Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amyloid beta protein (25-35) failed to significantly interact with tachykinin NK1 (rat forebrain, guinea-pig ileum) NK2 (rabbit pulmonary artery, hamster trachea) or NK-3 (guinea-pig cortex) receptors, as determined by radioligand binding and functional assays. A weak interaction (Ki 14.8 microM) was detected with NK2 receptors in rat small intestine. It appears unlikely that direct interaction with tachykinin receptors may account for the reported ability of amyloid beta protein (25-35) to affect neuronal survival.
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PMID:Interaction of amyloid beta protein (25-35) with tachykinin receptors. 132 24

The amyloid beta protein (ABP) has been shown to interact with the substance P (SP) receptor in a cell culture model that may mimic the pathogenesis of Alzheimer's disease. In the present study, however, 4 fragments of ABP (beta 1-42, beta 1-16, beta 17-28, and beta 25-35) failed to interact with SP-induced Ca2+ mobilization in SP receptor-expressing cultured cells. Therefore, the action of these ABP-related peptides in our cultured cells is unrelated to the SP receptor.
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PMID:Amyloid beta protein substituent peptides do not interact with the substance P receptor expressed in cultured cells. 166 16

The amyloid beta protein is deposited in the brains of patients with Alzheimer's disease but its pathogenic role is unknown. In culture, the amyloid beta protein was neurotrophic to undifferentiated hippocampal neurons at low concentrations and neurotoxic to mature neurons at higher concentrations. In differentiated neurons, amyloid beta protein caused dendritic and axonal retraction followed by neuronal death. A portion of the amyloid beta protein (amino acids 25 to 35) mediated both the trophic and toxic effects and was homologous to the tachykinin neuropeptide family. The effects of the amyloid beta protein were mimicked by tachykinin antagonists and completely reversed by specific tachykinin agonists. Thus, the amyloid beta protein could function as a neurotrophic factor for differentiating neurons, but at high concentrations in mature neurons, as in Alzheimer's disease, could cause neuronal degeneration.
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PMID:Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. 221 31

Neurodegenerative processes in Alzheimer disease (AD) are thought to be driven in part by the deposition of amyloid beta (A beta), a 39- to 43-amino acid peptide product resulting from an alternative cleavage of amyloid precursor protein. Recent descriptions of in vitro neurotoxic effects of A beta support this hypothesis and suggest toxicity might be mediated by A beta-induced neuronal calcium disregulation. In addition, it has been reported that "aging" A beta results in increased toxic potency due to peptide aggregation and formation of a beta-sheet secondary structure. In addition, A beta might also promote neuropathology indirectly by activating immune/inflammatory pathways in affected areas of the brain (e.g., cortex and hippocampus). Here we report that A beta can modulate cytokine secretion [interleukins 6 and 8 (IL-6 and IL-8)] from human astrocytoma cells (U-373 MG). Freshly prepared and aged A beta modestly stimulated IL-6 and IL-8 secretion from U-373 MG cells. However, in the presence of interleukin-1 beta (IL-1 beta), aged, but not fresh, A beta markedly potentiated (3- to 8-fold) cytokine release. In contrast, aged A beta did not potentiate substance P (NK-1)- or histamine (H1)-stimulated cytokine production. Further studies showed that IL-1 beta-induced cytokine release was potentiated by A beta-(25-35), while A beta-(1-16) was inactive. Calcium disregulation may be responsible for the effects of A beta on cytokine production, since the calcium ionophore A23187 similarly potentiated IL-1 beta-induced cytokine secretion and EGTA treatment blocked either A beta or A23187 activity. Thus, chronic neurodegeneration in AD-affected brain regions may be mediated in part by the ability of A beta to exacerbate inflammatory pathways in a conformation-dependent manner.
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PMID:Amyloid beta peptide potentiates cytokine secretion by interleukin-1 beta-activated human astrocytoma cells. 747 75

The neurotoxic effects of soluble and aggregated synthetic amyloid beta protein (A beta P) have been investigated in rat primary cultures. Freshly solubilized beta(1-40) was neurotoxic not to immature, but to mature hippocampal neurons. On the other hand, aggregated beta(1-40) was neurotoxic to both. Neurotoxicity induced by aggregated beta(1-40) was 10-fold more potent than soluble beta(1-40) and was not prevented by substance P. The neurotoxicity of aggregated beta(1-40) to cultured neurons depended on the peptide concentration and the duration of exposure to it. Cerebral cortical and hippocampal neurons were significantly susceptible to aggregated beta(1-40) than cerebellar granular cells, and cultured astrocytes were not vulnerable to aggregated beta(1-40) even at high concentrations.
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PMID:Amyloid beta protein-induced neuronal cell death: neurotoxic properties of aggregated amyloid beta protein. 751 62

We have tested the interaction between amyloid beta protein (A beta P) and tachykinin receptors in cultured UC-11MG astrocytoma cells, which express high affinity substance P receptors and respond to substance P with an unusually large stimulation of polyphosphoinositide hydrolysis. Both the full-length A beta P (A beta P1-40) and the fragment 25-35 (A beta P25-35) did not affect the stimulation of [3H]inositolmonophosphate (InsP) formation by substance P. A beta P25-35 was also inactive when applied to the cultures 18 or 72 h prior to the assay. In addition, A beta P25-35 did not displace specifically bound [3H]SarMet substance P from its recognition sites in intact UC-11MG cells. These results suggest that, at least in this specific cell type, amyloid peptides do not interact with substance P receptors.
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PMID:Amyloid beta protein does not interact with tachykinin receptors coupled to inositol phospholipid hydrolysis in human astrocytoma cells. 767 35

A peptide consisting of residues 25-35 of the amyloid beta protein was applied to single neurons while monitoring membrane current by whole cell voltage clamp recording. Within minutes of direct exposure of a neuron to the amyloid beta peptide, a paroxysmal increase in neuronal membrane conductance was observed. This conductance does not resemble previously described ionic conductances in terms of its time-dependence, voltage-dependence or sensitivity to changes in extracellular or intracellular ionic constituents. The effect of the amyloid beta peptide was not mimicked or blocked by substance P nor was it prevented by low intracellular or extracellular Ca. The increased membrane permeability elicited by the peptides may lead to the neuropathology observed in Alzheimer's disease.
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PMID:Amyloid beta peptides act directly on single neurons. 768 10

1. Synthetic amyloid beta-peptide was toxic to NB41A3 neuroblastoma cells in serum-free culture as judged by decreasing cell numbers and release of the cytosolic enzyme, lactic dehydrogenase. 2. Without amyloid beta-peptide, bovine serum albumin increased the number of cells surviving in culture. 3. In the presence of amyloid beta-peptide, BSA appeared to potentiate the amyloid beta-peptide toxicity. 4. The toxic dose response for amyloid beta-peptide varied between different cell lines (NB41A3, NB2a and IMR32), in a range of 100-1000 nM amyloid beta-peptide. 5. Amyloid beta-peptide toxicity was inhibited by the concurrent treatment of the cells with the tachykinin physalaemin with an ED50 of 10(-6) M.
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PMID:Comparative toxicity of amyloid beta-peptide in neuroblastoma cell lines: effects of albumin and physalaemin. 790 10

The three-dimensional structure of amyloid beta peptide (25-35), which has neurotoxic activity, in lithium dodecyl sulfate micelles was determined by two-dimensional 1H NMR spectroscopy with simulated annealing calculations. A total of 20 converged amyloid beta peptide structures were obtained on the basis of 110 experimental constraints, including 106 distance constraints reduced from the nuclear Overhauser effect (NOE) connectivities and four torsion angle (phi) constraints. The atomic root mean square difference about averaged coordinates is 1.04 +/- 0.25 A for the backbone atoms (N, C alpha, C) and 1.39 +/- 0.27 A for all heavy atoms of the entire peptide. The molecular structure of amyloid beta peptide in membrane-mimicking environment is composed of a short alpha helix in the C terminal position. The three residues from the N-terminus are disordered, but the remaining eight C-terminal residues are well-ordered, which is supported by the RMSD values of the C-terminal region, Lys28-Leu34. In this region, the RMS differences from averaged coordinates are 0.26 +/- 0.11 A for the backbone atoms (N, C alpha, C) and 0.77 +/- 0.21 A for all heavy atoms, which is very low compared with those for the entire peptide. The four amino acid residues from the N-terminus are hydrophilic and the other seven amino acid residues in C-terminus are hydrophobic. So, our results show that the C-terminal region of amyloid beta peptide (25-35) is buried in the membrane and assumes alpha-helical structure, whereas the N-terminal region is exposed to the solvent with a flexible structure. This structure is very similar to membrane-mediated structure of substance P previously reported. The three-dimensional structure of a non-neurotoxic mutant of amyloid beta peptide (25-35), where Asn27 is replaced by Ala, in lithium dodecyl sulfate micelles was also determined. The structure is similar to that of the wild type amyloid beta peptide (25-35) in the C-terminal region, but the N-terminal flexible region is different. The structural comparison of amyloid beta peptide (25-35), its non-neurotoxic mutant and substance P gives a structural basis to understand the mechanism of neurotoxicity caused by amyloid beta peptide.
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PMID:Three-dimensional structures of the amyloid beta peptide (25-35) in membrane-mimicking environment. 897 80

Alzheimer's disease (AD) is primarily nonfamilial or sporadic (SAD) in origin, although several genetic linkages are reported. Tissues from AD patients contain fibrillar plaques made of 39 to 43 amino acid-long amyloid beta peptide (AbetaP), although the mechanisms of AbetaP toxicity are poorly understood. AbetaP(1-40) is the most prevalent AbetaP present in the neuronal and non-neuronal tissues from SAD patients. AbetaP(1-40) toxicity has been examined mainly after prolonged incubation and correlates with the age and fibrillar morphology of AbetaP(1-40). Globular and nonfibrillar AbetaPs are released continually during normal cellular metabolism; they elevate cellular Ca(2+) and form cation-permeable channels. However, their role in cellular toxicity is poorly understood. We have used an integrated atomic force and light fluorescence microscopy (AFM-LFM), laser confocal microscopy, and calcium imaging to examine real-time and acute effect of fresh and globular AbetaP(1-40) on cultured, aged human, AD-free fibroblasts. AFM images show that freshly prepared AbetaP(1-40) in phosphate-buffered saline (PBS) are globular and do not form fiber for an extended time period. AbetaP(1-40) induced rapid structural modifications, including cytoskeletal reorganization, retraction of cellular processes, and loss of cell-cell contacts, within minutes of incubation. This led to eventual cellular degeneration. AbetaP(1-40)-induced degeneration was prevented by anti-AbetaP antibody, zinc, and Tris, but not by tachykinin neuropeptides. In Ca(2+)-free extracellular medium, AbetaP(1-40) did not induce cellular degeneration. In the presence of extracellular Ca(2+), AbetaP(1-40) induced a sustained increase in the cellular Ca(2+). Thus, short-term and acute AbetaP(1-40) toxicity is mediated by Ca(2+) uptake, most likely via calcium-permeable AbetaP pores. Such rapid degeneration does not require fibrillar plaques, suggesting that the plaques may not have any causative role.
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PMID:Fresh and nonfibrillar amyloid beta protein(1-40) induces rapid cellular degeneration in aged human fibroblasts: evidence for AbetaP-channel-mediated cellular toxicity. 1083 46


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