, it also is a receptor for cardiotonic steroids, regulating cell proliferation and apoptosis. Na,K-ATPase in neurons consumes up to 80% of ATP, since it not only sustains the Na + , K + gradient, but generates the action potential, maintaining the cell electrotonic characteristics 1. Disruption of ion homeostasis and osmotic balance may hinder the normal electro-tonic properties of dendrites by blocking intracellular signaling and contributing to degeneration of neurons 2. Malfunction of Na,K-ATPase underlies a series of pathologies, such as ischemic tissue damage, cancer and neu-rodegenerative diseases, such as Alzheimer's disease (AD). AD is the most widely occurring neurodegenerative disease and is diagnosed in approximately 11% of population older than 65 years and 32% older than 85 years. A therapeutic strategy aimed at increasing the activity of Na,K-ATPase in AD was proposed as symptomatic relief and slowing down the progression of the disease 2,3. Development of AD is accompanied by the decreased activity of Na,K-ATPase 2–5 , while the causal link between the two phenomena has not yet been established. In the presence of beta-amyloid (Aβ), a major component of the amyloid plaques formed in AD, the Na,K-ATPase activity in the postmortem brain tissue samples from AD patients is reduced in contrast with the samples from age-matched control 4 ; similar correlation was made for the samples from hippocampus and the microsomal fraction of brain tissue of transgenic mice and rats which showed memory deficiencies characteristic of AD 5. Importantly, reduced activity of Na,K-ATPase was observed only in the areas of the brain where amyloid plaques were formed, i.e. in the hippocampus, but not in the plaques-free cerebellum 2 , suggesting possibility of a direct regulation of the Na,K-ATPase activity by Aβ. Beta-amyloid (Aβ) is a 36 to 43 amino acids long product of the amyloid precursor protein (APP) hydrolysis 6 , while the 40 and 42 a.a. peptides constitute the main fraction. Aβ in mammals was suggested to be an important
Effect of sex and localization dependent differences of Na,K-ATPase properties in brain of rat
Journal of Physiology and Pharmacology, 2020
Na,K-ATPase is the main system effectively excluding the superfluous sodium out of the cells on the expense of energy derived from hydrolysis of ATP. In brain 3 different isoforms of the catalytic α-subunit are known. The present study was focused to energy utilization and ability to bind sodium by the Na,K-ATPase as well as expression of all 3 isoforms of the catalytic α-subunit concerning its sex specificity in two selected regions of the brain, in cortex and in cerebellum of rats. Western blot analysis showed higher expression of all 3 catalytic α-subunits of Na,K-ATPase in cerebellum when compared to cortex which was not followed by higher activity. On contrary the total activity of the enzyme was lower in cerebellum comparing with cortex in females with no significant localization dependent differences of activities in males. Concerning sex dependence only the expression of α3 isoform was higher in cortex of male rats with no differences in the levels of α1 and α2 isoforms. However, the total activity of Na,K-ATPase in cortex was similar in male and female groups. On the other hand in cerebellum of females the total activity of Na,K-ATPase was significantly lower as compared with males. The obtained data indicate localization and sex dependent variations in maintenance of sodium homeostasis in the brain.
Selective inhibition of brain Na,K-ATPase by drugs
Physiological research / Academia Scientiarum Bohemoslovaca
The effect of drugs from the class of cardiac (methyldigoxin, verapamil, propranolol), antiepileptic (carbamazepine), sedative (diazepam) and antihistaminic (promethazine) drugs on Na,K-ATPase activity of plasma membranes was studied in rat brain synaptosomes. Methyldigoxin in a concentration of 0.1 mmol/l inhibits enzyme activity by 80 %. Verapamil, propranolol and promethazine in concentrations of 20, 20 and 2 mmol/l respectively, entirely inhibit the ATPase activity. Carbamazepine and diazepam in concentrations of 0.02-60 mmol/l have no effect on the activity of this enzyme. According to the drug concentrations that inhibit 50 % of enzyme activity (IC 50 ), the potency can be listed in the following order: methyldigoxin >> promethazine > verapamil ≥ propranolol. From the inhibition of commercially available purified Na,K-ATPase isolated from porcine cerebral cortex in the presence of chosen drugs, as well as from kinetic studies on synaptosomal plasma membranes, it may be concluded that the drugs inhibit enzyme activity, partly by acting directly on the enzyme proteins. Propranolol, verapamil and promethazine inhibitions acted in an uncompetitive manner. The results suggest that these three drugs may contribute to neurological dysfunctions and indicate the necessity to take into consideration the side effects of the investigated drugs during the treatment of various pathological conditions.
General physiology and biophysics, 1997
The activities and basic enzymatic properties of Na,K-ATPase were examined in synaptosomal plasma membranes (SPM) prepared from rat hippocampus and striatum. A kinetic analysis showed profound differences in apparent affinities for ATP (Km) between hippocampal (1.21 mmol/l) and striatal (0.76 mmol/l) enzyme preparations, as well as in the corresponding Vmax values. However, physiological efficiencies were almost the same. The complex pattern of dose-response curves to ouabain indicated the presence of two high-affinity forms of Na,K-ATPase in the striatum ("very high-": Ki = 3.73 x 10(-8) mol/l and "high-": Ki = 4.21 x 10(-5) mol/l), and one high affinity form in the hippocampus (Ki = 6.6 x 10(-7) mol/l). In addition, both SPM preparations contained one low affinity form with similar Ki. The "very high-affinity" form had positive cooperativity for ouabain inhibition of Na,K-ATPase activity, in contrast to "high" and "low-affinity" fo...
Effect of duration of diabetes mellitus type 1 on properties of Na, K-ATPase in cerebral cortex
Molecular and Cellular Biochemistry, 2015
Time sequence study was performed to characterize the effects of diabetes mellitus type 1 on properties of the Na, K-ATPase in cerebral cortex derived from normal and streptozotocin (STZ)-diabetic rats of both genders. The samples were excised at varying time intervals of diabetes induced by STZ (65 mg kg-1) for 8 days, and 8 and 16 weeks. Expression of a1-3 isoforms of Na, K-ATPase was not altered in statistically significant level during all stages of diabetes neither in female nor in male rats as revealed from Western blot analysis. Studies of kinetic properties of the enzyme resulted in variations in active number of Na, K-ATPase molecules as well as its qualitative properties. Sixteen-week-old control male rats showed better affinity to substrate as indicated by 13 % decrease of K m value. The effect persisted also in males subjected to 8 days lasting diabetes; however, in males subjected to 8 weeks lasting diabetes, the effect was lost. In 25-week-old rats, the Na, K-ATPase revealed again altered properties in males and females but the mechanism of the variation was different. In females, the number of active molecules of Na, K-ATPase was higher by 32 % in controls and by 17 % in rats with chronic diabetes when comparing to respective male groups as suggested by increased value of V max. So the properties of Na, K-ATPase in cerebral cortex, playing crucial role in maintaining intracellular homeostasis of Na ? ions, depend on gender, age, and duration of diabetic insult.
Heterogeneous Na + Sensitivity of Na + ,K + -ATPase Isoenzymes in Whole Brain Membranes
Journal of Neurochemistry, 1993
The >.laf sensitivity of whole brain membrane Na+,K+-ATPase isoenzymes was studied using the differential inhibitory effect of ouabain ( a I , low affinity for ouabain; a2, high affinity; and 013, very high affinity). At 100 mM Na+, we found that the proportion of isoforms with low, high, and very high ouabain affinity was 21, 38, and 4 1 %, respectively. Using two ouabain concentrations (lo-' and lo-' M ) , we were able to discriminate Na+ sensitivity of Na+, K+-ATPase isoenzymes using nonlinear regression. The ouabain lowaffinity isoform, a 1, exhibited high Na+ sensitivity [K, of3.88 f 0.25 mMNa+ and a Hill coefficient (n) of I .98 t 0.131; the ouabain high-affinity isoform, a2, had two Na+ sensitivities, a high (K, of 4.98 k 0.2 M N a + andnof 1.34t-0.10)andalow(K,of28-+0.5mMNa+and an n of 1.92 t-0.18) Na+ sensitivity activated above a threshold (22 * 0.3 mMNa+); and the ouabain very-high-affinity isoform, a3, was resolved by two processes and appears to have two Na' sensitivities (apparent K, values of 3.5 and 20 m M Naf). We show that Na+ dependence in the absence of ouabain is the result of at least of five Na' reactivities. This molecular functional characteristic of isoenzymes in membranes could explain the diversity of physiological roles attributed to isoenzymes. Key Words: Na+,K+-ATPase-Mathematical analysis-Na+ sensitivity-Ouabain-Isoenzyme-Whole brain (rat). Gerbi A. et al. Heterogeneous Na+ sensitivity of Na+,K+-ATPase isoenzymes in whole brain membranes. J. Nrurochem. 60,[246][247][248][249][250][251][252].
Na+ and K+ ion imbalances in Alzheimer's disease
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2012
Alzheimer's disease (AD) is associated with impaired glutamate clearance and depressed Na + /K + ATPase levels in AD brain that might lead to a cellular ion imbalance. To test this hypothesis, [Na + ] and [K + ] were analyzed in postmortem brain samples of 12 normal and 16 AD individuals, and in cerebrospinal fluid (CSF) from AD patients and matched controls. Statistically significant increases in [Na + ] in frontal (25%) and parietal cortex (20%) and in cerebellar [K + ] (15%) were observed in AD samples compared to controls. CSF from AD patients and matched controls exhibited no differences, suggesting that tissue ion imbalances reflected changes in the intracellular compartment. Differences in cation concentrations between normal and AD brain samples were modeled by a 2-fold increase in intracellular [Na + ] and an 8-15% increase in intracellular [K + ]. Since amyloid beta peptide (Aβ) is an important contributor to AD brain pathology, we assessed how Aβ affects ion homeostasis in primary murine astrocytes, the most abundant cells in brain tissue. We demonstrate that treatment of astrocytes with the Aβ 25-35 peptide increases intracellular levels of Na + (~2-3-fold) and K + (~1.5-fold), which were associated with reduced levels of Na + /K + ATPase and the Na +-dependent glutamate transporters, GLAST and GLT-1. Similar increases in astrocytic Na + and K + levels were also caused by Aβ 1-40, but not by Aβ 1-42 treatment. Our study suggests a previously unrecognized impairment in AD brain cell ion homeostasis that might be triggered by Aβ and could significantly affect electrophysiological activity of brain cells, contributing to the pathophysiology of AD.