Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Properties of a partially oxidized form of serotonin (5-HT), 4,5-diketotryptamine (4,5-DKT), synthesized by electrochemical oxidation of 5-HT, were investigated. Administration of 4,5-DKT into the lateral ventricles (i.c.v.) of rats resulted in cell death and terminal degeneration in entorhinal, insular, and posterior cingulate cortices, and in the CA1, CA3 and dentate gyrus sectors of hippocampus. Furthermore, i.c.v. administration of 4,5-DKT resulted in a significant depletion of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in prefrontal cortex, striatum and hippocampus. 4,5-DKT injection into cingulate and hippocampal cortices resulted in cell death and terminal degeneration in these structures. In brain fragment perfusion and incubation experiments, 4,5-DKT increased dose dependently 5-HT efflux from rat hippocampus and striatum. The efflux of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid from striatum was unaffected. In hippocampal preparations, fluoxetine decreased 4,5-DKT-stimulated efflux of 5-HT by 24%, and pargyline did not affect it. In vitro, 4,5-DKT bound covalently to nucleophilic -SH groups in glutathione and mercaptoethanol and the binding was blocked by N-ethyl-maleimide. 4,5-DKT bound selectively to purified guanine nucleotide binding proteins, and inhibited pertussis toxin-catalyzed ribosylation at 1nM-1 microM concentrations. Analysis of cerebrospinal fluid (CSF) by a 16-channel high pressure liquid chromatography with coulometric detection did not confirm presence of 4,5-DKT in Alzheimer CSF, but detected several peaks, significantly different in control and Alzheimer CSF, which were caused by unknown compounds.
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PMID:Neurotoxic properties of a serotonin oxidation product: possible role in Alzheimer's disease. 248 22

Although a neurotoxic role has been postulated for the beta-amyloid protein (beta AP), which accumulates in brain tissues in Alzheimer's disease, a precise mechanism underlying this toxicity has not been identified. The peptide fragment consisting of amino acid residues 25 through 35 (beta AP25-35), in particular, has been reported to be toxic in cultured neurons. We report that beta AP25-35, applied to rat hippocampal neurons in culture, caused reversible and repeatable increases in the intracellular Ca2+ concentration ([Ca2+]i), as measured by fura 2 fluorimetry. Furthermore, beta AP25-35 induced bursts of excitatory potentials and action potential firing in individual neurons studied with whole cell current clamp recordings. The beta AP25-35-induced [Ca2+]i elevations and electrical activity were enhanced by removal of extracellular Mg2+, and they could be blocked by tetrodotoxin, by non-N-methyl-D-aspartate (NMDA) and NMDA glutamate receptor antagonists, and by the L-type Ca2+ channel antagonist nimodipine. Similar responses of bursts of action potentials and [Ca2+]i increases were evoked by beta AP1-40. Responses to beta AP25-35 were not prevented by pretreatment with pertussis toxin. Excitatory responses and [Ca2+]i elevations were not observed in cerebellar neuron cultures in which inhibitory synapses predominate. Although the effects of beta AP25-35 depended on the activation of glutamatergic synapses, there was no enhancement of kainate- or NMDA-induced currents by beta AP25-35 in voltage-clamp studies. We conclude that beta AP25-35 enhances excitatory activity in glutamatergic synaptic networks, causing excitatory potentials and Ca2+ influx. This property may explain the toxicity of beta AP25-35.
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PMID:The Ca2+ influx induced by beta-amyloid peptide 25-35 in cultured hippocampal neurons results from network excitation. 777 66

A total of 1044 children selected in age groups of 4, 8 and 12 years old from 12 countries (cities) with stratified random sampling method were monitored on the present situation of immune levels according to the programme on immunization in 1991. The results showed that the positive rates and the geometric mean titers of antibodies to measles were 87.16% +/- 3.14%, 5.83 +/- 0.41 (56.90%, < 1:8), respectively; to pertussis were 78.13% +/- 9.19% 218.10 +/- 23.39 (41.62%, > or = 1:320); to DAT were 74.4% +/- 11.04%, 0.098 +/- 0.025; to TAT were 75.86% +/- 11.09%, 0.136 +/- 0.03; to poliomyelitis (ELISA) were type I 89.99%, 220.51, type II 83.38%, 201.27, type III 86.09%, 275.08, 3 types 79.48%, 255.91 (27.23%, > or = 1:400); to Japanese B encephalitis (HI) were 67.47% +/- 3.34%, 39.44 +/- 1.48. The conversion of OT was 24.73%. It showed significant difference among these counties and among 3 age groups (P < 0.01). In 4-year age group, the vaccinated rate and the result of immune surveillance were the same. The antibody level and the incidence of measles showed negative correlation.
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PMID:[The surveillance on the present situation of immune levels of 1044 children vaccinated with seven kinds of vaccines in Dali Prefecture]. 783 90

Phorbol esters (PDBu) stimulate alpha-secretase cleavage and secretion of the Alzheimer amyloid precursor protein (APP). To determine whether any cytoplasmic residues or sequence motifs mediate the PDBu effect on APP processing, this region of APP was altered by point mutations or deletions. To differentiate the mutated APP from the endogenous APP, the APP751 ectodomain between amino acids 1 and 647 was replaced by a human secreted alkaline phosphatase derivative (SEAP). The resultant fusion protein (SEAP-APP751) was cleaved by alpha-secretase at the same site as full-length APP, and its secretion was stimulated by PDBu at a level similar to APP751. However, PDBu-stimulated secretion of the SEAP-APP751 fusion protein reached its maximum level after 30 min of treatment, while secretion of APP751 reached its maximum after 60 min, suggesting that the APP ectodomain affects the kinetics of APP secretion. Mutation of the cytoplasmic serines to alanines had no effect on the PDBu-stimulated secretion of the SEAP-APP, indicating that protein kinase C (PKC) phosphorylation of the cytoplasmic domain of APP is not important for stimulation of APP secretion. Similarly, deletion of the cytoplasmic domain between amino acids 719 and 751 had no effect on the PDBu-stimulated secretion. However, deletion of amino acids 707-751 resulted in a significant increase in the secretory cleavage of the SEAP-APP707 delta C construct, suggesting that the sequence 707-719 is important for the regulated secretion of APP. Cholera toxin, but not pertussis toxin, reduced the PDBu-induced secretion of APP by more than two-fold, suggesting that the PDBu response may be modulated by a cholera toxin sensitive heterotrimeric G-protein.
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PMID:Study of the phorbol ester effect on Alzheimer amyloid precursor processing: sequence requirements and involvement of a cholera toxin sensitive protein. 805 94

An alteration in signal transduction systems in Alzheimer's disease would likely be of pathophysiological significance, because these steps are critical to normal brain function. Since dynamic processes are difficult to study in autopsied brain, the current studies utilized cultured skin fibroblasts. The beta-adrenergic-stimulated increase in cAMP was reduced approximately 80% in fibroblasts from Alzheimer's disease compared with age-matched controls. The deficit in Alzheimer fibroblasts in response to various adrenergic agonists paralleled their beta-adrenergic potency, and enhancement of cAMP accumulation by a non-adrenergic agonist, such as prostaglandin E1, was similar in Alzheimer and control fibroblasts. Diminished adenylate cyclase activity did not underlie these abnormalities, since direct stimulation of adenylate cyclase by forskolin elevated cAMP production equally in Alzheimer and control fibroblasts. Cholera toxin equally stimulated cAMP formation in Alzheimer and control fibroblasts. Moreover, cholera toxin partially reduced isoproterenol-induced cAMP deficit in Alzheimer fibroblasts. Pertussis toxin, on the other hand, did not alter the Alzheimer deficits. The results suggest either that the coupling of the GTP-binding protein(s) to the beta-adrenergic receptor is abnormal or that the sensitivity of receptor is altered with Alzheimer's disease. Further, any hypothesis about Alzheimer's disease must explain why a reduced beta-adrenergic-stimulated cAMP formation persists in tissue culture.
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PMID:Altered beta-adrenergic receptor-stimulated cAMP formation in cultured skin fibroblasts from Alzheimer donors. 810 Aug 16

APP695 is a transmembrane precursor of Abeta amyloid. In familial Alzheimer's disease (FAD), three mutations V642I/F/G were discovered in APP695, which has been suggested by multiple studies to be a cell surface signaling receptor. We previously reported that normal APP695 encodes a potential GO-linked receptor with ligand-regulated function and that expression of the three FAD mutants (FAD-APPs), not normal APP, induces cellular outputs by GO-dependent mechanisms. This suggests that FAD-APPs are constitutively active GO-linked receptors. Here, we provide direct evidence for this notion. Reconstitution of either recombinant FAD-APP with GO vesicles induced activation of GO, which was inhibitable by pertussis toxin, sensitive to Mg2+ and proportional in quantity to the reconstituted amounts of FAD-APP. Consistent with the dominant inheritance of this type of FAD, this function was dominant over normal APP, because little activation was observed in APP695-GO vesicles. Experiments with antibody competition and sequence deletion indicated that His657-Lys676 of FAD-APP, which has been specified as the ligand-dependent GO-coupling domain of normal APP, was responsible for this constitutive activation, confirming that the three FAD-APPs are mutationally activated APP695. This study identifies the intrinsic signaling function of APP to be a novel target of hereditary Alzheimer's disease mutations, providing an in vitro system for the screening of potential FAD inhibitors.
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PMID:Intrinsic signaling function of APP as a novel target of three V642 mutations linked to familial Alzheimer's disease. 867 Aug 81

To better understand the molecular mechanisms that underlie the exaggerated bradykinin (BK)-stimulated release of Ins(1,4,5)P3 in fibroblasts from Alzheimer patients, the role of G-proteins, protein kinase C (PKC) and cyclic AMP in BK-induced Ins(1,4,5)P3 formation was determined. A role for G-proteins in the coupling of the BK receptor to intracellular signals was indicated by guanosine 5'-(3-O-thio)triphosphate (GTP gamma S) enhanced BK-stimulated Ins(1,4,5)P3 release. The coupling of G-proteins to Ins(1,4,5)P3 formation was sensitive to cholera toxin (CTX), but not pertussis toxin (PTX), and was not altered by PKC activation. The inhibition by CTX appeared to be secondary to its ability to increase cyclic AMP, because forskolin also inhibited the BK-mediated Ins (1,4,5)P3 release. Activation of PKC with TPA diminished the number of BK receptors by 33% and proportionally decreased BK-mediated Ins(1,4,5)P3 formation by 28%. The latter response was abolished by PKC inhibitors. Depletion of PKC by prolonged TPA treatment did not further alter the number of BK receptors but further decreased the Ins(1,4,5)P3 response by 65%. Thus, changes in PKC probably do not underlie the enhanced BK-induced Ins(1,4,5)P3 formation in AD fibroblasts, because both activation and depletion of the PKC diminished the Ins(1,4,5)P3 response.
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PMID:Regulation of bradykinin-induced Ins(1,4,5)P3 formation by protein kinase C in human fibroblasts. 889 Sep 34

Overexpression of the familial Alzheimer's disease gene Presenilin 2 (PS2) in nerve growth factor-differentiated PC12 cells increased apoptosis induced by trophic factor withdrawal or beta-amyloid. Transfection of antisense PS2 conferred protection against apoptosis induced by trophic withdrawal in nerve growth factor-differentiated or amyloid precursor protein-expressing PC12 cells. The apoptotic cell death induced by PS2 protein was sensitive to pertussis toxin, suggesting that heterotrimeric GTP-binding proteins are involved. A PS2 mutation associated with familial Alzheimer's disease was found to generate a molecule with enhanced basal apoptotic activity. This gain of function might accelerate the process of neurodegeneration that occurs in Alzheimer's disease, leading to the earlier age of onset characteristic of familial Alzheimer's disease.
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PMID:Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation. 893 61

The proinflammatory cytokine, interleukin-1 (IL-1) is elevated in the Alzheimer's disease (AD) brain. Studies from our laboratory have demonstrated that beta-amyloid (A beta) 1-42, fibrillar A beta 1-40 and A beta 25-35 induce the release of IL-1 beta from activated THP-1 cells, a human monocyte cell line. A beta also is chemotactic for primary rodent microglia and peritoneal macrophages. We hypothesize that A beta is a chemokine and induces these responses by interaction with chemotactic receptors. If this is true, then these A beta-induced responses should be calcium-dependent and require activation of pertussis toxin-sensitive G-proteins. To test this hypothesis, THP-1 cells were grown in culture with lipopolysaccharide (LPS) and incubated with A beta 1-42 (5 muM) in the presence and absence of a calcium chelator, an inhibitor of intracellular calcium mobilization, a calcium channel blocker, or pertussis toxin, a bacterial endotoxin which uncouples G proteins from receptors by catalyzing the ADP ribosylation of cysteine near the carboxy-terminus of the alpha subunit. The media was collected and IL-1 beta present in the media was measured using an ELISA. Treatment of LPS-activated THP-1 cells with A beta 1-42 significantly elevated IL-1 beta released into the media as previously shown. Addition or ethylene glycol-bis (beta-aminothyl ether) N,N,N'N'-tetraacetic acid (EGTA) (0.5 mM), a calcium chelator, to the media blocked A beta-induced IL-1 beta release, but had no effect on LPS-activated THP-1 cell release of IL-1 beta. The presence of 3,4,5-trimethoxybenzoic acid 8-(diethyl amino)-octyl ester (TMB-8), an inhibitor of intracellular calcium mobilization, as well as nickel chloride, a non-specific calcium channel blocker, in the media also inhibited A beta-induced IL-1 release from LPS-activated THP-1 cells. IL- 1 beta release from activated THP-1 monocytes incubated with TMB-8 and nickel chloride without A beta remained at baseline values. Pretreatment of THP-1 monocytes with pertussis toxin for 4 h, followed by LPS activation and incubation with A beta, antagonized the release of IL-1 beta from these cells, but did not alter IL-1 beta release from activated THP-1 monocytes. These data suggest that A beta-induced IL-1 beta release from these cells is calcium-dependent and requires the activation of specific G-proteins. These findings are consistent with known second messengers that are activated following stimulation of chemotactic receptors.
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PMID:beta-Amyloid-induced IL-1 beta release from an activated human monocyte cell line is calcium- and G-protein-dependent. 914 72

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


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