UMLS:C0043167 - FACTA Search

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The amyloid beta protein (25-35) stimulated appearance of 3H-inositol phosphates from [3H]inositol-prelabeled LA-N-2 cells was investigated. This stimulation was unaltered by extra- and intracellular calcium chelators in a calcium-free medium or by several protein kinase inhibitors. This phospholipase C stimulation by amyloid beta protein appeared to be pertussis toxin sensitive. It is possible that this phospholipase C stimulation by amyloid beta protein is a receptor-mediated process. This possibility is based on two related observations. The stimulation is ablated by the presence of conventional antagonists for metabotropic, adrenergic, and bombesin agonists. The IC50 values were 12 microM for propranolol, 15 microM for AP-3, and 25 nM for [Tyr4,D-Phe12]bombesin. Additional support comes from results of desensitization and resensitization experiments. Amyloid beta protein stimulation of phospholipase C was absent from LA-N-2 cells previously treated with norepinephrine, trans-1-amino-1,3-cyclopentanedicarboxylic acid (t-ACPD), bombesin, or amyloid beta peptide. In a similar manner, LA-N-2 cells previously treated with amyloid beta protein were no longer responsive to norepinephrine, t-ACPD, or bombesin. The responsiveness to amyloid beta protein returned, subsequent to a period of resensitization for the individual agonists. It is suggested that this observed amyloid beta protein stimulation of phospholipase C may be responsible for the elevated quantity of inositol seen in the brains of Alzheimer's disease patients.
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PMID:Amyloid beta protein (25-35) stimulation of phospholipase C in LA-N-2 cells. 920 17

Amyloid beta protein is the major protein component of neuritic plaques found in the brain of Alzheimer's disease. The activation of phospholipase D by amyloid beta protein (25-35), quisqualate and phorbol 12, 13-dibutyrate was investigated in LA-N-2 cells by measuring phosphatidylethanol formation. The activation of phospholipase D by quisqualate and APP (25-35) was calcium-independent. The AbetaP (25-35) and quisqualate activation of phospholipase D appeared to be mediated through a pertussis toxin-sensitive GTP-binding protein. Phospholipase D activation by AbetaP (25-35), quisqualate and phorbol dibutyrate was not blunted by the protein kinase C inhibitors, staurosporine, H-7 and RO-31-8220. However, it was abolished by overnight exposure to phorbol dibutyrate. This activation of phospholipase D was prevented by the tyrosine kinase inhibitor, genistein but not by tyrophostin A. Several excitatory amino acid antagonists were tested for their ability to prevent the phospholipase D activation by quisqualate and AbetaP (25-35). Only NBQX was effective with an IC50 of 75 microM for AbetaP (25-35) and quisqualate. Activation of phospholipase D by AbetaP or quisqualate was absent in LA-N-2 cells previously desensitized by quisqualate or AbetaP (25-35), but the activation by phorbol dibutyrate was unaltered. The responsiveness to AbetaP and quisqualate in previously desensitized cells reappeared subsequent to a period of resensitization. The observations with the antagonist NBQX, and the desensitization and resensitization experiments, are consistent with a receptor occupancy mediated activation of phospholipase D by quisqualate and by AbetaP (25-35).
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PMID:Activation of LA-N-2 cell phospholipase D by amyloid beta protein (25-35). 980 77

Myristoylated alanine-rich C kinase substrate (MARCKS) is a widely distributed specific protein kinase C (PKC) substrate and has been implicated in membrane trafficking, cell motility, secretion, cell cycle, and transformation. We found that amyloid beta protein (A beta) (25-35) and A beta (1-40) phosphorylate MARCKS in primary cultured rat microglia. Treatment of microglia with A beta (25-35) at 10 nM or 12-O-tetradecanoylphorbol 13-acetate (1.6 nM) led to phosphorylation of MARCKS, an event inhibited by PKC inhibitors, staurosporine, calphostin C, and chelerythrine. The A beta (25-35)-induced phosphorylation of MARCKS was inhibited by pretreatment with the tyrosine kinase inhibitors genistein and herbimycin A, but not with pertussis toxin. PKC isoforms alpha, delta, and epsilon were identified in microglia by immunocytochemistry and western blots using isoform-specific antibodies. PKC-delta was tyrosine-phosphorylated by the treatment of microglia for 10 min with A beta (25-35) at 10 nM. Other PKC isoforms alpha and epsilon were tyrosine-phosphorylated by A beta (25-35), but only to a small extent. We propose that a tyrosine kinase-activated PKC pathway is involved in the A beta (25-35)-induced phosphorylation of MARCKS in rat microglia.
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PMID:Amyloid beta protein (25-35) phosphorylates MARCKS through tyrosine kinase-activated protein kinase C signaling pathway in microglia. 1003 91

Modulation of GTPase and adenylate cyclase (ATP pyrophosphate-lyase, EC 4.6.1.1) activity by Alzheimer's disease related amyloid beta-peptide, A beta (1-42), and its shorter fragments, A beta (12-28), A beta (25-35), were studied in isolated membranes from rat ventral hippocampus and frontal cortex. In both tissues, the activity of GTPase and adenylate cyclase was upregulated by A beta (25-35), whereas A beta (12-28) did not have any significant effect on the GTPase activity and only weakly influenced adenylate cyclase. A beta (1-42), similar to A beta (25-35), stimulated the GTPase activity in both tissues and adenylate cyclase activity in ventral hippocampal membranes. Surprisingly, A beta (1-42) did not have a significant effect on adenylate cyclase activity in the cortical membranes. At high concentrations of A beta (25-35) and A beta (1-42), decreased or no activation of adenylate cyclase was observed. The activation of GTPase at high concentrations of A beta (25-35) was pertussis toxin sensitive, suggesting that this effect is mediated by Gi/G(o) proteins. Addition of glutathione and N-acetyl-L-cysteine, two well-known antioxidants, at 1.5 and 0.5 mM, respectively, decreased A beta (25-35) stimulated adenylate cyclase activity in both tissues. Lys-A beta (16-20), a hexapeptide shown previously to bind to the same sequence in A beta-peptide, and prevent fibril formation, decreased stimulation of adenylate cyclase activity by A beta (25-35), however, NMR diffusion measurements with the two peptides showed that this effect was not due to interactions between the two and that A beta (25-35) was active in a monomeric form. Our data strongly suggest that A beta and its fragments may affect G-protein coupled signal transduction systems, although the mechanism of this interaction is not fully understood.
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PMID:Regulation of GTPase and adenylate cyclase activity by amyloid beta-peptide and its fragments in rat brain tissue. 1062 63

Compound 24, an alkyl-substituted amino acid amide, previously found to activate pertussis toxin-sensitive G proteins in cell membranes and membrane protein fractions, was used as a tool to determine the mechanism/location of nicotine inhibition of amyloid beta peptide-stimulated phospholipase A2 and D activities in a human neuroblastoma cell line, LA-N-2, in vitro. In contrast to our previous findings with amyloid beta peptide, these phospholipase activations by compound 24 were not inhibited by (-)-nicotine, cholera toxin or tetanus toxin pretreatment. The contrasting activation of these phospholipases by amyloid beta peptide and compound 24 are discussed.
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PMID:Activation of phospholipases A2 and D of a human neuroblastoma cell line (LA-N-2) by N-dodecyl-L-lysine amide (compound 24), a putative G protein activator: characteristics of inhibition by (-)-nicotine. 1251 13

Amyloid precursor protein (AbetaPP), a precursor of amyloid beta (Abeta) peptide, is one of the molecules involved in the pathogenesis of Alzheimer's disease (AD). Specific mutations in AbetaPP have been found in patients inheriting familial AD (FAD). These mutant AbetaPP proteins cause cell death in neuronal cell lines in vitro, but the molecular mechanism of cytotoxicity has not yet been clarified completely. We analyzed the cytotoxic mechanisms of the London-type AbetaPP mutant, V642I-AbetaPP, in primary cortical neurons utilizing an adenovirus-mediated gene transfer system. Expression of V642I-AbetaPP protein induced degeneration of the primary neurons. This cytotoxicity was blocked by pertussis toxin, a specific inhibitor for heterotrimeric G proteins, Go/i, and was suppressed by an inhibitor of caspase-3/7 and an antioxidant, glutathione ethyl ester. A specific inhibitor for NADPH oxidase, apocynin, but not a xanthine oxidase inhibitor or a nitric oxide inhibitor, blocked V642I-AbetaPP-induced cytotoxicity. Among mitogen-activated protein kinase (MAPK) family proteins, c-Jun N-terminal kinase (JNK) and p38MAPK, but not extracellular regulated kinase (ERK), were involved in this cytotoxic pathway. The V642I-AbetaPP-induced cytotoxicity was not suppressed by two secretase inhibitors, suggesting that Abeta does not play a major role in this cytotoxicity. Two neuroprotective factors, insulin-like growth factor I (IGF-I) and Humanin, protected these primary neurons from V642I-AbetaPP-induced cytotoxicity. Furthermore, interleukin-6 and -11 also attenuated this cytotoxicity. This study demonstrated that the signaling pathway activated by mutated AbetaPP in the primary neurons is the same as that by the other artificial insults such as antibody binding to AbetaPP and the artificial dimerization of cytoplasmic domain of AbetaPP. The potential of neurotrophic factors and cytokines in AD therapy is also indicated.
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PMID:Characterization of V642I-AbetaPP-induced cytotoxicity in primary neurons. 1519 38

Human G protein-coupled formyl peptide receptor like 1 (FPRL1) and its mouse homologue murine formyl peptide receptor 2 (mFPR2) mediate the chemotactic activity of amyloid beta 1-42 (Abeta42), a key pathogenic peptide in Alzheimer's disease (AD). Since mFPR2 is up-regulated in mouse microglia by lipopolysaccharide (LPS), a Toll-like receptor 4 ligand, we investigated the capacity of CpG-containing oligodeoxynucleotide (ODN), a Toll-like receptor (TLR) 9 ligand, to regulate the expression of mFPR2 in mouse microglia. CpG ODN markedly enhanced the expression and function of mFPR2 in microglial cells, which exhibited increased chemotactic responses to mFPR2 agonists, including Abeta42. The effect of CpG ODN is dependent on activation of p38 MAPK. Further studies showed that CpG ODN-treated microglia increased their capacity to endocytose Abeta42 through mFPR2, as this process was abrogated by pertussis toxin, a Gi protein inhibitor, and W peptide, another potent mFPR2 agonist. Our results suggest that TLR9 may play an important role in promoting microglial recognition of Abeta42, thus affecting the pathogenic process of AD.
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PMID:CpG-containing oligodeoxynucleotide promotes microglial cell uptake of amyloid beta 1-42 peptide by up-regulating the expression of the G-protein- coupled receptor mFPR2. 1621 4

This study examined the effect of amyloid beta peptide (Abeta) and the secretase inhibitors of amyloid precursor proteins (APP) on the spontaneous apoptosis of neutrophils. Abeta(1-40) decreased the apoptotic rate of neutrophils. The delayed apoptosis by Abeta was not blocked by pertussis toxin and N-formyl peptide receptor-like 1 antagonistic peptide, WRWWWW. The inhibitors of phoshoinositide 3-kinase (LY294002), phospholipase C (U73122), or Ca++-dependent protein kinase C (Go6976) abrogated the anti-apoptotic effect of Abeta on neutrophils. Moreover, the Abeta-induced delay of apoptosis was inhibited by a calcium chelator, BAPTA/AM. The amount of the APP protein was reduced in the cultured neutrophils and the APP level in the Abeta or pancaspase-treated neutrophils was lower than that in the cultured neutrophils. However, the reduction in APP level was recovered after treating them with the secretase inhibitors or anti-Fas antibody. The exogenous addition of cell permeable beta- and gamma-secretase inhibitors resulted in an increase in the rate of the apoptosis. The regulation of neutrophil apoptosis by the addition of Abeta and secretase inhibitors occurred via the caspase -8, -9, -3, and mitochondrial-dependent pathways. This suggests that the intracellular beta-amyloid proteins play a role as regulating factor of neutrophil survival and that Abeta-induced delay of apoptosis is mediated by other receptors rather than a seven-transmembrane G protein-coupled receptor(s).
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PMID:Modulation of neutrophil apoptosis by beta-amyloid proteins. 1671 9

We have investigated the possibility that soluble, blood-borne amyloid beta (Abeta) peptides can cross a defective blood-brain barrier (BBB) and interact with neurons in the brain. Immunohistochemical analyses revealed extravasated plasma components, including Abeta42 in 19 of 21 AD brains, but in only 3 of 13 age-matched control brains, suggesting that a defective BBB is common in AD. To more directly test whether blood-borne Abeta peptides can cross a defective BBB, we tracked the fate of fluorescein isothiocyanate (FITC)-labeled Abeta42 and Abeta40 introduced via tail vein injection into mice with a BBB rendered permeable by treatment with pertussis toxin. Both Abeta40 and Abeta42 readily crossed the permeabilized BBB and bound selectively to certain neuronal subtypes, but not glial cells. By 48 h post-injection, Abeta42-positive neurons were widespread in the brain. In the cerebral cortex, small fluorescent, Abeta42-positive granules were found in the perinuclear cytoplasm of pyramidal neurons, suggesting that these cells can internalize exogenous Abeta42. An intact BBB (saline-injected controls) blocked entry of blood-borne Abeta peptides into the brain. The neuronal subtype selectivity of Abeta42 and Abeta40 was most evident in mouse brains subjected to direct intracranial stereotaxic injection into the hippocampal region, thereby bypassing the BBB. Abeta40 was found to preferentially bind to a distinct subset of neurons positioned at the inner face of the dentate gyrus, whereas Abeta42 bound selectively to the population of large neurons in the hilus region of the dentate gyrus. Our results suggest that the blood may serve as a major, chronic source of soluble, exogenous Abeta peptides that can bind selectively to certain subtypes of neurons and accumulate within these cells.
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PMID:Abeta peptides can enter the brain through a defective blood-brain barrier and bind selectively to neurons. 1730 34

Alzheimer's disease is characterized by neuropathological accumulations of amyloid beta(1-42) [A beta(1-42)], a cleavage product of the amyloid precursor protein (APP). Recent studies have highlighted the role of APP in A beta-mediated toxicity and have implicated the G-protein system; however, the exact mechanisms underlying this pathway are as yet undetermined. In this context, we sought to investigate the role of calcium upregulation following APP-dependent, A beta-mediated G-protein activation. Initial studies on the interaction between APP, A beta and Go proteins demonstrated that the interaction between APP, specifically its C-terminal -YENPTY- region, and Go was reduced in the presence of A beta. Cell death and calcium influx in A beta-treated cells were shown to be APP dependent and to involve G-protein activation because these effects were blocked by use of the G-protein inhibitor, pertussis toxin. Collectively, these results highlight a role for the G-protein system in APP-dependent, A beta-induced toxicity and calcium dysregulation. Analysis of the APP:Go interaction in human brain samples from Alzheimer's disease patients at different stages of the disease revealed a decrease in the interaction, correlating with disease progression. Moreover, the reduced interaction between APP and Go was shown to correlate with an increase in membrane A beta levels and G-protein activity, showing for first time that the APP:Go interaction is present in humans and is responsive to A beta load. The results presented support a role for APP in A beta-induced G-protein activation and suggest a mechanism by which basal APP binding to Go is reduced under pathological loads of A beta, liberating Go and activating the G-protein system, which may in turn result in downstream effects including calcium dysregulation. These results also suggest that specific antagonists of G-protein activity may have a therapeutic relevance in Alzheimer's disease.
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PMID:Interactions between the amyloid precursor protein C-terminal domain and G proteins mediate calcium dysregulation and amyloid beta toxicity in Alzheimer's disease. 1936 57

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