Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Earlier studies have shown that the intracellular killing of Staphylococcus aureus by human monocytes requires continuous stimulation by serum factors, e.g., immunoglobulin G (IgG). In the present study, we demonstrate that IgG, at concentrations that stimulate the intracellular killing of S. aureus, induces a transient increase in the intracellular free calcium concentration ([Ca2+]i) in monocytes. The Ca2+ ionophores A23187 and ionomycin stimulate the killing process as efficiently as IgG does and initiate O2- production in resting monocytes but not in monocytes containing bacteria. The Ca2+ ionophore-stimulated killing process was markedly inhibited by the NADPH oxidase inhibitor diphenyleneiodonium bisulfate, which indicates that these ionophores stimulate oxygen-dependent bactericidal mechanisms. Reduction of the [Ca2+]i to values below 1 nM, obtained by loading monocytes with MAPT/AM (1,2-bis-5-methyl-aminophenoxylethane-N,N,N',N'-tetraacetoxymet hyl acetate) in the absence of extracellular Ca2+, rendered the cells unresponsive to IgG or Ca2+ ionophore stimulation of the intracellular killing of S. aureus, but the response could be restored by reincubating these cells in the presence of extracellular Ca2+. It is concluded that cytosolic free Ca2+ is essential for the IgG-stimulated intracellular killing of S. aureus by human monocytes.
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PMID:Cytosolic free calcium is essential for immunoglobulin G-stimulated intracellular killing of Staphylococcus aureus by human monocytes. 132 66

Paired helical filament (PHF) tau is the principal component of neurofibrillary tangles, a characteristic feature of the neurodegenerative pathology in Alzheimer's disease (AD). Post-translational modification of tau, especially phosphorylation, has been considered a major factor in aggregation and diminished microtubule interactions of PHF-tau. Recently, it has been recognized that PHF-tau is also subject to non-enzymatic glycation, with formation of advanced glycation end products (AGEs). We now show that as a consequence of glycation, PHF-tau from AD and AGE-tau generate oxygen free radicals, thereby activating transcription via nuclear factor-kappa B, increasing amyloid beta-protein precursor and release of approximately 4 kD amyloid beta-peptides. These data provide insight into how PHF-tau disturbs neuronal function, and add to a growing body of evidence that oxidant stress contributes to the pathogenesis of AD.
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PMID:Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. 758 53

Neuronal degeneration in Alzheimer's disease (AD) has been variously attributed to increases in cytosolic calcium, reactive oxygen species, and phosphorylated forms of the microtubule-associated protein tau. beta-Amyloid (betaA), which accumulates extracellularly in AD brain, induces calcium influx in culture via the L voltage-sensitive calcium channel. Since this channel is normally activated by protein kinase A-mediated phosphorylation, we examined kinase activities recruited following betaA treatment of cortical neurons and SH-SY-5Y neuroblastoma. betaA increased channel phosphorylation; this increase was unaffected by the protein kinase A inhibitor H89 but was reduced by the mitogen-activated protein (MAP) kinase inhibitor PD98059. Pharmacological and antisense oligonucleotide-mediated reduction of MAP kinase activity also reduced betaA-induced accumulation of calcium, reactive oxygen species, phospho-tau immunoreactivity, and apoptosis. These findings indicate that MAP kinase mediates multiple aspects of betaA-induced neurotoxicity and indicates that calcium influx initiates neurodegeneration in AD. betaA increased MAP kinase-mediated phosphorylation of membrane-associated proteins and reduced phosphorylation of cytosolic proteins without increasing overall MAP kinase activity. Increasing MAP kinase activity with epidermal growth factor did not increase channel phosphorylation. These findings indicate that redirection, rather than increased activation, of MAP kinase activity mediates betaA-induced neurotoxicity.
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PMID:Activation of the L voltage-sensitive calcium channel by mitogen-activated protein (MAP) kinase following exposure of neuronal cells to beta-amyloid. MAP kinase mediates beta-amyloid-induced neurodegeneration. 1051 28

There is a great deal of evidence to support a pathogenic role of oxidative stress in Alzheimer's disease (AD), but the sources of reactive oxygen species have not been directly demonstrated. In this study, using a novel in situ detection system, we show that neurofibrillary tangles and senile plaques are major sites for catalytic redox reactivity. Pretreatment with deferoxamine or diethylenetriaminepentaacetic acid abolishes the ability of the lesions to catalyze the H2O2-dependent oxidation of 3,3'-diaminobenzidine (DAB), strongly suggesting the involvement of associated transition metal ions. Indeed, following chelated removal of metals, incubation with iron or copper salts reestablished lesion-dependent catalytic redox reactivity. Although DAB oxidation can also detect peroxidase activity, this was inactivated by H2O2 pretreatment before use of DAB, as shown by a specific peroxidase detection method. Model studies confirmed the ability of certain copper and iron coordination complexes to catalyze the H2O2-dependent oxidation of DAB. Also, the microtubule-associated protein tau, as an in vitro model for proteins relevant to AD pathology, was found capable of adventitious binding of copper and iron in a redox-competent manner. Our findings suggest that neurofibrillary tangles and senile plaques contain redox-active transition metals and may thereby exert prooxidant or possibly antioxidant activities, depending on the balance among cellular reductants and oxidants in the local microenvironment.
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PMID:In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals. 1061 29

Alzheimer's disease (AD) is a degenerative disease of the brain, which causes dementia. The disease is characterised by three main pathogenic factors: senile plaques, neurofibrillary tangles and inflammation. the participation of the local inflammatory reaction is confirmed especially by the results of studies dealing with activated microglia, reactive astrocytes, complement system, cytokines, reactive mediators of oxygen and nitrogen (free radicals), all of which participate significantly in inflammatory processes. These inflammatory markers are locally produced by brain cells, and occur in close proximity of beta-amyloid and tau protein deposits. Moreover, some epidemiologic and pilot clinical studies have proven that long-term administration of anti-inflammatory drugs have a protective effect on the onset of AD. Out of them, non-steroidal anti-inflammatory drugs (NSAIDs) are most extensively investigated medicaments. Despite some contradictory findings, the prevalent majority of these studies prove that long-term application of anti-inflammatory treatment can delay the onset, or at least slow down the progression of AD, namely in people between 65 and 75 years of age. The most appropriate prophylactic effect seems to be achieved by specific inhibitors of cyclooxygenase-2 (COX-2), namely celecoxib and rofecoxib. These preparations protect the gastrointestinal tract better than classical NSAIDs which inhibit both isoenzymes--COX-1 and COX-2. COX-2 is expressed in higher concentrations in the degenerating cells of the brain and this excessive expression can be decreased by selective inhibitors. The latter decrease also the excessive activation of some transcription factors (PPARgama and the nuclear factor kapa-B), which are responsible for the initiation of transcription of a number of pro-inflammatory genes. The selective inhibitors COX-2 can thereby have an anti-inflammatory effect operating on several levels. (Tab. 1, Fig. 1, Ref. 75.)
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PMID:Alzheimer's disease, inflammation and non-steroidal anti-inflammatory drugs. 1143

It was well known that beta-amyloid (Abeta) and tau protein play an important role in pathological procedure of Alzheimer's disease (AD), a senile dementia. The growth inhibitory factor (GIF, also named metallothionein-3, MT-3) had been demonstrated to inhibit the outgrowth of cortex neurons in the medium with extract of the AD patient brain. In our experiments, it was found that the neurons of cortex and the PC12 (pheochromocytoma) cells could be protected from the cytotoxicity of beta-amyloid 25-35 in presence of GIF and its domains. Additionally, GIF can scavenge the hydroxyl radical efficiently in CytC-VitC radical producing system and its alpha-domain shown more effective potentials than its beta-domain. The electron paramagnetic resonance spectra also show that the alpha-domain has more potential ability for eliminating reactive oxygen free radicals than its beta-domain. The results suggest that GIF could act as an efficient scavenger against free radicals in vitro and the alpha-domain in GIF molecule shows more potential in protecting against reactive oxygen species injury than the beta-domain.
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PMID:Different protective roles in vitro of alpha- and beta-domains of growth inhibitory factor (GIF) on neuron injuries caused by oxygen free radicals. 1175 Jul 60

Exposure of cultured neurons and neuronal cells to aggregated amyloid-beta (Abeta) induces multiple neurodegenerative events including accumulation of cytosolic calcium, generation of reactive oxygen species, abnormal levels of phosphorylation of the microtubule-associated protein tau, and apoptosis. Prevention of accumulation of calcium within the cytosol also prevents all other events, suggesting that calcium accumulation is an early and pivotal event in Abeta neurotoxicity. Calcium influx has been suggested to occur via L voltage-sensitive calcium channels or NMDA channels. Calcium influx into differentiated human neuroblastoma cells has been previously attributed to the L voltage-sensitive calcium channel, but the contribution of the NMDA channel was not examined. In the present study, treatment of these cells with MK-801, an antagonist of NMDA channels, failed to attenuate Abeta-induced calcium influx or neurodegeneration, while nimopridine, an antagonist of the L voltage-sensitive calcium channel, blocked Abeta-induced calcium influx. Our findings suggest that NMDA channels do not contribute significantly to Abeta neurotoxicity in these acute cell culture analyses.
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PMID:Amyloid-beta promotes calcium influx and neurodegeneration via stimulation of L voltage-sensitive calcium channels rather than NMDA channels in cultured neurons. 1221 34

Oxidative stress phenomena have been related with the onset of neurodegenerative diseases. Particularly in Alzheimer Disease (AD), oxygen reactive species (ROS) and its derivatives can be found in brain samples of postmortem AD patients. However, the mechanisms by which oxygen reactive species can alter neuronal function are still not elucidated. There is a growing amount of evidence pointing to a role for mitochondrial damage as the source of free radicals involved in oxidative stress. Among the species that participate in the production of oxygen reactive radicals, transition metals are one of the most important. Several reports have implicated the involvement of redox-active metals with the onset of different neurodegenerative diseases such as Alzheimer's Disease (AD), Progressive Supranuclear Palsy (PSP), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's Disease (PD). On the other hand, our previous studies have indicated that A beta-induced deregulation of the protein kinase Cdk5 associated with tau protein hyperphosphorylation constitute a critical pathway toward neurodegeneration. In the current paper we have shown that iron induces an imbalance in the function of Cdk5/p25 system of hippocampal neurons, resulting in a marked decrease in tau phosphorylation at the typical Alzheimer's epitopes. The loss of phosphorylated tau epitopes correlated with an increase in 4-hydroxy-nonenal (HNE) adducts revealing damage by oxidative stress. This effects on tau phosphorylation patterns seems to be a consequence of a decrease in the Cdk5/p25 complex activity that appears to result from a depletion of the activator p25, a mechanism in which calcium transients could be implicated.
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PMID:Iron-induced oxidative stress modify tau phosphorylation patterns in hippocampal cell cultures. 1257 81

Oxidative stress is a pivotal factor in neuronal degeneration including that induced by exposure to amyloid-beta (Abeta). Treatment with antioxidants such as vitamin E can alleviate Abeta neurotoxicity. However, vitamin E was only marginally effective in clinical trials in Alzheimer's disease. Recent studies indicate that treatment with vitamin E (as a-tocopherol), sodium pyruvate and phosphatidyl choline (PC) is more effective than vitamin E alone against neuronal oxidative stress. We demonstrate herein that treatment of cultured murine cortical neurons with these 3 agents is also more effective than vitamin E alone against Abeta neurotoxicity as assayed by generation of reactive oxygen species and increased levels of phospho-isoforms of the microtubule-associated protein tau. These data underscore the potential efficacy of a combinatorial neuroprotective formulation against Abeta neurotoxicity.
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PMID:Efficacy of vitamin E, phosphatidyl choline and pyruvate on Abeta neurotoxicity in culture. 1291 50

Alzheimer's disease (AD) includes etiologically heterogeneous disorders characterized by senile or presenile dementia, extracellular amyloid protein aggregations containing an insoluble amyloid precursor protein derivative, and intracytoplasmic tau protein aggregations. Recent studies also show excess neuronal aneuploidy, programmed cell death (PCD), and mitochondrial dysfunction. The leading AD molecular paradigm, the "amyloid cascade hypothesis", is based on studies of rare autosomal dominant variants and does not specify what initiates the common late-onset, sporadic form. We propose for late-onset, sporadic AD a "mitochondrial cascade hypothesis" that comprehensively reconciles seemingly disparate histopathologic and pathophysiologic features. In our model, the inherited, gene-determined make-up of an individual's electron transport chain sets basal rates of reactive oxygen species (ROS) production, which determines the pace at which acquired mitochondrial damage accumulates. Oxidative mitochondrial DNA, RNA, lipid, and protein damage amplifies ROS production and triggers three events: (1) a reset response in which cells respond to elevated ROS by generating the beta-sheet protein, beta amyloid, which further perturbs mitochondrial function, (2) a removal response in which compromised cells are purged via PCD mechanisms, and (3) a replace response in which neuronal progenitors unsuccessfully attempt to re-enter the cell cycle, with resultant aneuploidy, tau phosphorylation, and neurofibrillary tangle formation. In addition to defining a role for aging in AD pathogenesis, the mitochondrial cascade hypothesis also allows and accounts for histopathologic overlap between the sporadic, late-onset and autosomal dominant, early onset forms of the disease.
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PMID:A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease. 1519 40


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