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)

Alzheimer's disease (AD) is more prevalent following an ischemic or hypoxic episode, such as stroke. Indeed, brain levels of amyloid precursor protein (APP) and the cytotoxic amyloid beta peptide (Abeta) fragment are enhanced in these patients and in animal models following experimental ischaemia. We have investigated the effect of chronic hypoxia (CH; 2.5% O2, 24 h) on processing of APP in the human neuroblastoma, SH-SY5Y. We demonstrate that constitutive and muscarinic-receptor-enhanced secretion of the alpha-secretase cleaved fragment of APP, sAPPalpha, was reduced by approximately 60% in CH cells. The caspase inhibitor BOC-D(Ome)FMK did not reverse this effect of CH, and CH cells were as viable as controls, based on MTT assays. Thus, loss of sAPPalpha is not related to cell death or caspase processing of APP. Pre-incubation with antioxidants did not reverse the effect of CH, and the effect could not be mimicked by H2O2, discounting the involvement of reactive oxygen species in hypoxic loss of sAPPalpha. CH did not affect muscarinic activation of extracellular-signal regulated kinase. However, expression of ADAM 10 (widely believed to be alpha-secretase) was decreased approximately 50% following CH. Thus, CH selectively decreases processing of APP by the alpha-secretase pathway, most likely by decreasing levels of ADAM 10.
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PMID:Altered processing of amyloid precursor protein in the human neuroblastoma SH-SY5Y by chronic hypoxia. 1247 81

Acetylcholinesterase inhibitors (AChEIs) are the only currently available drugs for treating Alzheimer's Disease (AD). Some authors have suggested a function of AChEIs not only in the induction of AChE overproduction and alternative splicing shifts but also a possible role of these drugs in amyloid metabolism beyond their well-known symptomatic effect. Here, we investigate the mechanisms of action of the AChEI donepezil on APP (amyloid precursor protein) metabolism and on the activity/trafficking of the alpha-secretase candidate ADAM 10, in differentiated human neuroblastoma cells (SH-SY5Y). In these cells, the activity of AChE is significantly decreased after 2 h of donepezil treatment. Further, SH-SY5Y cells released significantly more sAPPalpha into the medium, whereas total APP levels in cell lysates were unchanged. Interestingly, treated cells showed increased ADAM 10 levels in membrane compartments. This effect was prevented by pretreatment with tunicamycin or brefeldin, suggesting that donepezil affects trafficking and/or maturation of ADAM 10; additionally, this pretreatment significantly decreased sAPPalpha levels. Pre-incubation with atropine decreased release of sAPPalpha significantly but did not revert ADAM 10 activity to control levels further suggesting that donepezil acts not solely through a purely receptor mediated pathway. These findings indicate that donepezil exerts multiple mechanisms involving processing and trafficking of key proteins involved in AD pathogenesis.
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PMID:Acetylcholinesterase inhibitors increase ADAM10 activity by promoting its trafficking in neuroblastoma cell lines. 1534 32

Clinical studies suggest that the incidence of Alzheimer's disease (AD) is increased following an ischaemic or hypoxic episode, such as stroke. Furthermore, levels of the AD-associated amyloid beta-peptides (Abeta) and the amyloid precursor protein (APP) are enhanced in experimental ischaemia. In our previous study [Webster, N.J., Green, K.N., Peers, C., Vaughan, P.F., Altered processing of amyloid precursor protein in the human neuroblastoma SH-SY5Y by chronic hypoxia, J. Neurochem., 83 (2002) 1262-1271] we reported that exposing cells of neuronal origin to a period of chronic hypoxia (CH; 2.5% O(2), 24 h) led to a decrease in processing of the amyloid precursor protein (APP) by the alternative and neuroprotective alpha-secretase pathway. In SH-SY5Y cells, the most likely mechanism was that CH inhibits the protein level of ADAM 10, a disintegrin metalloprotease widely believed to be the alpha-secretase. One effect of CH is to alter the activity of the stress-activated protein kinases (SAPKs) c-Jun amino terminal kinase (JNK) and p38. Thus, the main aims of this study were to investigate the effect of CH on (1) the activity of these SAPKs in SH-SY5Y and (2) whether changes in the activity of these kinases may account for the CH-induced decreases in ADAM 10 expression and sAPPalpha secretion. We demonstrated that the phosphorylation (activity) of JNK was decreased approximately 50% following a period of CH. An inhibitor of JNK did not mimic the effects of CH on either ADAM 10 expression or sAPPalpha secretion under conditions in which the phosphorylation of c-Jun was inhibited by approximately 80%. Thus the loss of JNK activity does not appear to be linked to the decrease in expression of ADAM 10 and secretion of sAPPalpha. In contrast, phosphorylation (activity) of p38 was enhanced approximately 300% following a period of CH. However, inhibitors of p38 were unable to reverse the loss of sAPPalpha in CH cells, indicating that this increase in activity was not linked to the altered processing of APP.
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PMID:Altered processing of the amyloid precursor protein and decreased expression of ADAM 10 by chronic hypoxia in SH-SY5Y: no role for the stress-activated JNK and p38 signalling pathways. 1551 86

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has neurotrophic as well as anti-apoptotic properties and is involved in learning and memory processes. Its specific G protein-coupled receptor PAC1 is expressed in several central nervous system (CNS) regions, including the hippocampal formation. Here we examined the effect of PAC1 receptor activation on alpha-secretase cleavage of the amyloid precursor protein (APP) and the production of secreted APP (APPsalpha). Stimulation of endogenously expressed PAC1 receptors with PACAP in human neuroblastoma cells increased APPsalpha secretion, which was completely inhibited by the PAC1 receptor specific antagonist PACAP-(6-38). In HEK cells stably overexpressing functional PAC1 receptors, PACAP-27 and PACAP-38 strongly stimulated alpha-secretase cleavage of APP. The PACAP-induced APPsalpha production was dose dependent and saturable. This increase of alpha-secretase activity was completely abolished by hydroxamate-based metalloproteinase inhibitors, including a preferential ADAM 10 inhibitor. By using several specific protein kinase inhibitors, we show that the MAP-kinase pathway [including extracellular-regulated kinase (ERK) 1 and ERK2] and phosphatidylinositol 3-kinase mediate the PACAP-induced alpha-secretase activation. Our findings provide evidence for a role of the neuropeptide PACAP in stimulation of the nonamyloidogenic pathway, which might be related to its neuroprotective properties.
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PMID:The neuropeptide PACAP promotes the alpha-secretase pathway for processing the Alzheimer amyloid precursor protein. 1640 44

The nature of the association between ischemic stroke and Alzheimer's disease (AD) at the cellular and molecular level is still unknown. We evaluated the effect of ischemic neuronal insults on the regulation of amyloid precursor protein (APP) processing. We used an in vitro model of cerebral ischemia (oxygen-glucose deprivation) to evaluate the effect of ischemic neuronal insults on the amyloidogenic and non-amyloidogenic pathways using human neuroblastoma cell line and primary cultured cells of transgenic mice which expressed human APP (Tg2576). Ischemic neuronal insults increased the production of Abeta in Tg2576 primary culture cells compared to controls. A disintegrin and metalloprotease 10 (ADAM 10) was markedly increased in early stage of ischemic insults, which was followed by decreased level of ADAM 10 expression in later stage. The protein and mRNA expression of beta-site cleavage enzyme (BACE) and BACE activity was not significantly different between the group of ischemic insults and control. By contrast, the activity of gamma-secretase was significantly increased after 4 h of ischemic insults, as compared to controls. The present study showed that the ischemic neuronal insults increased the production of Abeta by influencing APP metabolism, which may link the role of ischemic insults to the pathogenesis of AD.
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PMID:Effect of ischemic neuronal insults on amyloid precursor protein processing. 1679 58