Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Widespread proliferation of dystrophic neurites in the cerebral cortex represents an important neuroanatomical correlate of dementia in Alzheimer's disease (AD). Increased CNS expression of the 21-kDa neuronal thread protein (NTP) species is also correlated with dementia in AD. Pilot in vitro experiments provided evidence that high-level NTP expression might be linked to neuritic growth. The present study examines retinoic acid (RA) modulation of NTP expression during neurite outgrowth and neuronal differentiation in SH-Sy5y neuroblastoma and PNET2 CNS-derived cells. In both cell lines, RA-induced neuronal differentiation resulted in increased synthesis, expression, and phosphorylation of several NTP species, with high steady-state levels and stepwise hyper-phosphorylation of 21-kDa NTP molecules. With neurite outgrowth, NTP molecules were translocated from the perikarya to long, slender, unbranched cell processes (axons) and growth cones. RA-mediated changes in NTP expression were independent of DNA synthesis. The findings suggest that high-level expression of 21-kDa, and closely related phosphorylated NTP molecules correlates with neuritic growth. Therefore, over-expression of 21-kDa NTP molecules in AD probably reflects the widespread cortical neuritic sprouting associated with dementia. In view of the rapid phosphorylation and cell process translocation of NTP that occurs during neurite outgrowth in vitro, the accumulation of NTP in AD cortical neuronal perikarya suggests a further problem related to post-translational processing and transport of NTP molecules in AD neurodegeneration.
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PMID:Modulation of neuronal thread protein expression with neuritic sprouting: relevance to Alzheimer's disease. 879 Dec 35

Oxidative stress appears to contribute to neuronal dysfunction in a number of neurodegenerative conditions, notably including Alzheimer's disease, in which cholinergic receptor-linked signal transduction activity is severely impaired. To test whether oxidative stress could contribute to deficits in cholinergic signaling, responses to carbachol were measured in human neuroblastoma SH-SY5Y cells exposed to H2O2. DNA binding activities of two transcription factors that are respondent to oxidative conditions, AP-1 and NF kappa B, were measured in nuclear extracts. H2O2 and carbachol individually induced dose- and time-dependent increases in AP-1 and NF kappa B. In contrast, when given together, H2O2 concentration dependently (30-300 microM) inhibited the increase after carbachol in AP-1. Carbachol's stimulation of NF kappa B was not inhibited except with a high concentration (300 microM) of H2O2, which was associated with impaired activation of protein kinase C. Lower concentrations of H2O2 (30-300 microM) inhibited carbachol-induced [3H]phosphoinositide hydrolysis, and this inhibition correlated (r = 0.95) with the inhibition of carbachol-induced AP-1. Activation [3H]phosphoinositide hydrolysis by the calcium ionophore ionomycin was unaffected by H2O2, indicating that phospholipase C and phosphoinositides were impervious to this treatment. In contrast, activation with NaF of G-proteins coupled to phospholipase C was concentration dependently inhibited by H2O2, indicating impaired G-protein function. These effects of H2O2 are similar to signaling impairments reported in Alzheimer's disease brain, which involve deficits in receptor- and G-protein-stimulated phosphoinositide hydrolysis, but not phospholipase C activity. Thus, these findings indicate that oxidative stress may contribute to impaired phosphoinositide signaling in neurological disorders in which oxidative stress occurs, and that oxidative stress can differentially influence transcription factors activated by cholinergic stimulation.
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PMID:Cholinergic stimulation of AP-1 and NF kappa B transcription factors is differentially sensitive to oxidative stress in SH-SY5Y neuroblastoma: relationship to phosphoinositide hydrolysis. 881 74

There is growing evidence that cytoskeletal instability of neuronal cells is an important step towards tangle formation and subsequent functional disconnection in the AD brain. Sabeluzole, a new drug in clinical trials for Alzheimer's disease (AD), has been shown to slow down the clinical progression of the disease. In a search for the mechanism of action of this compound, the effect of sabeluzole on the neuronal cytoskeleton was investigated. Previous studies have shown that in human TR14 neuroblastoma cells and in rat hippocampal neurons a hyperstimulating medium of kinase activators leads to induction of aberrant tau phosphorylation followed by neurotoxicity. This report documents the attenuation of this neurotoxicity by sabeluzole. By selective permeabilization procedures and quantitative immunocytochemistry we show that the compound is found to preferentially increase the fraction of polymerized tubulin. Evidence is presented that the compound differentially modulates a nocodazole-induced depolymerization in contrast to a cold-induced depolymerization. In the mouse, N4 neuroblastoma cells sabeluzole decreases the spontaneous retraction frequency of neurites and lowers the lateral mobility of the cells. We, therefore, propose that sabeluzole exerts its neuroprotective effect by a stabilization of the neuronal cytoskeleton and that this mechanism provides a completely new approach for treatment in Alzheimer's disease.
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PMID:Sabeluzole stabilizes the neuronal cytoskeleton. 883 32

The senile plaque in Alzheimer's disease (AD) consists mainly of the amyloid beta-peptide (A beta) derived from a family of large integral membrane glycoproteins, beta-amyloid precursor proteins (beta APP). Soluble derivatives of beta APP generated by the proteolytic processing of full-length beta APP are normally secreted into the conditioned medium of cultured cells. Here we have investigated the possibility that the processing of beta APP can be regulated by the cholinesterase inhibitors physostigmine and tacrine. Both drugs mildly improve cognitive functions in some patients with AD. We analyzed the level of beta APP in glial, neuroblastoma, and pheochromocytoma cells by immunoblotting cell lysates and conditioned media using a monoclonal antibody, MAb22C11. The levels of soluble beta APP derivatives normally present in conditioned media were severely inhibited by treating cells with tacrine but not with physostigmine. Whereas the treatment of cells with tacrine resulted in a small decrease in the intracellular levels of beta APP, treating cells with physostigmine resulted in a slight increase in the intracellular levels of beta APP compared to untreated cells. The effect of tacrine on the secretion of beta APP was not affected by cotreating cells with muscarinic agents, staurosporine, or the calcium ionophore. Our results suggest that a decrease in the secretion of beta APP by tacrine did not depend on its anticholinesterase activity and that tacrine operates via a noncholinergic mechanism.
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PMID:Differential effect of tacrine and physostigmine on the secretion of the beta-amyloid precursor protein in cell lines. 883 81

Cerebral deposition of betaA4 (beta-amyloid) peptide is a major pathological feature of Alzheimer's disease. Although the mechanism of betaA4 production from cells has been investigated extensively, so far little is known about the catabolism of the peptide. We report here that the human neuroblastoma cell line SH-SY5Y can rapidly clear betaA4 in the culture medium. The clearance was not due to the degradation by extracellularly released protease, but rather due to intracellular degradation after cellular uptake. This clearance activity was specific to SH-SY5Y cells among several cell types examined. Some of the betaA4-derived peptides lacking the N-terminal part of the molecule were not catabolized, suggesting a specific interaction between the cells and betaA4. Although most of the peptide was degraded after uptake, small amounts of peptide were accumulated in insoluble fractions of the cells and remained stable for several days. These observations suggest that this uptake-degradation activity may contribute to AD pathogenesis in two different ways: either to prevent the amyloid deposition by reducing extracellular betaA4 concentrations, or to promote the deposition by producing insoluble seeds for amyloid formation.
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PMID:Rapid cellular uptake of Alzheimer amyloid betaA4 peptide by cultured human neuroblastoma cells. 884 58

Treatment of primary rat embryo hippocampal neuronal cultures with 10(-5) M beta-amyloid peptide fragment 25-35 (A beta P) for 24 h resulted in a 60% decrease in cell viability as determined by MTT incorporation. When these cells were treated with 0.1-10 ng/ml of either transforming growth factor-beta (TGF-beta) 1, 2 or 3 for 24 h before exposure to A beta P, there was a 2.9-, 1.9-, and 3.2-fold increase in cell survival, respectively, compared to cells treated with A beta P alone. The viability of cells treated with A beta P and 0.1-10 ng/ml TGF-beta was comparable to that of cells not treated with A beta P. The protective effects were less pronounced at lower TGF-beta concentrations. The protective effects of pretreatment with TGF-beta were less striking in mouse CCL-N-2a and human SK-N-SH neuroblastoma cell lines. When all cells were treated with TGF-beta for 24 h following a 24 h exposure to A beta P, there was a trend toward increased cell viability which was less significant than pretreatment with TGFs-beta. An isoform-specific TGF-beta SELISA showed that primary hippocampal neuronal cultures and the neuroblastoma cell lines secrete all 3 TGF-beta isoforms. Based on our results, we propose that the increased expression of TGF-beta observed in brains of patients with Alzheimer's disease may offer some degree of neuroprotection.
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PMID:Transforming growth factors-beta protect primary rat hippocampal neuronal cultures from degeneration induced by beta-amyloid peptide. 889 Dec 64

There is evidence available suggesting that membrane alterations occur in Alzheimer's disease including the metabolism of membrane phospholipids. We have quantitated in vitro the phospholipase D activity of homogenates from Alzheimer's disease brain tissue. There was a significant increase of this enzyme activity as compared to controls. Amyloid beta protein is the predominant protein of the characteristic senile plaques found in Alzheimer's disease. Treatment of LA-N-2 cells, a human cholinergic neuroblastoma clone, with amyloid beta protein results in an activation of phospholipases A, C and D.
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PMID:Phospholipid metabolism in Alzheimer's disease and in a human cholinergic cell. 890 82

Previous studies indicated that a chemically-defined, differentiation medium (DM) induces neuroblastoma cells, especially IMR32K cells, to exhibit phenotypes of mature neurons (including neurite outgrowth and synthesis of neurofilament polypeptides) and develop certain attributes of the neurons which are affected by neurofibrillary degeneration in Alzheimer's disease, such as expression of tangle-associated epitopes and accumulation of paired helical filaments-(PHF-) like fibrils. Immunocytochemical staining suggested that this cytoskeletal abnormality most likely results from altered expression of tau proteins. In the current study, we addressed this issue by analyzing tau-enriched preparations of IMR32K cells that were previously exposed to different incubation media using a panel of antibodies specific to tau and related microtubule-associated proteins. These cultured cells exhibited three groups of tau immunoreactivities which differ in molecular weight. Among them the level of high molecular weight tau (MW 90-112 kDa) was selectively augmented after DM incubation. The tau proteins produced in these neuron-like cells shared phosphorylated sites with PHF-tau and fetal tau, but differed from PHF-tau in their lack of the N-terminal insert which characterizes adult isoforms.
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PMID:Modulated induction of tau proteins in cultured human neuroblastoma cells. 891 3

This study addresses the developmental regulation of amyloid precursor protein (APP) fragments comprising the amyloid-beta peptide (AP) and the amyloid-promoting factor acetylcholinesterase (AChE) in a mouse neuronal cell line (Neuro-2a). Results indicate that a 35-kDa amyloidogenic fragment of APP and the major molecular forms of AChE (G1 and G4) in Neuro-2a cells significantly increase with increasing levels of cell confluence. The foregoing molecules undergo further increases when neuroblastoma cells differentiate in the presence of dibutyryl cAMP. In contrast, a 17-kDa fragment of APP and butyrylcholinesterase were not affected by cell confluence or differentiation. These findings are the first to indicate that a selective Abeta-containing fragment of APP is subject to developmental regulation. Moreover, our data show that the 35-kDa fragment and AChE forms respond in parallel to the same developmental stimuli, i.e., cell confluence and differentiation. This points to the existence of a functional relationship between both molecules, a notion that is consistent with the potential role that has been ascribed to AChE in both APP processing and the formation of amyloid deposits in Alzheimer's brains.
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PMID:Amyloid precursor protein fragment and acetylcholinesterase increase with cell confluence and differentiation in a neuronal cell line. 894 Feb 53

To study the metabolism of amyloid beta protein (Abeta) in Alzheimer's disease, we have developed a new approach for analyzing the profile of soluble Abeta and its variants. In the present method, Abeta and its variants are immuno-isolated with Abeta-specific monoclonal antibodies. The identities of the Abeta variants are determined by measuring their molecular masses using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The levels of Abeta variants are determined by their relative peak intensities in mass spectrometric measurements by comparison with internal standards of known identities and concentrations. We used this method to examine the Abeta species in conditioned media of mouse neuroblastoma cells transfected with cDNAs encoding wild type or mutant human amyloid precursor protein. In addition to human Abeta-(1-40) and Abeta-(1-42), more than 40 different human Abeta variants were identified. Endogenous murine Abeta and its variants were also identified by this approach. The present approach is a new and sensitive method to characterize the profile of soluble Abeta in conditioned media and biological fluids. Furthermore, it allows direct measurement of each individual peptide in a peptide mixture and provides comprehensive information on the identity and concentration of Abeta and Abeta variants.
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PMID:The profile of soluble amyloid beta protein in cultured cell media. Detection and quantification of amyloid beta protein and variants by immunoprecipitation-mass spectrometry. 894 33


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