Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Amyloid-beta peptides (Abeta), generated by proteolysis of the beta-amyloid precursor protein (APP) by beta- and gamma-secretases, play an important role in the pathogenesis of Alzheimer disease (AD). Inflammation is also believed to be integral to the pathogenesis of AD. Here we show that prostaglandin E(2) (PGE(2)), a strong inducer of inflammation, stimulates the production of Abeta in cultured human embryonic kidney (HEK) 293 or human neuroblastoma (SH-SY5Y) cells, both of which express a mutant type of APP. We have demonstrated using subtype-specific agonists that, of the four main subtypes of PGE(2) receptors (EP(1-4)), EP(4) receptors alone or EP(2) and EP(4) receptors together are responsible for this PGE(2)-stimulated production of Abeta in HEK293 or SH-SY5Y cells, respectively. An EP(4) receptor antagonist suppressed the PGE(2)-stimulated production of Abeta in HEK293 cells. This stimulation was accompanied by an increase in cellular cAMP levels, and an analogue of cAMP stimulated the production of Abeta, demonstrating that increases in the cellular level of cAMP are responsible for the PGE(2)-stimulated production of Abeta. Immunoblotting experiments and direct measurement of gamma-secretase activity suggested that PGE(2)-stimulated production of Abeta is mediated by activation ofgamma-secretase but not of beta-secretase. Transgenic mice expressing the mutant type of APP showed lower levels of Abeta in the brain, when they were crossed with mice lacking either EP(2) or EP(4) receptors, suggesting that PGE(2)-mediated activation of EP(2) and EP(4) receptors is involved in the production of Abeta in vivo and in the pathogenesis of AD.
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PMID:Involvement of prostaglandin E2 in production of amyloid-beta peptides both in vitro and in vivo. 1776 11

Cellular cholesterol levels alter the processing of the amyloid precursor protein (APP) to produce Abeta. Activation of liver X receptors (LXRs), one cellular mechanism to regulate cholesterol homeostasis, has been found to alter Abeta levels in vitro and in vivo. To identify genes regulated by LXR, we treated human neuroblastoma cells with an LXR agonist (TO-901317) and examined gene expression by microarray. As expected, TO-901317 upregulated several cholesterol metabolism genes, but it also decreased expression of a metalloprotease inhibitor, TIMP-3. We confirmed this finding using real-time PCR and by measuring TIMP-3 protein in glia, SY5Y cells, and COS7 cells. TIMP-3 is a member of a family of metalloproteinase inhibitors and blocks A disintegrin and metalloproteinase-10 (ADAM-10) and ADAM-17, two APP alpha-secretases. We found that TIMP-3 inhibited alpha-secretase cleavage of APP and an apolipoprotein E (apoE) receptor, ApoER2. TIMP-3 decreased surface levels of ADAM-10, APP, and ApoER2. These changes were accompanied by increased APP beta-C-terminal fragment and Abeta production. These data suggest that TIMP-3 preferentially routes APP and ApoER2 away from the cell surface and alpha-secretase cleavage and encourages endocytosis and beta-secretase cleavage. In vivo, TO-901317 decreased brain TIMP-3 levels. TIMP-3 protein levels were increased in human Alzheimer's disease (AD) brain and in APP transgenic mice, suggesting that increased levels of TIMP-3 in AD may contribute to higher levels of Abeta.
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PMID:The metalloprotease inhibitor TIMP-3 regulates amyloid precursor protein and apolipoprotein E receptor proteolysis. 1791 23

Retinoic acid stimulates alpha-secretase processing of amyloid precursor protein (APP) and decreases beta-secretase cleavage that leads to amyloid-beta formation. Here, we investigated the effect of retinoic acid on the two putative alpha-secretases, the disintegrin metalloproteinases ADAM10 and TACE, and the beta-site cleaving enzyme BACE1, in human neuroblastoma SH-SY5Y cells. Western blot analysis showed that exposure to retinoic acid resulted in significantly increased levels of ADAM10 and TACE, suggesting that regulation of alpha-secretases causes the effects on APP processing. The presence of the phosphatidylinositol 3-kinase inhibitor LY 294002 selectively reduced the effect on ADAM10 protein levels but not on ADAM10 mRNA levels as determined by RT-PCR. On the other hand, the effect on TACE was shown to be dependent on protein kinase C, since it was completely blocked in the presence of the inhibitor bisindolylmaleimide XI. Our data indicate that different signalling pathways are involved in retinoic acid-induced up-regulation of the secretases.
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PMID:PI3-K- and PKC-dependent up-regulation of APP processing enzymes by retinoic acid. 1798 85

The proinflammatory cytokine interleukin (IL)-1beta is up-regulated in microglial cells surrounding amyloid plaques, leading to the hypothesis that IL-1beta is a risk factor for Alzheimer's disease. However, we unexpectedly found that IL-1beta significantly enhanced alpha-cleavage, indicated by increases in sAPPalpha and C83, but reduced beta-cleavage, indicated by decreases in sAPPbeta and Abeta40/42, in human neuroblastoma SK-N-SH cells. IL-1beta did not significantly alter the mRNA levels of BACE1, ADAM-9, and ADAM-10, but up-regulated that of TACE by threefold. The proform and mature form of TACE protein were also significantly up-regulated. A TACE inhibitor (TAPI-2) concomitantly reversed the IL-1beta-dependent increase in sAPPalpha and decrease in sAPPbeta, suggesting that APP consumption in the alpha-cleavage pathway reduced its consumption in the beta-cleavage pathway. IL-1Ra, a physiological antagonist for the IL-1 receptor, reversed the effects of IL-1beta, suggesting that the IL-1beta-dependent up-regulation of alpha-cleavage is mediated by the IL-1 receptor. IL-1beta also induced this concomitant increase in alpha-cleavage and decrease in beta-cleavage in mouse primary cultured neurons. Taken together we conclude that IL-1beta is an anti-amyloidogenic factor, and that enhancement of its signaling or inhibition of IL-1Ra activity could represent potential therapeutic strategies against Alzheimer's disease.
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PMID:Interleukin-1 beta up-regulates TACE to enhance alpha-cleavage of APP in neurons: resulting decrease in Abeta production. 1802 Dec 99

In Alzheimer's disease there is abnormal brain copper distribution, with accumulation of copper in amyloid plaques and a deficiency of copper in neighbouring cells. Excess copper inhibits Abeta (amyloid beta-peptide) production, but the effects of deficiency have not yet been determined. We therefore studied the effects of modulating intracellular copper levels on the processing of APP (amyloid precursor protein) and the production of Abeta. Human fibroblasts genetically disposed to copper accumulation secreted higher levels of sAPP (soluble APP ectodomain)alpha into their medium, whereas fibroblasts genetically manipulated to be profoundly copper deficient secreted predominantly sAPPbeta and produced more amyloidogenic beta-cleaved APP C-termini (C99). The level of Abeta secreted from copper-deficient fibroblasts was however regulated and limited by alpha-secretase cleavage. APP can be processed by both alpha- and beta-secretase, as copper-deficient fibroblasts secreted sAPPbeta exclusively, but produced primarily alpha-cleaved APP C-terminal fragments (C83). Copper deficiency also markedly reduced the steady-state level of APP mRNA whereas the APP protein level remained constant, indicating that copper deficiency may accelerate APP translation. Copper deficiency in human neuroblastoma cells significantly increased the level of Abeta secretion, but did not affect the cleavage of APP. Therefore copper deficiency markedly alters APP metabolism and can elevate Abeta secretion by either influencing APP cleavage or by inhibiting its degradation, with the mechanism dependent on cell type. Overall our results suggest that correcting brain copper imbalance represents a relevant therapeutic target for Alzheimer's disease.
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PMID:Intracellular copper deficiency increases amyloid-beta secretion by diverse mechanisms. 1824 25

Accumulation of senile plaques composed of amyloid beta-peptide (Abeta) is a pathological hallmark of Alzheimer disease (AD), and Abeta is generated through the sequential cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase. Although oxidative stress has been implicated in the AD pathogenesis by inducing Abeta production, the underlying mechanism remains elusive. Here we show that the pro-oxidant H(2)O(2) promotes Abeta production through c-Jun N-terminal kinase (JNK)-dependent activation of gamma-secretase. Treatment with H(2)O(2) induced significant increase in the levels of intracellular and secreted Abeta in human neuroblastoma SH-SY5Y cells. Although gamma-secretase-mediated cleavage of APP or C99 was enhanced upon H(2)O(2) treatment, expression of APP or its alpha/beta-secretase-mediated cleavage was not affected. Silencing of the stress-activated JNK by small interfering RNA or the specific JNK inhibitor SP600125 reduced H(2)O(2)-induced gamma-secretase-mediated cleavage of APP. JNK activity was augmented in human brain tissues from AD patients and active JNK located surrounding the senile plaques in the brain of AD model mouse. Our data suggest that oxidative stress-activated JNK may contribute to senile plaque expansion through the promotion of gamma-secretase-mediated APP cleavage and Abeta production.
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PMID:Hydrogen peroxide promotes Abeta production through JNK-dependent activation of gamma-secretase. 1843 31

Four new chromone glycosides allo-aloeresin D (2) , C-2'-decoumaroyl-aloeresin G (8), 2'-O-coumaroyl-(S)-aloesinol (9), 2'-O-[ P-methoxy-(E)-cinnamoyl]-(S)-aloesinol (10) and nine known chromone glycosides ( 1, 3 - 7, 11 - 13) were isolated from two Aloe spp. plants, A. vera and A. nobilis. Among them, 1 and 8 showed significant inhibitory activity against BACE1 (beta-secretase) with IC (50) values of 39.0 and 20.5 x 10 (-6) M, as well as inhibition of Abeta (1-42) production by 7.4 and 12.3 %, respectively, in B103 neuroblastoma cells at 30 ppm. The preliminary structure-activity relationships of ALOE chromone glucosides were also discussed.
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PMID:BACE1 (beta-secretase) inhibitory chromone glycosides from Aloe vera and Aloe nobilis. 1854 51

Cholesterol transport is a key regulator of amyloid precursor protein (APP) processing and beta-amyloid (Abeta production, implicated in Alzheimer's disease. Perturbation of cholesterol transport can be pharmacologically induced by the class II amphiphile 3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one, U18666a; however, the mechanisms by which U18666a controls APP metabolism and trafficking have not been elucidated. We proposed to determine how U18666a regulates APP holoprotein metabolism and trafficking in N2a mouse neuroblastoma cells stably expressing the human APP protein. Secretion of Abeta1-40 was reduced in U18666a-treated cells. U18666a elevated the steady state level of the APP holoprotein but not APP mRNA levels. U18666a increased sAPPalpha secretion and intracellular alpha-CTF/C83 levels but intracellular betaCTF/C99 levels were reduced. The increase in APP protein level was due to decreased catabolism rather than increased APP synthesis. Interestingly, U18666a regulated APP trafficking and increased the level of the holoprotein at the cell surface for alpha-secretase processing and reduced internalization for beta-secretase processing. These data demonstrate that U18666a effects on cholesterol transport function to regulate amyloid precursor protein metabolism and trafficking.
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PMID:The cholesterol transport inhibitor U18666a regulates amyloid precursor protein metabolism and trafficking in N2aAPP "Swedish" cells. 1885 86

Alzheimer disease beta-amyloid (Abeta) peptides are generated via sequential proteolysis of amyloid precursor protein (APP) by BACE1 and gamma-secretase. A subset of BACE1 localizes to cholesterol-rich membrane microdomains, termed lipid rafts. BACE1 processing in raft microdomains of cultured cells and neurons was characterized in previous studies by disrupting the integrity of lipid rafts by cholesterol depletion. These studies found either inhibition or elevation of Abeta production depending on the extent of cholesterol depletion, generating controversy. The intricate interplay between cholesterol levels, APP trafficking, and BACE1 processing is not clearly understood because cholesterol depletion has pleiotropic effects on Golgi morphology, vesicular trafficking, and membrane bulk fluidity. In this study, we used an alternate strategy to explore the function of BACE1 in membrane microdomains without altering the cellular cholesterol level. We demonstrate that BACE1 undergoes S-palmitoylation at four Cys residues at the junction of transmembrane and cytosolic domains, and Ala substitution at these four residues is sufficient to displace BACE1 from lipid rafts. Analysis of wild type and mutant BACE1 expressed in BACE1 null fibroblasts and neuroblastoma cells revealed that S-palmitoylation neither contributes to protein stability nor subcellular localization of BACE1. Surprisingly, non-raft localization of palmitoylation-deficient BACE1 did not have discernible influence on BACE1 processing of APP or secretion of Abeta. These results indicate that post-translational S-palmitoylation of BACE1 is not required for APP processing, and that BACE1 can efficiently cleave APP in both raft and non-raft microdomains.
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PMID:Alzheimer disease Abeta production in the absence of S-palmitoylation-dependent targeting of BACE1 to lipid rafts. 1907 28

Research into the cause of Alzheimer's disease (AD) has identified strong connections to cholesterol. Cholesterol and cholesterol esters can modulate amyloid precursor protein (APP) processing, thus altering production of the Abeta peptides that deposit in cortical amyloid plaques. Processing depends on the encounter between APP and cellular secretases, and is thus subject to the influence of cholesterol-dependent factors including protein trafficking, and distribution between membrane subdomains. We have directly investigated endogenous membrane beta-secretase activity in the presence of a range of membrane cholesterol levels in SH-SY5Y human neuroblastoma cells and human platelets. Membrane cholesterol significantly influenced membrane beta-secretase activity in a biphasic manner, with positive correlations at higher membrane cholesterol levels, and negative correlations at lower membrane cholesterol levels. Platelets from individuals with AD or mild cognitive impairment (n = 172) were significantly more likely to lie within the negative correlation zone than control platelets (n = 171). Pharmacological inhibition of SH-SY5Y beta-secretase activity resulted in increased membrane cholesterol levels. Our findings are consistent with the existence of a homeostatic feedback loop between membrane cholesterol level and membrane beta-secretase activity, and suggest that this regulatory mechanism is disrupted in platelets from individuals with cognitive impairment.
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PMID:A novel reciprocal and biphasic relationship between membrane cholesterol and beta-secretase activity in SH-SY5Y cells and in human platelets. 1909 65


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