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)

The 4-kilodalton amyloid beta protein (A beta), which forms fibrillar deposits in Alzheimer's disease (AD), is derived from a large protein referred to as the amyloid beta protein precursor (beta APP). Human neuroblastoma (M17) cells transfected with constructs expressing wild-type beta APP or a mutant, beta APP delta NL, recently linked to familial AD were compared. After continuous metabolic labeling for 8 hours, cells expressing beta APP delta NL had five times more of an A beta-bearing, carboxyl terminal, beta APP derivative than cells expressing wild-type beta APP and they released six times more A beta into the medium. Thus this mutant beta APP may cause AD because its processing is altered in a way that releases increased amounts of A beta.
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PMID:Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. 842 67

Proteoglycans (PGs) may play a fundamental role in all forms of amyloidosis. In Alzheimer's disease, proteoglycans are found deposited in senile plaques and in neurofibrillary tangles. However, the cellular source of these deposited PGs and their role in amyloidosis in Alzheimer's disease is unknown. Proteoglycans were purified from conditioned medium of human neuroblastoma cells (SKNSH-SY 5Y). Two species of proteoglycans were identified by enzyme susceptibility including a heparan sulfate proteoglycan and a dermatan sulfate proteoglycan. A monoclonal antibody to the protein core of a vascular basement membrane heparan sulfate proteoglycan found in senile plaques in Alzheimer's disease cross-reacted with the proteoglycans secreted by human neuroblastoma cells. Binding between 35SO4-labelled neuroblastoma proteoglycans and the Alzheimer amyloid (A4) peptide was demonstrated by affinity chromatography. Specificity studies demonstrated that binding of human neuroblastoma proteoglycans to the amyloid peptide was specific for a heparan sulfate glycosaminoglycan, with some binding to a dermatan sulfate proteoglycan. Binding to A4 was also demonstrated by a chemically deglycosylated protein core preparation. No significant binding of neuroblastoma proteoglycans was found to two other basic peptides derived from the extracellular domain of the beta-amyloid precursor, demonstrating the specificity of proteoglycan binding to the A4 peptide. Human neuroblastoma proteoglycans may bind to the-Alzheimer amyloid A4 peptide in a region with a heparin binding consensus sequence [VHHQKL] which also contains the cleavage site of the beta-amyloid precursor protein. Neuronal proteoglycans may either regulate the secretion of the amyloid protein precursor or modify the binding of the amyloid protein precursor to other cellular adhesion molecules. Alterations in this binding may be related to the pathogenesis of amyloid deposition in Alzheimer's disease.
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PMID:Binding of secreted human neuroblastoma proteoglycans to the Alzheimer's amyloid A4 peptide. 843 62

Monoclonal antibodies (TB1 & TB2), which were obtained by immunization of 24 amino acids in BALB/c mice, bound specifically to the amyloid senile plaque and amyloid-angiopathic lesions of brain tissues of patients with Alzheimer's disease (AD) or with senile dementia of Alzheimer type (SDAT), and strongly reacted with the 1st part (Asp-Ala-Glu-Phe-Arg-His-Asp) of beta-protein. Western blotting and two-dimensional immunoelectrophoresis of cerebrospinal fluid (CSF) and serum revealed bands of 125 and 20 kilodaltons. The positive frequency of 125 and 20 KD bands detected by two-dimensional immunoelectrophoresis was higher in the serum of AD and SDAT patients (12 cases) than in that of normal control patients. ELISA employing various anti-amyloid precursor protein (APP) antibodies was performed using the extract of the human neuroblastoma cell line (NB39) which produces APP. In the near future, we hope to measure APP in CSF and sera from patients with Alzheimer's disease.
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PMID:[Immunological study on Alzheimer's disease using anti-beta-protein monoclonal antibodies]. 847 24

To study amyloid precursor protein (APP) processing we expressed different APP isoforms with and without the Swedish mutation and the membrane inserted C-terminal 100 residues of APP (SPA4CT) in the human neuroblastoma cell line SY5Y. We show that expression of the Swedish mutation results in a significant production of the amyloidogenic intermediate A4CT, which is further processed by gamma-secretase leading to an overproduction of beta A4. Treatment with methylamine and ammonium chloride, inhibitors interfering with intracellular transport mechanisms, inhibits beta-secretase activity without influencing the physiological APP cleavage by alpha-secretase activity. By expressing SPA4CT, we demonstrate that secretion, but not generation, of beta A4 from SPA4CT is inhibited by methylamine resulting in intracellular beta A4. This provides experimental evidence for the intracellular localization of gamma-secretase activity and beta A4 generation.
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PMID:Inhibition of beta A4 production by specific modulation of beta-secretase activity. 856 17

The amyloid beta-peptide (A beta) is a toxic derivative of the beta-amyloid precursor protein. Alternative processing of this precursor also yields large soluble forms (APPSs) which are secreted from many cell types. These APPSs have neuritogenic and neuroprotective activities; indeed, APPSs can protect primary neurons from the toxicity of A beta itself. To begin to explore the regulation of gene expression by APPS, we have focused on the NF-kappa B transcription factor family. NF-kappa B is induced by conditions of stress, including cellular oxidation. We report that NF-kappa B can also be induced by APPS. Furthermore, we effected direct activation of NF-kappa B through disinhibition using antisense oligonucleotide technology. This means of activating NF-kappa B resulted in protection of neuroblastoma cells from the toxicity of a calcium ionophore and protection of primary hippocampal neurons from the toxicity of A beta. Together, these data suggest that NF-kappa B may exist as a common agent inducing a neuroprotective pattern of gene expression in response to either trophic cytokines or stress itself.
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PMID:Participation of gene expression in the protection against amyloid beta-peptide toxicity by the beta-amyloid precursor protein. 862 4

It has previously been shown that stimulation of muscarinic m1 or m3 receptors can, by generating diacylglycerol (DAG) and activating protein kinase C (PKC), accelerate the breakdown of the amyloid precursor protein (APP) to form soluble, non-amyloidogenic peptides (APPs). This relationship has been demonstrated in human glioma and neuroblastoma cells as well as in transfected human embryonic kidney (HEK) cells and PC12 cells. We now provide evidence that stimulation of metabotropic glutamate receptors (mGluRs), which also are coupled to DAG and PKC, similarly accelerates processing of APP into non-amyloidogenic APPs in hippocampal neurons and cortical astrocytes derived from normal fetal rats. The mGluR antagonist, L(+)-2-amino-3-phosphonopropionic acid (L-AP3), and GF 109203X, an inhibitor of PKC, both blocked the release of APPs from hippocampal neurons and astrocytes evoked by glutamate receptor stimulation. Inasmuch as glutamatergic neurons in cortex and hippocampus are known to be damaged in Alzheimer's disease, our findings suggest that amyloid formation may be enhanced by the resulting glutamate deficiency and that selective mGluR agonists may be useful in facilitating synaptic efficacy and treating the disease.
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PMID:Metabotropic glutamate receptors regulate APP processing in hippocampal neurons and cortical astrocytes derived from fetal rats. 862 10

Attenuating beta-amyloid precursor protein (beta-APP) gene expression may have relevance in diseases such as Alzheimer's disease, where beta-APP has been implicated in neuropathological processes. We report here on the transcriptional down-regulation of beta-APP by interferon-gamma (IFN-gamma) in SKNMC human neuroblastoma cells. Treatment of the cells with IFN-gamma resulted in a 85% dose-dependent inhibition of beta-APP promoter activity after 24 h of exposure, with no changes observed at 5 h. For comparison, additional cytokines and signaling agents were also investigated for effects on beta-APP promoter activity. Elevated levels of activity were observed after treatment with phorbol 12-myristate 13-acetate and basic fibroblast growth factor whereas no significant effects were seen after treatment with lipopolysaccharide or interleukin-1 beta. Thus, IFN-gamma was shown here to be a suppressor of beta-APP promoter activity and is the first cytokine reported to possess such down-regulating effects.
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PMID:Transcriptional inhibition of the beta-amyloid precursor protein by interferon-gamma. 869 21

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

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

Purified bovine brain G-protein was used in a solution phase assay to identify membrane-associated proteins that influenced the activation of heterotrimeric G-proteins. Detergent-solubilized membrane extracts from the neuroblastoma-glioma cell hybrid NG108-15, but not the parent C6B4 glioma cell line, increased [35S]GTPgammaS binding to purified G-protein by approximately 460%. The G-protein activator was heat-sensitive, and the magnitude of its action was related to the amount of extract protein. The biophysical and biochemical properties of the G-protein activator were determined using DEAE ion exchange chromatography, gel filtration, and a lectin affinity matrix. In the presence of added GDP (1 microM), the enriched G-protein activator increased the initial rate of [35S]GTPgammaS binding to brain G-protein by up to 4-fold. In the absence of added GDP, the G-protein activator elicited an initial burst in [35S]GTPgammaS binding to brain G-protein within the first 30 s, after which the rate of nucleotide binding to G-protein was similar in the absence or presence of the G-protein activator. The stimulation of nucleotide binding to brain G-protein by the activator was also observed after resolution of Galpha from Gbetagamma. The G-protein activator was distinct from other proteins (neuromodulin, tubulin, and beta-amyloid precursor protein) that influence nucleotide binding to G-protein, indicating the existence of a novel signal accelerator.
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PMID:Characterization of a G-protein activator in the neuroblastoma-glioma cell hybrid NG108-15. 893 52


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