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

The amyloid beta-protein (Abeta) is an approximately 4 kD secreted protein normally found in human plasma and cerebrospinal fluid. Abeta is invariably deposited as insoluble amyloid fibrils in the brains of patients with Alzheimer's disease (AD), and there is increasing evidence that Abeta deposition plays an important role in AD pathogenesis. Abeta is released from the larger beta-amyloid precursor protein (betaAPP) through cleavage on the amino and carboxyl side of Abeta by proteolytic activities referred to as beta and gamma secretase, respectively. betaAPP is also cleaved at Abeta16 by a third protease, alpha secretase, which may prevent amyloid deposition by bisecting the Abeta peptide. Tacrine, a cholinesterase inhibitor, has been shown to improve memory and cognitive functions in some patients with AD, and we have previously demonstrated that it significantly reduces the levels of the secretion of soluble betaAPP fragments (sAPP) in cultured cells. In this study, we extended our studies by analysis of Abeta40 and Abeta42 and report that in a human neuroblastoma cell line tacrine reduced the levels of total Abeta, Abeta40 and Abeta42 in addition to sAPP. These inhibitory results cannot be attributed to a reduction in total betaAPP synthesis as tacrine treatment did not cause a significant change in the rate of betaAPP synthesis. Furthermore, significant toxicity was not observed in tacrine-treated cultures as determined by analysis of lactate dehydrogenase (LDH) in the conditioned media. Taken together, these results suggest that tacrine affects the processing of betaAPP by alterations in betaAPP trafficking and/or increased intracellular proteolysis. This study raises the possibility that tacrine may aid in the treatment of AD due to its effects on betaAPP processing as well as by its effects on the cholinergic pathway.
 ...
PMID:The secretion of amyloid beta-peptides is inhibited in the tacrine-treated human neuroblastoma cells. 981 82

Amyloid beta peptide (Abeta), a proteolytic fragment of the amyloid precursor protein (APP), is a major component of the plaques found in the brain of Alzheimer's disease (AD) patients. These plaques are thought to cause the observed loss of cholinergic neurons in the basal forebrain of AD patients. In these neurons, particularly those of the nucleus basalis of Meynert, an up-regulation of 75kD-neurotrophin receptor (p75NTR), a nonselective neurotrophin receptor belonging to the death receptor family, has been reported. p75NTR expression has been described to correlate with beta-amyloid sensitivity in vivo and in vitro, suggesting a possible role for p75NTR as a receptor for Abeta. Here we used a human neuroblastoma cell line to investigate the involvement of p75NTR in Abeta-induced cell death. Abeta peptides were found to bind to p75NTR resulting in activation of NFKB in a time- and dose-dependent manner. Blocking the interaction of Abeta with p75NTR using NGF or inhibition of NFKB activation by curcumin or NFKB SN50 attenuated or abolished Abeta-induced apoptotic cell death. The present results suggest that p75NTR might be a death receptor for Abeta, thus being a possible drug target for treatment of AD.
 ...
PMID:Beta-amyloid binds to p57NTR and activates NFkappaB in human neuroblastoma cells. 985 63

The excessive generation and accumulation of 40- and 42-aa beta-amyloid peptides (Abeta40/Abeta42) in selectively vulnerable brain regions is a major neuropathological feature of Alzheimer's disease. Abeta, derived by proteolytic cleavage from the beta-amyloid precursor protein (betaAPP), is normally secreted. However, recent evidence suggests that significant levels of Abeta also may remain inside cells. Here, we have investigated the subcellular compartments within which distinct amyloid species are generated and the compartments from which they are secreted. Three experimental approaches were used: (i) immunofluorescence performed in intact cortical neurons; (ii) sucrose gradient fractionation performed with mouse neuroblastoma cells stably expressing wild-type betaAPP695 (N2a695); and (iii) cell-free reconstitution of Abeta generation and trafficking from N2a695 cells. These studies demonstrate that: (i) Abeta40 (Abeta1-40 plus Abetax-40, where x is an NH2-terminal truncation) is generated exclusively within the trans-Golgi Network (TGN) and packaged into post-TGN secretory vesicles; (ii) Abetax-42 is made and retained within the endoplasmic reticulum in an insoluble state; (iii) Abeta42 (Abeta1-42 plus Abetax-42) is made in the TGN and packaged into secretory vesicles; and (iv) the amyloid peptides formed in the TGN consist of two pools (a soluble population extractable with detergents and a detergent-insoluble form). The identification of the organelles in which distinct forms of Abeta are generated and from which they are secreted should facilitate the identification of the proteolytic enzymes responsible for their formation.
 ...
PMID:Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer beta-amyloid peptides. 989 4

Metalloprotease MP100 was originally isolated as a beta-secretase candidate from human brain using a beta-amyloid precursor protein (beta-APP)-derived p-nitroanilide (pNA) peptide substrate. Peptide sequences from purified MP100 were now found to resemble sequences reported for a puromycin-sensitive aminopeptidase (PSA) highly enriched in brain, and cDNA cloning revealed nearly complete homology of MP100 to PSA, with only a single bp difference resulting in an amino acid change at position 184. Another MP100 cDNA encoded a protein with a 36-amino acid deletion (positions 180-217) and a two-amino acid insertion after Val533. Purified recombinant human MP100 cleaved the original pNA substrate as well as a free beta-site-spanning amyloid beta (A beta) peptide (A beta(-10/+10)), generating A beta(1-10). The latter substrate, however, remained uncleaved, if N- and C-terminally blocked, and also purified beta-APP was not cleaved. Double immunoimaging revealed partial, patchy, colocalization of beta-APP and MP100 in doubly transfected human embryonic kidney cells (HEK cells) and in normal neuroblastoma cells, and both proteins could be coimmunoprecipitated from rat brain extracts, suggesting their close vicinity in vivo. Coexpression of MP100 and beta-APP695, however, did not boost A beta levels in HEK cells, although active enzyme was produced. Thus, MP100 does not exert true beta-secretase-like function in cells, although it may well act as a secondary exoprotease in a complex beta-APP/A beta metabolism.
 ...
PMID:cDNA cloning and molecular characterization of human brain metalloprotease MP100: a beta-secretase candidate? 1003 94

The presence of the alpha2macroglobulin receptor/low density lipoprotein receptor-related protein (alpha2Mr/LRP) and its ligands alpha2macroglobulin (alpha2M), apoliprotein E, and plasminogen activators was detected in senile plaques of Alzheimer's disease (AD). To explore a possible role of alpha2M in neurodegenerative processes occurring in AD, we analyzed the effect of alpha2M on Abeta 25-35-induced neurotoxicity. Treatment of LAN5 human neuroblastoma cells with 10 microM beta-amyloid peptide fragment 25-35 (Abeta 25-35) for 72 h resulted in a 50% decrease in cell viability as determined by MTT incorporation and cell counts. The addition of alpha2M to the culture medium of these cells did not determine any effect, but when the activated form alpha2M* was used a dose-dependent decrease in cell viability was observed, the maximum effect being reached at 140 and 280 nM. Moreover, treatment of LAN5 cells with alpha2M* in combination with Abeta 25-35 increased the neurotoxicity of the amyloid peptide by 25%. This neurotoxic effect of alpha2M* seems to be related to its capability to bind and inactivate TGFbeta in the culture medium, since it was mimicked by a TGFbeta neutralizing antibody. A possible involvement of receptor-mediated endocytosis was ruled out, since alpha2M receptor is not present on LAN5, as revealed by RT-PCR and Western blotting experiments. The presence of alpha2M* in amyloid deposits of Alzheimer's disease has been recently reported and a possible impairment of LRP internalization processes has been hypothesized. Our data suggest that the local accumulation of alpha2M* in AD plaques may increase Abeta 25-35-induced neurotoxicity by neutralizing TGFbeta-mediated neuroprotective mechanisms.
 ...
PMID:Activated alpha2macroglobulin increases beta-amyloid (25-35)-induced toxicity in LAN5 human neuroblastoma cells. 1007

Numerous lines of evidence suggest that some of the neurotoxicity associated with Alzheimer's disease (AD) is due to proteolytic fragments of the amyloid precursor protein (APP). Most research has focused on the amyloid beta peptide (Abeta). However, the possible role of other cleaved products of APP is less clear. We have previously shown that a recombinant carboxy-terminal 105 amino acid fragment (CT 105) of APP induced strong non-selective inward currents and also showed neurotoxicity in PC 12 cells and primary cortical neurons and blocked later phase of long term potentiation (LTP) in rat hippocampus in vivo. In this study, we investigated the effects of CT 105 on Na+-Ca2+ exchanger activity in SK-N-SH human neuroblastoma, in the presence of ouabain and monensin, which are considered to drive Na+-Ca2+ exchanger in the reverse mode. CT 105 inhibited the activity of this exchanger in SK-N-SH cells by approximately 50%.
 ...
PMID:C-terminal fragment of Alzheimer's amyloid precursor protein inhibits sodium/calcium exchanger activity in SK-N-SH cell. 1009 44

The molecular mechanisms of the nonamyloidogenic and the amyloidogenic pathways of the amyloid precursor protein (APP) are unknown, but proteolysis of APP is essential for the generation of beta-amyloid. To study the time-course of C-terminal fragment generation by alpha- and beta-secretase, we expressed the APP751 isoform with the Swedish mutation in the human neuroblastoma cell line SY5Y as previously described (Urmoneit et al., 1995). We show in pulse-chase experiments that the C-terminal fragments, CT, generated by alpha-secretase and A4CT, generated by beta-secretase, could be generated from immature full-length APP before O-glycosylation is completed. Thus beta A4 may be generated from immature APP that has not passed through the trans-Golgi-network (TGN), which presents experimental evidence for the intracellular localization of beta-secretase activity in an earlier Golgi complex.
 ...
PMID:Pulse-chase experiments revealed beta-secretase cleavage from immature full-length amyloid precursor protein harboring the Swedish mutation. Implications for distinct pathways. 1009 41

We have investigated the functional relationship between metalloendopeptidase EC 3.4.24.15 (MP24.15) and the amyloid precursor protein involved in Alzheimer's disease (AD) and discovered that the enzyme promotes Abeta degradation. We show here that conditioned medium (CM) of MP24.15 antisense-transfected SKNMC neuroblastoma has significantly higher levels of Abeta. Furthermore, synthetic-Abeta degradation was increased or decreased following incubation with CM of sense or antisense-transfected cells, respectively. Soluble Abeta1-42 was degraded more slowly than soluble Abeta1-40, while aggregated Abeta1-42 showed almost no degradation. Pretreatment of CM with serine proteinase inhibitors 4-(2-aminoethyl)benzenesulfonyl fluoride and diisopropyl fluorophosphate completely inhibited Abeta degradation. Additionally, alpha1-antichymotrypsin (ACT), a serpin family inhibitor tightly associated with plaques and elevated in AD brain, blocked up to 60% of Abeta degradation. Interestingly, incubation of CM of MP24. 15-overexpressing cells with ACT formed an SDS-resistant ACT complex, suggesting an ACT-serine proteinase interaction. Recombinant MP24. 15 alone did not degrade Abeta. 14C-Diisopropyl fluorophosphate-radiolabeled CM from MP24.15-overexpressing cells contained increased levels of several active serine proteinases, suggesting that MP24.15 activates one or more Abeta-degrading serine proteases. Thus, ACT may cause Abeta accumulation by inhibiting an Abeta-degrading enzyme or by direct binding to Abeta, rendering it degradation-resistant. Identification of the Abeta-degrading enzyme and MP24.15's role in its activation is underway. Pharmacological modulation of either enzyme may provide a means of regulating Abeta in the brain.
 ...
PMID:Metalloendopeptidase EC 3.4.24.15 is necessary for Alzheimer's amyloid-beta peptide degradation. 1037 94

Alzheimer's disease (AD) is characterized by the aggregation of the amyloid beta-peptide (Abeta) which is generated from a larger beta-amyloid precursor protein (betaAPP). An overexpression of the betaAPP gene in certain areas of the AD brain has been suggested to be an important factor in the neuropathology of AD. Here we have further characterized an upstream regulatory element (URE) located between -2257 and -2234 of the human betaAPP promoter. In addition to its location in the promoter, BLAST search reveals that URE is present in several introns of the betaAPP gene and is also detected in many other genes. For functional studies, two promoter regions were cloned upstream of the reporter gene, chloramphenicol acetyl transferase (CAT): (i) phbetaE-B - the plasmid that contains the human (h) promoter region (-2832 to +101) including URE, and (ii) prhbetaE-B - the plasmid that contains the rhesus (rh) promoter region excluding URE as it lacks a 270 bp region of the hbetaAPP promoter (-2435 to -2165). Transient transfection studies indicate that phbetaE-B displayed significantly less CAT-promoter activity than prhbetaE-B in C6, PC12 and SK-N-SH cells. To determine the role of URE in a heterologous promoter, a pbetaURE construct was made by subcloning URE in an enhancerless promoter vector pCATP. The pbetaURE-CAT construct displayed threefold to fourfold less promoter activity than pCATP when different cell lines were transfected with the plasmids. URE interacts with a novel protein(s) as determined by the electrophoretic mobility shift assay (EMSA). Although the core DNA region of URE resembles with the NF-kB element, URE-binding protein is not related to the NF-kB transcription factor. When EMSA was performed with specific competitors in different cell lines, the labeled URE probe was not competed by the oligonucleotides specific for either the AP3, NF-1 or NF-kB transcription factor. The migration of the URE-protein complex was different from the NF-kB-protein complex in the EMSA gel. A distinct URE-specific nuclear factor was also detected in frontal cortex of a normal human brain. These results suggest that the URE region acts as a repressor element, that the URE-binding protein is not related to the known transcription factors tested, and that the protein is present in astrocytic, neuroblastoma, PC12 cells and in the human brain.
 ...
PMID:Promoter activity of the beta-amyloid precursor protein gene is negatively modulated by an upstream regulatory element. 1040 84

In clinical studies, it has been shown that estrogen replacement therapy in menopause is strongly correlated with a reduced risk of the development of Alzheimer's disease (AD). In in vitro experiments, it was demonstrated that estradiol protects cells against the toxic effects of beta-amyloid, the major component of plaques in brains of AD patients. Therefore, estrogens have become interesting candidates for a possible treatment of neurodegeneration. In plants, a class of compounds has been identified that bind to human estrogen receptor, so-called phytoestrogens, which are part of our daily diet. Here, we compared the effects of alpha- and beta-estradiol with plant-derived kaempferol on beta-amyloid peptide-induced toxicity in PC12 neuroblastoma and T47D human breast cancer cells. The present results demonstrate a protective effect of kaempferol comparable to that observed with estradiol. The effects of the weak estrogen receptor agonists alpha-estradiol and kaempferol were found to be similar to the effects of the strong estrogen receptor agonist beta-estradiol, suggesting a mode of action independent from the nuclear estrogen receptor.
 ...
PMID:Phytoestrogen kaempferol (3,4',5,7-tetrahydroxyflavone) protects PC12 and T47D cells from beta-amyloid-induced toxicity. 1041 31


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>