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)

Appicans are secreted or cell-associated brain chondroitin sulfate proteoglycans produced by glia cells and containing Alzheimer amyloid precursor protein (APP) as a core protein. Here, we report that rat C6 glioma cells transfected with appican displayed a dramatic change in their phenotypic appearance compared with untransfected cells or cells transfected with APP. Appican-transfected cells lost the round appearance of the untransfected control C6 cells, acquired a flat morphology, and elaborated more processes than control cells. Untransfected, or APP-transfected C6, cells were completely dissociated from their substrate after 40 min of treatment with cell dissociation solution. Under the same conditions, however, <20% of the appican-transfected C6 cells were dissociated from their substrate, suggesting that the appican-transfected glia cells attach more avidly to their substrate than do untransfected or APP transfected control cells. In contrast, appican-transfected fibroblast cells showed no morphological changes and dissociated from their substrate similarly to untransfected fibroblast cells. Extracellular matrix (ECM) prepared from appican-transfected C6 cell cultures contained high levels of appican and was a significantly better substrate for the attachment of C6 cells than ECM from either untransfected or APP-transfected cultures. Furthermore, cell adhesion to ECM was independent of the level of appican expression of the plated cells. ECM from appican-transfected C6 cultures stimulated adhesion of other neural cells including primary astrocytes, Neuro2a neuroblastoma, and PC12 pheochromocytoma, but not fibroblast cells. Conditioned media from appican-transfected C6 cultures failed to promote cell adhesion. Together, these data suggest that secreted appican incorporates into ECM and promotes adhesion of neural cells. Furthermore, our data suggest that the chondroitin sulfate chain engenders APP with novel biological functions.
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PMID:Appican expression induces morphological changes in C6 glioma cells and promotes adhesion of neural cells to the extracellular matrix. 918 36

The processing of Alzheimer's amyloid precursor protein was studied by Western blotting during H2O2 induced apoptosis in cultures of human neuroblastoma cells. A new 5.5 kDa fragment putatively containing intact A beta was detected and found to be highly associated with apoptosis. The results suggest a possible vicious cycle involving H2O2, A beta and apoptosis which may contribute to the neuronal death mechanism in Alzheimer's Disease.
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PMID:Processing of Alzheimer's amyloid precursor protein during H2O2-induced apoptosis in human neuronal cells. 920 49

Amyloid plaques, composed mainly of the 39-43 amino acid betaA4 peptide, are a characteristic feature of Alzheimer's disease. Generation of betaA4 by proteolytic processing of the amyloid precursor protein (APP) is thought to occur in a pathway that includes the activity of two as yet unknown proteases, with beta-secretase cleaving at the N terminus and gamma-secretase releasing the C terminus of betaA4. Inhibition studies and the finding that cell surface APP can serve as a direct precursor of betaA4 suggest that the endosomal/lysosomal compartment is involved in the proteolysis of APP into betaA4. In this study we targeted APP695 chimeric proteins directly into the endosomal/lysosomal compartment. This decreased the amount of released betaA4, while the generation of the betaA4 N terminus continued. APP695 proteins were constructed also, which carried sorting signals responsible for recycling between the trans-Golgi network (TGN) and the cell surface. These proteins were processed into secreted betaA4 at even higher levels than wild-type APP695. Moreover, retention of APP695 proteins in the endoplasmic reticulum led to neither betaA4 secretion nor to processing by beta-secretase in human SH-SY5Y neuroblastoma cells. These data suggest that a beta-cleavage activity resides in a late endosomal compartment and that a gamma-cleavage occurs in early endosomes, resulting in the generation of betaA4 peptides with the majority ending at residue 40.
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PMID:Late compartments of amyloid precursor protein transport in SY5Y cells are involved in beta-amyloid secretion. 931 93

One of the main characteristics of Alzheimer's disease (AD) is the cerebrovascular deposition of the amyloid beta-peptide (A beta), which is derived from a larger beta-amyloid precursor protein (beta APP). The majority of beta APP is processed by either a secretory of lysosomal/endosomal pathway. Carboxyl-truncated soluble derivatives of beta APP (sAPP) are generated by the proteolytic processing of full-length beta APP by either alpha- or beta-secretase enzyme. Our objective is to determine whether the processing of beta APP can be regulated by cholinesterase inhibitors, some of which were shown to produce a moderate improvement in memory and cognitive functions in patients with Alzheimer's disease. Here we have analyzed the levels of sAPP derivatives in cultured cells treated with different drugs by immunoblotting samples of conditioned media. The immunoreactive protein bands were developed by probing with the monoclonal antibody 22C11. Treating neuroblastoma, pheochromocytoma and fibroblast cells with high dose of either 3,4-diaminopyridine, metrifonate, or physostigmine did not inhibit the secretion of sAPP. Treating glioblastoma with either 3,4-diaminopyridine or metrifonate showed an increase in secretion of sAPP. However, treatment of cells with tacrine reduced release of sAPP in conditioned media of cell lines studied. The difference in action of metrifonate, physostigmine, and tacrine on beta APP is independent of their anticholinesterase activities. Our results suggests that noncatalytic functions of cholinesterase inhibitors can be utilized to alter the metabolism of beta APP, which might in turn affect the process of deposition of A beta, a key component of the cerebrovascular amyloid detected in AD.
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PMID:Effects of cholinesterase inhibitors on the secretion of beta-amyloid precursor protein in cell cultures. 932 15

The recently identified Alzheimer's disease-associated presenilin 1 and 2 (PS1 and PS2) genes encode two homologous multi membrane-spanning proteins. Rabbit antibodies to the N-terminal domain of PS1 detected PS1 in human neuroblastoma SH-SY5Y wild type and PS1 transfectants (SY5Y-PS1) as well as in mouse P19, in CHO-K1 and CHO-APP770 transfected cells, in rat cerebellar granule and hippocampal neurons, and astrocytes. Immunoblotting detected full-length protein of 50 kDa, and a major presumptive cleavage product of 30 kDa. The immunofluorescence pattern resembled labeling of the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) marker protein ERGIC-53. PS1 distribution showed slight condensation after brefeldin A and more marked condensation after incubation of cells at 16 degrees C, characteristic of the ERGIC compartment. Double labeling showed colocalization of ERGIC-53 with PS1 in the SY5Y-PS1 cells. PS1 labeling of SY5Y-PS1 and P19 cells showed overlap of the cis-Golgi marker p210 and colocalization with p210 after brefeldin A which causes redistribution of p210 to the ERGIC. Expression of PS1 did not change in level or cellular distribution during development of neurons in culture. Double labeling for the amyloid precursor protein (APP) and PS1 on SY5Y-PS1 cells and CHO-APP770 cells showed some overlap under control conditions. These results indicate that PS1 is a resident protein of the ERGIC and could be involved in trafficking of proteins, including APP, between the ER and Golgi compartments.
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PMID:Alzheimer's disease-associated presenilin 1 in neuronal cells: evidence for localization to the endoplasmic reticulum-Golgi intermediate compartment. 933 59

The amyloid precursor protein may be processed by several different pathways, one of which produces the amyloid beta-peptide betaA4 present in the amyloid plaques characteristic of Alzheimer's disease. A recent report suggested that axonal-amyloid precursor protein is present in a membrane fraction "with caveolae-like properties." In the present study we have isolated detergent-insoluble, caveolae-like membranes from both mouse cerebellum and the human neuroblastoma cell line SH-SY5Y. Detergent-insoluble membranes from mouse cerebellum retained nearly all of the glycosylphosphatidylinositol-anchored proteins--alkaline phosphatase, 5'-nucleotidase, and the F3 protein--while excluding the majority of the plasmalemmal marker protein alkaline phosphodiesterase I. Although the inositol trisphosphate receptor was highly enriched in this detergent-insoluble fraction, neither amyloid precursor protein nor clathrin immunoreactivity could be detected. Similar results were obtained with SH-SY5Y cells, where 5'-nucleotidase activity was enriched at least 30-fold in the detergent-insoluble membranes, but no amyloid precursor protein or clathrin immunoreactivity could be detected. Caveolin could not be detected in microsomal membranes from either mouse cerebellum or SH-SY5Y cells. These observations suggest that amyloid precursor protein is not normally present in detergent-insoluble, caveolae-like membrane microdomains.
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PMID:The amyloid precursor protein is not enriched in caveolae-like, detergent-insoluble membrane microdomains. 934 65

The deposition of amyloid plaques in brain parenchyma is one of the major pathological hallmarks of Alzheimer's disease (AD). The amyloid in senile plaques is composed of the amyloid beta-peptide (A beta) of 39-43 amino acid residues derived from a larger beta-amyloid precursor protein (beta APP). Soluble derivatives of beta APP (sAPP) lacking the cytoplasmic tail, transmembrane domain, and a small portion of the extracellular domain are generated proteolytically by "secretases." Using cell cultures, the authors analyzed the level of sAPP in neuroblastoma and pheochromocytoma (PC12) cells by immunoblotting samples from conditioned media and cell lysates. Normal levels of secretion of sAPP into conditioned media were severely inhibited by treating cells with melatonin (3-4 mM). The inhibitory effect of melatonin on the secretion of sAPP can be reversed. When the cells that were pretreated with melatonin for 10 h were washed, the normal level of secretion of sAPP was restored. Northern blot analyses indicated that the treatment of PC12 cells with melatonin resulted in a significant decrease in the level of mRNA encoding beta APP, beta-actin, and glyceraldehyde-3-phosphate dehydrogenase, and that the treatment of a human neuroblastoma cell line with melatonin resulted in no change in levels of these messages. The secretion of sAPP into the conditioned medium was substantially reduced in the differentiated cells similar to reductions observed in melatonin-treated undifferentiated PC12 cells. Melatonin was found to potentiate the nerve growth factor-mediated differentiation in PC12 cells at 24 h. Taken together, these data suggest that melatonin regulates the metabolism of beta APP and other housekeeping genes in a cell-type specific manner, and that melatonin accelerates the early process of neuronal differentiation.
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PMID:Melatonin alters the metabolism of the beta-amyloid precursor protein in the neuroendocrine cell line PC12. 940 89

During development in vivo and in vitro, estrogens: a) increase brain excitability, particularly in limbic structures; b) are responsible for the maturation and cyclicity of limbic-hypothalamic interrelations; c) enhance myelinogenesis; and d) may act with NGF to stimulate neurite formation. In senescence, estrogen administration would improve memory in postmenopausal women. The absence or low levels of estrogens after menopause would increase prevalence of Alzheimer's dementia (AD) more in women than men, irrespective of age or ethnicity. In the present study, addition of 17-beta estradiol to cultured human neuroblastoma cells affected growth slightly, but stimulated cell maturation as shown by increased tyrosine hydroxylase activity. The extracellular deposition in brain tissue and around blood vessels of the amyloid beta-peptide (A beta), a 4.3 kD fragment of the larger integral membrane protein, beta-amyloid precursor protein (beta-APP), is considered an important characteristic of AD. We investigated whether 17-beta estradiol may influence the formation of the A beta (thus the abnormal accumulation of amyloid proteins) in neuroblastoma cells and in a beta-APP transfected human kidney 293 cell line. Two doses of 17 beta-estradiol were added to the cultures of both cell lines. Cells were grown until confluence, metabolically labeled with 35S-methionine, immunoprecipitated with the rabbit antiserum R1282, gel electrophoresed and autoradiographed in order to compare levels of A beta under the different estradiol concentrations. While in neuroblastoma cells, levels of A beta were only slightly reduced after estradiol and a dose-effect relationship with the hormone could not be demonstrated, in the 293 cells, A beta band intensity decreased as concentration of estradiol increased. These data support the role of estrogen in normal and abnormal brain metabolism and suggest potential hormonal interventions which may reduce or prevent the formation of amyloid deposits occur in AD.
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PMID:Estrogens influence growth, maturation, and amyloid beta-peptide production in neuroblastoma cells and in a beta-APP transfected kidney 293 cell line. 941 80

We have previously demonstrated that full-length heparin stimulates the synthesis and secretion of beta-amyloid precursor protein (APP) through an amyloidogenic pathway in neuroblastoma cells. In the present study, heparin was chemically depolymerized, and the effect of low-molecular-weight (LMW) heparin on APP secretion was investigated. In contrast to full-length heparin, LMW heparin had no significant effect on APP secretion. However, LMW heparin fragments, especially heparin disaccharides, were able to inhibit efficiently the stimulatory effect of heparin on APP secretion. LMW heparin derivatives also inhibit the binding of heparin to the beta-amyloid peptide (1-28). Using an in vitro model, we further demonstrated the passage of LMW heparin derivatives through the blood-brain barrier. This study suggests that LMW heparin derivatives or analogues may be effective as therapeutic agents to prevent or slow the process of amyloidogenesis in Alzheimer's disease.
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PMID:Heparin oligosaccharides that pass the blood-brain barrier inhibit beta-amyloid precursor protein secretion and heparin binding to beta-amyloid peptide. 945 69

The beta-amyloid protein (Abeta), the major component of the senile plaques found in Alzheimer brains, derives from a larger beta-amyloid precursor protein (APP). Alternative splicing of the APP gene yields three major APP messenger RNAs (mRNAs), which, in turn, give rise to the APP770, APP751, and APP695 protein isoforms. In this study we examined the effects of thyroid hormone on APP expression in N2a-beta neuroblastoma cells. T3 caused a significant increase in the APP770 mRNA band, in detriment of the APP695 mRNA, which was proportionately reduced. In agreement with these results, T3 markedly altered the relative ratio of intracellular APP isoforms, increasing the amount of APP770 and causing an equivalent reduction of the immature APP695 isoform. In accordance with these results, the soluble APP695-derived form was specifically reduced in the culture medium obtained from T3-treated cells. In contrast, the increase in intracellular APP770 was not followed by an enhanced release of soluble derivatives of this isoform. These results suggest that T3 regulates not only APP gene splicing, but also the processing and secretion of the APP peptides. According to our results, thyroid hormone might play a role in the development of Alzheimer's disease by modulating the intracellular and extracellular contents of APP isoforms.
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PMID:Thyroid hormones regulate beta-amyloid gene splicing and protein secretion in neuroblastoma cells. 960 74


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