Abstract
Amyloid β 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 AβP (25–35) was calcium-independent. The AβP (25–35) and quisqualate activation of phospholipase D appeared to be mediated through a pertussis toxin-sensitive GTP-binding protein. Phospholipase D activation by AβP (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 AβP (25–35). Only NBQX was effective with an IC50 of 75 μM for AβP (25–35) and quisqualate. Activation of phospholipase D by AβP or quisqualate was absent in LA-N-2 cells previously desensitized by quisqualate or AβP (25–35), but the activation by phorbol dibutyrate was unaltered. The responsiveness to AβP 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 AβP (25–35).
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REFERENCES
Khachaturian, Z.S. 1985. Diagnosis of Alzheimer's Disease. Arch. Neurol. 42:1097-1105.
Selkoe, D. 1994. Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer's Disease. Annu. Rev. Cell Biol. 10:373-403.
Iversen, L.L., Mortshire-Smith, R.J., Pollack, S.J., and Shearman, M.S. 1995. The toxicity in vitro of beta-amyloid protein. Biochem. J. 311:1-16.
Pike, C.J., Walencewicz-Wasserman, A.J., Kosmoski, J., Cribbs, D.H., Globe, C.C., and Cotman, C.W. 1995. Structure activity analyses of beta-amyloid peptides: contributions of the beta 25–35 region to aggregation and neurotoxicity. J. Neurochem. 64:253-265.
Roses, A.D. 1996. Apolipoprotein E in neurology. Curr. Opin. Neurol. 9:265-270.
Tanzi, R.E., Kovacs, D.M., Kim. T-W., Moir, R.D., Guenette, S.Y., and Wasco, W. 1996. The gene defects responsible for familial Alzheimer's disease. Neurobiol. Dis. 3:159-168.
Singh, I.N., McCartney, D.G., and Kanfer, J.N. 1995. Amyloid beta protein (25–35) stimulation of phospholipases A, C and D activities of LA-N-2 cells. FEBS Letts. 365:125-128.
Singh, I.N., Sato, K., Takashima, A., and Kanfer, J.N. 1997. Activation of LA-N-2 cell phospholipases by single alanine substitution analogs of amyloid β peptide (25–35). FEBS Lett. 405:65-67.
Singh, I.N., Sorrentino, G., and Kanfer, J.N. 1996. Amyloid β protein (25–35) activation of phospholipase A2 in LA-N-2 cells. Alzheimer's Res. 2:121-128.
Singh, I.N., Sorrentino, G., and Kanfer, J.N. 1997. Amyloid β protein (25–35) stimulation of phospholipase C in LA-N-2 cells. J. Neurochem. 69:252-258.
Singh, I.N., Sorrentino, G., McCartney, D.G., Massarrelli, R., and Kanfer, J.N. 1990. Enzymatic activities during differentiation of the human neuroblastoma cells, LA-N-1 and LA-N-2. J. Neurosci. Res. 25:476-485.
Singh, I.N., Massarrelli, R., and Kanfer, J.N. 1993. Activation of phospholipases D and A by amphiphilic cations of cultured LA-N-2 cells is G-protein and protein kinase C-independent. J. Lipid. Mediat. 7:85-96.
Wilkinson, L. 1990. Systat: The system for statistics, Systat. Inc., Evanston, IL.
English, D., Taylor, G., and Garcia, J.G. 1991. Diacylglycerol generation in fluoride-treated neutrophils: involvement of phospholipase D. Blood 77:2746-275.
Liscovitch, M., and Eli, Y. 1991. Ca2+ inhibits guanine nucleotide-activated phospholipase D in neural derived NG 108-15 cells. Cell Regul. 2:1011-1019.
Natarajan, V., Jayaram, H.M., Scribner, W.M., and Garcia, J.G. 1994. Activation of endothelial cell phospholipase D by sphingosine and spingosine 1-phosphate. Am. J. Respir. Cell. Mol. Biol. 11:221-229.
Zoukhri, D., and Dartt, A. 1995. Cholinergic activation of phospholipase D in lacrimal gland acinic is independent of protein kinase C and calcium. Amer. J. Physiol. 268:C713-C720.
Desogher, S., Cordier, J., Glowinski, J., and Tence, M. 1997. Endothelin stimulate phospholipase D in striatal astrocytes. J. Neurochem. 68:78-87.
MacNulty, E.E., McClure, S.J., Carr, I.C., Jess, T., Wakelman, M.J., and Milligan, G. 1992. Alpha 2-C10-adrenergic receptors expressed in rat 1 fibroblasts can regulate both adenylcylase and phospholipase D—mediated hydrolysis of phosphatidylcholine by interacting with pertussis-sensitive guanine nucleotide binding proteins. J. Biol. Chem. 267:2149-2156.
Mullmann, T.J., Cheewatrakoolpong, B., Anthes, J.C., Seigel, M.I., Egan, R.W., and Billah, M.M. 1993. Phospholipase C and phospholipase D are activated independently of each other in chemotactic peptide—stimulated human neutrophils. J. Leukoc. Biol. 53:630-635.
Martinson, E.A., Scheible, S., Greenacher, A., and Presek, P. 1995. Platelet phospholipase D is activated by PKC via an integrin alpha II beta 3-independent mechanism. Biochem. J. 310:623-628.
Pyne, S., and Pyne, N.J. 1995. Bradykinin-stimulated phosphatidylcholine hydrolysis in airway smooth muscle: role of Ca+2 and PKC. Biochem. J. 311:637-642.
Seymour, L.W., Shoaibi, M.A., Martin, A., Ahmed, A., Elven, P., Kerr, D.J., and Wakelman, M.J. 1996. Vascular EGF stimulates protein kinase C-dependent phospholipase D activity in endothelial cells. Lab. Invest. 75:424-437.
Shinoda, J., Suzuki, A., Osio, Y., and Kozawa, O. 1995. Thromboxane A-2 stimulated phospholipase D in osteoclast-like cells and possible involvement of PKC. Am. J. Physiol. 269:E524-E525.
Matsushima, H., Shimohana, S., Chachin, M., Taniguchi, T., and Kimura, J. 1996. Ca+2-dependent and Ca+2-independent protein kinase C changes in the brains of patients with Alzheimer's disease. J. Neurochem. 67:317-323.
Nishizuka, Y. 1992. Intracellular signalling by hydrolysis of phospholipids and activation of protein kinase C. Science 258:607-611.
Pascale, A., Fortino, I., Govani, S., Trabucchi, M., Wetsel, W.C., and Battaini, F. 1996. Differential isoform-specific regulation of calium-independent protein kinase C in rat cerebral cortex. Neurosci. Letts. 214:99-102.
Brouard, A., Pelaprat, D., Vial, M., Thiaubet, A.M., and Rostene, W. 1994. Effects of ion channel blockers and phorbol ester treatments on [3H] dopamine release and neurotensin facilitation of [3H] dopamine release from rat mesencephalic cells in primary culture. J. Neurochem. 62:1416-1425.
Hofmann, J. 1997. The potential for isoenzyme-selective modulation of protein kinase C. FASEB J. 11:649-669.
Ison, A.J., MacEwan, D.J., Johnson, M.S., Clegg, R.A., Connor, K., and Mitchell, R. 1993. Evidence for a distinct H7-resistant form of protein kinase C in rat anterior pituitary gland. FEBS Letts. 329:199-204.
Lee, C.G., and O'Brien, W.E. 1995. A unique form of thymidine kinase family that is induced during macrophage activation. J. Immunol. 154:6094-6102.
Stevens, M.F., McCall, C.J., Lelieveld, P., Alexander, P., Richter, A., and Davies, D.E. 1994. Structural studies on bioactive compounds. 23 Synthesis of polyhydroxylated 2-phenylthiazoles with a comparison of their cytotoxic and pharmacological properties with genistein and quercetin. J. Med. Chem. 37:1689-1695.
Markovits, J., Larsen, A.K., Segal-Bendirdjian, E., Fosse, P., Saucier, J.M., Gozet, A., Levitzki, A., Umezawa, K., and Jacquemin-Sablon, A. 1994. Inhibition of DNA topoisomerases I and II and induction of apoptosis by erbstatin and tyrophostin derivatives. Biochem. Pharm. 48:549-560.
Boss, V., and Conn, P.J. 1992. Metabotropic excitatory amino acid receptor activation stimulates phospholipase D in hippocampal slices. J. Neurochem. 59:2340-2343.
Pellegrini-Giampietro, D.E., Torregrossa, S.A., and Moroni, F. 1996. Pharmacological characterization of the metabotropic glutamate receptors coupled to phospholipase D in the rat hippocampus. Br. J. Pharmacol. 118:1035-1043.
Sorrentino, G., Singh, I.N., Massarelli, R., and Kanfer, J.N. 1996. Stimulation of phospholipase C activity by norepinephrine, t-ACP D and bombesin in LA-N-2 cells. Eur. J. Pharmacol. 308:81-86.
Kelly, J.F., Furukawa, K., Barger, S.W., Rengen, M.R., Mark, R.J., Blanc, E.M., Roth, G.S., and Mattson, M.R. 1996. Amyloid beta peptide disrupts carbachol-induced muscarinic cholinergic signal transduction in cortical neurons. Proc. Natl. Acad. Sci. 93:6753-6758.
Boland, K., Behrens, M., Choi, D., Manias, K., and Perlmutter, D.H. 1996. The serpin-enzyme complex receptor recognizes soluble, nontoxic amyloid-beta-peptide but not aggregated, cytotoxic amyloid beta peptide. J. Biol. Chem. 271:18032-18044.
Paresce, D.M., Ghosh, R.N., and Maxfield, F.R. 1996. Microglia cells internalize aggregates of the Alzheimer's disease amyloid beta-protein via a scavenger receptor. Neuron. 17:553-565.
Shearman, M.S. 1996. Cellular MTT reduction distinguishes the mechanisms of action of beta amyloid from that of tachykinin receptor peptides. Neuropeptides 30:125-132.
Shimohigashi, Y., Matsumoto, H., Takano, Y., Saito, R., Iwata, T., Kamiya, H., and Ohno, M. 1993. Receptor-mediated specific biological activity of a beta-amyloid protein fragment for NK-1 substance P receptor. Biochem. Biophys. Res. Commun. 193:624-630.
Yan, S.D., Chen, X., Fu, J., Chen, M., Zhu, H., Roher, R., Slattery, T., Zhao, L., Nagashima, M., Morser, J., Migheli, A., Nawroth, P., Stern, D., and Schmidt, A.M. 1996. RAGE and amyloid beta-peptide neurotoxicity in Alzheimers disease. Nature 382:685-691.
Fagarasan, M.O., and Efthimiopoulos, S. 1996. Mechanism of amyloid β peptide (1–42) toxicity in PC 12 cells. Mol. Psychiatry 1:398-403.
Hartmann, H., Eckert, A., Crews, F.T., and Müller, E.W. 1996. β-amyloid amplifies PLC activity and Ca+2 signalling in fully differentiated brain cells of adult mice. Amyloid Int. J. Exp. Clin. Invest. 3:234-241.
Cribbs, D.H., Pike, C.J., Weinstein, S.L., Velazquez, P., and Cotman, C.W. 1997. All D-Enantiomers of β-amyloid exhibit similar biological properties to all L-β-amyloids. J. Biol. Chem. 272:7431-7436.
Pillot, T., Goethals, M., Vanloo, B., Talussot, C., Brasseur, R., Vandekerckhove, J., Rosseneu, M., and Lins, L. 1996. Fusogenic properties of the C-terminal domain of the Alzheimer β-amyloid peptide. J. Biol. Chem. 271:28757-28765.
Gottfries, C.G., Jungbjir, B., Karlsson, L., and Svenerholm, L. 1996. Reductions in membrane proteins and lipids in basal ganglia of classic Alzheimers disease patients. Alzheimer's Dis. Assoc. Disord. 10:77-81.
Nitsch, R.M., Blusztajn, J.K., Pettas, A.G., Slack, B.E., Growden, J.H., and Wurtman, R.J. 1992. Evidence for a membrane defect in Alzheimers disease brain. Proc. Natl. Acad. Sci. 89:1671-1675.
Pettegrew, J.W., Panchalingham, K., Strychor, S., and Branthoover, G. 1990. Analysis of membrane phospholipids in Alzheimers disease brain by 31 PNMR. Soc. Neurosci. Abstr. 16:498.
Svennerholm, L., and Gottfries, C.G. 1994. Membrane lipids, selectively diminished in Alzheimers brain, suggest synapse loss a primary event in early-onset (Type I) and demyelination in late onset form (Type II). J. Neurochem. 62:1039-1044.
Wells, K., Farooqui, A.A., Liss, L., and Horrocks, L.A. 1995. Neural membrane phospholipids in Alzheimers diseases. Neurochem. Res. 20:1329-1333.
Blusztajn, J.K., Gonzalec-Coviella, I.L., Logue, M., Growden, J.H., and Wurtman, R.J. 1990. Levels of phospholipid catabolic intermediates, glycerophosphocholine and glycerophosphoethanolamine, are elevated in brains of Alzheimers disease but not of Down's syndrome patients. Brain Res. 536:240-244.
Ellison, D.W., Beal, M.F., and Martin, J.B. 1987. Phosphoethanolamine and ethanolamine are decreased in Alzheimers and Huntingtons diseases. Brain Res. 417:389-392.
Klunk, W.E., Xu, C., Panchalingam, K., McClure, R.J., and Pettegrew, J.W. 1994. Analysis of magnetic resonance spectra by mole percent: comparison to absolute units, Neurobiol. Aging 15:133-140.
Pettegrew, J.W., Panchalingham, K., Moosy, J., Martinez, J., Rao, G., and Boller, F. 1981. Correlation of 31 P magnetic resonance spectroscopy and morphologic findings in Alzheimers disease. Arch. Neurol. 45:1093-1096.
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Singh, I.N., Sorrentino, G. & Kanfer, J.N. Activation of LA-N-2 Cell Phospholipase D by Amyloid Beta Protein (25–35). Neurochem Res 23, 1225–1232 (1998). https://doi.org/10.1023/A:1020731813973
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DOI: https://doi.org/10.1023/A:1020731813973