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. 1995 Aug 15;92(17):8083–8087. doi: 10.1073/pnas.92.17.8083

Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors.

R K Lee 1, R J Wurtman 1, A J Cox 1, R M Nitsch 1
PMCID: PMC41291  PMID: 7644542

Abstract

Stimulation of muscarinic m1 or m3 receptors can, by generating diacylglycerol and activating protein kinase C, accelerate the breakdown of the amyloid precursor protein (APP) to form soluble, nonamyloidogenic derivatives (APPs), as previously shown. This relationship has been demonstrated in human glioma and neuroblastoma cells, as well as in transfected human embryonic kidney 293 cells and PC-12 cells. We now provide evidence that stimulation of metabotropic glutamate receptors (mGluRs), which also are coupled to phosphatidylinositol 4,5-bisphosphate hydrolysis, similarly accelerates processing of APP into nonamyloidogenic APPs. This process is demonstrated both in hippocampal neurons derived from fetal rats and in human embryonic kidney 293 cells transfected with cDNA expression constructs encoding the mGluR 1 alpha subtype. In hippocampal neurons, both an mGluR antagonist, L-(+)-2-amino-3-phosphonopropionic acid, and an inhibitor of protein kinase C, GF 109203X, blocked the APPs release evoked by glutamate receptor stimulation. Ionotropic glutamate agonists, N-methyl-D-aspartate or S(-)-5-fluorowillardiine, failed to affect APPs release. These data show that selective mGluR agonists that initiate signal-transduction events can regulate APP processing in bona fide primary neurons and transfected cells. As glutamatergic neurons in the cortex and hippocampus are damaged in Alzheimer disease, amyloid production in these regions may be enhanced by deficits in glutamatergic neurotransmission.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abe T., Sugihara H., Nawa H., Shigemoto R., Mizuno N., Nakanishi S. Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca2+ signal transduction. J Biol Chem. 1992 Jul 5;267(19):13361–13368. [PubMed] [Google Scholar]
  2. Aramori I., Nakanishi S. Signal transduction and pharmacological characteristics of a metabotropic glutamate receptor, mGluR1, in transfected CHO cells. Neuron. 1992 Apr;8(4):757–765. doi: 10.1016/0896-6273(92)90096-v. [DOI] [PubMed] [Google Scholar]
  3. Berridge M. J., Downes C. P., Hanley M. R. Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands. Biochem J. 1982 Sep 15;206(3):587–595. doi: 10.1042/bj2060587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bramham C. R., Alkon D. L., Lester D. S. Arachidonic acid and diacylglycerol ACT synergistically through protein kinase C to persistently enhance synaptic transmission in the hippocampus. Neuroscience. 1994 Jun;60(3):737–743. doi: 10.1016/0306-4522(94)90501-0. [DOI] [PubMed] [Google Scholar]
  5. Bush A. I., Pettingell W. H., Multhaup G., d Paradis M., Vonsattel J. P., Gusella J. F., Beyreuther K., Masters C. L., Tanzi R. E. Rapid induction of Alzheimer A beta amyloid formation by zinc. Science. 1994 Sep 2;265(5177):1464–1467. doi: 10.1126/science.8073293. [DOI] [PubMed] [Google Scholar]
  6. Buxbaum J. D., Oishi M., Chen H. I., Pinkas-Kramarski R., Jaffe E. A., Gandy S. E., Greengard P. Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10075–10078. doi: 10.1073/pnas.89.21.10075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Buxbaum J. D., Ruefli A. A., Parker C. A., Cypess A. M., Greengard P. Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4489–4493. doi: 10.1073/pnas.91.10.4489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cai X. D., Golde T. E., Younkin S. G. Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science. 1993 Jan 22;259(5094):514–516. doi: 10.1126/science.8424174. [DOI] [PubMed] [Google Scholar]
  9. Caporaso G. L., Gandy S. E., Buxbaum J. D., Ramabhadran T. V., Greengard P. Protein phosphorylation regulates secretion of Alzheimer beta/A4 amyloid precursor protein. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3055–3059. doi: 10.1073/pnas.89.7.3055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Citron M., Oltersdorf T., Haass C., McConlogue L., Hung A. Y., Seubert P., Vigo-Pelfrey C., Lieberburg I., Selkoe D. J. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature. 1992 Dec 17;360(6405):672–674. doi: 10.1038/360672a0. [DOI] [PubMed] [Google Scholar]
  11. Coyle J. T., Price D. L., DeLong M. R. Alzheimer's disease: a disorder of cortical cholinergic innervation. Science. 1983 Mar 11;219(4589):1184–1190. doi: 10.1126/science.6338589. [DOI] [PubMed] [Google Scholar]
  12. Craig A. M., Blackstone C. D., Huganir R. L., Banker G. The distribution of glutamate receptors in cultured rat hippocampal neurons: postsynaptic clustering of AMPA-selective subunits. Neuron. 1993 Jun;10(6):1055–1068. doi: 10.1016/0896-6273(93)90054-u. [DOI] [PubMed] [Google Scholar]
  13. Dumuis A., Pin J. P., Oomagari K., Sebben M., Bockaert J. Arachidonic acid released from striatal neurons by joint stimulation of ionotropic and metabotropic quisqualate receptors. Nature. 1990 Sep 13;347(6289):182–184. doi: 10.1038/347182a0. [DOI] [PubMed] [Google Scholar]
  14. Emmerling M. R., Moore C. J., Doyle P. D., Carroll R. T., Davis R. E. Phospholipase A2 activation influences the processing and secretion of the amyloid precursor protein. Biochem Biophys Res Commun. 1993 Nov 30;197(1):292–297. doi: 10.1006/bbrc.1993.2474. [DOI] [PubMed] [Google Scholar]
  15. Felder C. C., Kanterman R. Y., Ma A. L., Axelrod J. Serotonin stimulates phospholipase A2 and the release of arachidonic acid in hippocampal neurons by a type 2 serotonin receptor that is independent of inositolphospholipid hydrolysis. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2187–2191. doi: 10.1073/pnas.87.6.2187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Francis P. T., Sims N. R., Procter A. W., Bowen D. M. Cortical pyramidal neurone loss may cause glutamatergic hypoactivity and cognitive impairment in Alzheimer's disease: investigative and therapeutic perspectives. J Neurochem. 1993 May;60(5):1589–1604. doi: 10.1111/j.1471-4159.1993.tb13381.x. [DOI] [PubMed] [Google Scholar]
  17. Gabuzda D., Busciglio J., Yankner B. A. Inhibition of beta-amyloid production by activation of protein kinase C. J Neurochem. 1993 Dec;61(6):2326–2329. doi: 10.1111/j.1471-4159.1993.tb07479.x. [DOI] [PubMed] [Google Scholar]
  18. Haass C., Koo E. H., Mellon A., Hung A. Y., Selkoe D. J. Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature. 1992 Jun 11;357(6378):500–503. doi: 10.1038/357500a0. [DOI] [PubMed] [Google Scholar]
  19. Hardy J. Framing beta-amyloid. Nat Genet. 1992 Jul;1(4):233–234. doi: 10.1038/ng0792-233. [DOI] [PubMed] [Google Scholar]
  20. Hung A. Y., Haass C., Nitsch R. M., Qiu W. Q., Citron M., Wurtman R. J., Growdon J. H., Selkoe D. J. Activation of protein kinase C inhibits cellular production of the amyloid beta-protein. J Biol Chem. 1993 Nov 5;268(31):22959–22962. [PubMed] [Google Scholar]
  21. Hyman B. T., Van Hoesen G. W., Damasio A. R. Alzheimer's disease: glutamate depletion in the hippocampal perforant pathway zone. Ann Neurol. 1987 Jul;22(1):37–40. doi: 10.1002/ana.410220110. [DOI] [PubMed] [Google Scholar]
  22. Jarrett J. T., Lansbury P. T., Jr Seeding "one-dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell. 1993 Jun 18;73(6):1055–1058. doi: 10.1016/0092-8674(93)90635-4. [DOI] [PubMed] [Google Scholar]
  23. Kang J., Lemaire H. G., Unterbeck A., Salbaum J. M., Masters C. L., Grzeschik K. H., Multhaup G., Beyreuther K., Müller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19;325(6106):733–736. doi: 10.1038/325733a0. [DOI] [PubMed] [Google Scholar]
  24. Martin L. J., Blackstone C. D., Huganir R. L., Price D. L. Cellular localization of a metabotropic glutamate receptor in rat brain. Neuron. 1992 Aug;9(2):259–270. doi: 10.1016/0896-6273(92)90165-a. [DOI] [PubMed] [Google Scholar]
  25. Masu M., Tanabe Y., Tsuchida K., Shigemoto R., Nakanishi S. Sequence and expression of a metabotropic glutamate receptor. Nature. 1991 Feb 28;349(6312):760–765. doi: 10.1038/349760a0. [DOI] [PubMed] [Google Scholar]
  26. Nakajima Y., Iwakabe H., Akazawa C., Nawa H., Shigemoto R., Mizuno N., Nakanishi S. Molecular characterization of a novel retinal metabotropic glutamate receptor mGluR6 with a high agonist selectivity for L-2-amino-4-phosphonobutyrate. J Biol Chem. 1993 Jun 5;268(16):11868–11873. [PubMed] [Google Scholar]
  27. Nakanishi S. Metabotropic glutamate receptors: synaptic transmission, modulation, and plasticity. Neuron. 1994 Nov;13(5):1031–1037. doi: 10.1016/0896-6273(94)90043-4. [DOI] [PubMed] [Google Scholar]
  28. Nakanishi S. Molecular diversity of glutamate receptors and implications for brain function. Science. 1992 Oct 23;258(5082):597–603. doi: 10.1126/science.1329206. [DOI] [PubMed] [Google Scholar]
  29. Nitsch R. M., Slack B. E., Wurtman R. J., Growdon J. H. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science. 1992 Oct 9;258(5080):304–307. doi: 10.1126/science.1411529. [DOI] [PubMed] [Google Scholar]
  30. Okamoto N., Hori S., Akazawa C., Hayashi Y., Shigemoto R., Mizuno N., Nakanishi S. Molecular characterization of a new metabotropic glutamate receptor mGluR7 coupled to inhibitory cyclic AMP signal transduction. J Biol Chem. 1994 Jan 14;269(2):1231–1236. [PubMed] [Google Scholar]
  31. Oltersdorf T., Ward P. J., Henriksson T., Beattie E. C., Neve R., Lieberburg I., Fritz L. C. The Alzheimer amyloid precursor protein. Identification of a stable intermediate in the biosynthetic/degradative pathway. J Biol Chem. 1990 Mar 15;265(8):4492–4497. [PubMed] [Google Scholar]
  32. Palmert M. R., Podlisny M. B., Witker D. S., Oltersdorf T., Younkin L. H., Selkoe D. J., Younkin S. G. The beta-amyloid protein precursor of Alzheimer disease has soluble derivatives found in human brain and cerebrospinal fluid. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6338–6342. doi: 10.1073/pnas.86.16.6338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Schoepp D. D., Conn P. J. Metabotropic glutamate receptors in brain function and pathology. Trends Pharmacol Sci. 1993 Jan;14(1):13–20. doi: 10.1016/0165-6147(93)90107-u. [DOI] [PubMed] [Google Scholar]
  34. Selkoe D. J. Normal and abnormal biology of the beta-amyloid precursor protein. Annu Rev Neurosci. 1994;17:489–517. doi: 10.1146/annurev.ne.17.030194.002421. [DOI] [PubMed] [Google Scholar]
  35. Shirasaki T., Harata N., Akaike N. Metabotropic glutamate response in acutely dissociated hippocampal CA1 pyramidal neurones of the rat. J Physiol. 1994 Mar 15;475(3):439–453. doi: 10.1113/jphysiol.1994.sp020084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Slack B. E., Breu J., Petryniak M. A., Srivastava K., Wurtman R. J. Tyrosine phosphorylation-dependent stimulation of amyloid precursor protein secretion by the m3 muscarinic acetylcholine receptor. J Biol Chem. 1995 Apr 7;270(14):8337–8344. doi: 10.1074/jbc.270.14.8337. [DOI] [PubMed] [Google Scholar]
  37. Slack B. E., Nitsch R. M., Livneh E., Kunz G. M., Jr, Breu J., Eldar H., Wurtman R. J. Regulation by phorbol esters of amyloid precursor protein release from Swiss 3T3 fibroblasts overexpressing protein kinase C alpha. J Biol Chem. 1993 Oct 5;268(28):21097–21101. [PubMed] [Google Scholar]
  38. Slunt H. H., Thinakaran G., Von Koch C., Lo A. C., Tanzi R. E., Sisodia S. S. Expression of a ubiquitous, cross-reactive homologue of the mouse beta-amyloid precursor protein (APP). J Biol Chem. 1994 Jan 28;269(4):2637–2644. [PubMed] [Google Scholar]
  39. Tanabe Y., Masu M., Ishii T., Shigemoto R., Nakanishi S. A family of metabotropic glutamate receptors. Neuron. 1992 Jan;8(1):169–179. doi: 10.1016/0896-6273(92)90118-w. [DOI] [PubMed] [Google Scholar]
  40. Toullec D., Pianetti P., Coste H., Bellevergue P., Grand-Perret T., Ajakane M., Baudet V., Boissin P., Boursier E., Loriolle F. The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J Biol Chem. 1991 Aug 25;266(24):15771–15781. [PubMed] [Google Scholar]
  41. Van Nostrand W. E., Wagner S. L., Shankle W. R., Farrow J. S., Dick M., Rozemuller J. M., Kuiper M. A., Wolters E. C., Zimmerman J., Cotman C. W. Decreased levels of soluble amyloid beta-protein precursor in cerebrospinal fluid of live Alzheimer disease patients. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2551–2555. doi: 10.1073/pnas.89.7.2551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Watson D. G., Wainer B. H., Lenox R. H. Phorbol ester- and retinoic acid-induced regulation of the protein kinase C substrate MARCKS in immortalized hippocampal cells. J Neurochem. 1994 Nov;63(5):1666–1674. doi: 10.1046/j.1471-4159.1994.63051666.x. [DOI] [PubMed] [Google Scholar]
  43. Weidemann A., König G., Bunke D., Fischer P., Salbaum J. M., Masters C. L., Beyreuther K. Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein. Cell. 1989 Apr 7;57(1):115–126. doi: 10.1016/0092-8674(89)90177-3. [DOI] [PubMed] [Google Scholar]
  44. Wolf B. A., Wertkin A. M., Jolly Y. C., Yasuda R. P., Wolfe B. B., Konrad R. J., Manning D., Ravi S., Williamson J. R., Lee V. M. Muscarinic regulation of Alzheimer's disease amyloid precursor protein secretion and amyloid beta-protein production in human neuronal NT2N cells. J Biol Chem. 1995 Mar 3;270(9):4916–4922. doi: 10.1074/jbc.270.9.4916. [DOI] [PubMed] [Google Scholar]
  45. Yankner B. A., Duffy L. K., Kirschner D. A. Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science. 1990 Oct 12;250(4978):279–282. doi: 10.1126/science.2218531. [DOI] [PubMed] [Google Scholar]

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