We would like to thank Dr. Carol Gray (SmithKline Beecham Pharmaceuticals) for the gift of the Ab54 and Ab790 antibodies, Dr. David Byres for the gift of the anti-MARCKS antibody, and Prof. Etic Berger for the anti-α2,3-sialyltransferase antibody. We would also like to thank Niki Georgopoulou for her assistance with the α2,3 sialyltransferase analysis and together with Tetsutaro Shinomura for their helpful discussions. This study was supported by a local trust through a Tenovus Initiative and by a Caledonian Research Foundation/Royal Society of Edinburgh Senior Research Fellowship to K.C.B.

  • 1
    Alessi D.R. (1997) The protein kinase C inhibitors Ro 318220 and GF 109203X are equally potent inhibitors of MAPKAP kinase-1 beta (Rsk-2) and p70 S6 kinase.FEBS Lett. 402,121123.
  • 2
    Ancolio K., Marambaud P., Dauch P., Checler F. (1997) α-Secretase-derived product of β-amyloid precursor protein is decreased by presenilin 1 mutations linked to familial Alzheimer's disease. J. Neurochem. 69,24942499.
  • 3
    Arai H., Lee V.M.Y., Messinger M.L., Greenberg B.D., Lowery D.E., Trojanowski J.Q. (1991) Expression patterns of beta-amyloid precursor protein (beta-APP) in neural and nonneural human tissues from Alzheimer's disease and control subjects.Ann. Neurol. 30,686693.
  • 4
    Beltman J., McCormick F., Cook S.J. (1996) The selective protein-kinase-C inhibitor, Ro-31-8220, inhibits mitogen-activated protein-kinase phosphatase-1 (Mkp-1) expression, induces C-Jun expression, and activates Jun N-terminal kinase.J. Biol. Chem. 271,2701827024.
  • 5
    Breen K.C., Coughlan C.M., Hayes F.D. (1998) The role of glycoproteins in neural development, function and disease.Mol. Neurobiol. 16,163220.
  • 6
    Buxbaum J.D., Gandy S.E., Cicchetti P., Ehrlich M.E., Czernik A.J., Fracasso R.P., Ramabhadran T.V., Unterbeck A.J., Greengard P. (1990) Processing of Alzheimer β/A4 amyloid precursor protein : modulation by agents that regulate protein phosphorylation. Proc. Natl. Acad. Sci. USA 87,60036006.
  • 7
    Buxbaum J.D., Oishi M., Chen H.I., Pinkas-Kramarski R., Jaffe E.A., Gandy S.E., Greengard P. (1992) Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer β/A4 amyloid protein precursor. Proc. Natl. Acad. Sci. USA 89,1007510078.
  • 8
    Caputi A., Barindelli S., Pastorino L., Cimino M., Buxbaum J.D., Cattabeni F., Di Luca M. (1997) Increased secretion of the amino-terminal fragment of the amyloid precursor protein in brains of rats with a constitutive up-regulation of protein kinase C.J. Neurochem. 68,25232529.
  • 9
    Chyung A.S.C., Greenberg B.D., Cook D.G., Doms R.W., Lee V.M.Y. (1997) Novel beta-secretase cleavage of beta-amyloid precursor protein in the endoplasmic reticulum intermediate compartment of NT2N cells.J. Cell Biol. 138,671680.
  • 10
    Desdouits-Magnen J., Desdouits F., Takeda S., Syu L., Saltiel A.R., Buxbaum J.D., Czernik A.J., Nairn A.C., Greengard P. (1998) Regulation of secretion of Alzheimer amyloid precursor protein by the mitogen-activated protein kinase cascade.J. Neurochem. 70,524530.
  • 11
    Dunkley P.R., Heath J.W., Harrison S.M., Jarvie P.E., Glenfield P.J., Rostas J.A.P. (1988) A rapid Percoll gradient procedure for isolation of synaptosomes directly from an S-1 fraction—homogeneity and morphology of subcellular-fractions. Brain Res. 441,5971.
  • 12
    Farber S.A., Nitsch R.M., Schulz J.G., Wurtman R.J. (1995) Regulated secretion of β-amyloid precursor protein in rat-brain. J. Neurosci. 15,74427451.
  • 13
    Fazeli M.S., Breen K.C., Errington M.L., Bliss T.V.P. (1994) Increase in extracellular NCAM and amyloid precursor protein following induction of long-term potentiation in the dentate gyrus of anaesthetized rats.Neurosci. Lett. 169,7780.
  • 14
    Furukawa K. & Mattson M.P. (1998) Secreted amyloid precursor protein alpha selectively suppresses N-methyl-d-aspartate currents in hippocampal neurons : involvement of cyclic GMP. Neuroscience 83,429438.
  • 15
    Furukawa K., Barger S.W., Blalock E.M., Mattson M.P. (1996) Activation of K+ channels and suppression of neuronal activity by secreted β-amyloid-precursor protein. Nature 379,7478.
  • 16
    Golde T.E., Estus S., Younkin L.H., Selkoe D.J., Younkin S.G. (1992) Processing of the amyloid protein-precursor to potentially amyloidogenic derivatives.Science 255,728730.
  • 17
    Hung A.Y. & Selkoe D.J. (1994) Selective ectodomain phosphorylation and regulated cleavage of β-amyloid precursor protein. EMBO J. 13,534542.
  • 18
    Ikin A.F., Annaert W.G., Takei K., De Camilli P., Jahn R., Greengard P., Buxbaum J.D. (1996) Alzheimer amyloid protein precursor is localized in nerve terminal preparations to Rab5-containing vesicular organelles distinct from those implicated in the synaptic vesicle pathway.J. Biol. Chem. 271,3178331786.
  • 19
    Ishida A., Furukawa K., Keller J.N., Mattson M.P. (1997) Secreted form of beta-amyloid precursor protein shifts the frequency dependency for induction of LTD, and enhances LTP in hippocampal slices.Neuroreport 8,21332137.
  • 20
    Johannes L., Doussau F., Clabecq A., Henry J.P., Darchen F., Poulain B. (1996) Evidence for a functional link between Rab3 and the SNARE complex.J. Cell Sci. 109,28752884.
  • 21
    Kametani F., Tanaka K., Ishii T., Ikeda S., Kennedy H.E., Allsop D. (1993) Secretory form of Alzheimer amyloid precursor protein 695 in human brain lacks β/A4 amyloid immunoreactivity. Biochem. Biophys. Res. Commun. 191,392398.DOI: 10.1006/bbrc.1993.1230
  • 22
    Kim S.H., Kim Y.K., Jeong S.J., Haass C., Kim Y.H., Suh Y.H. (1997) Enhanced release of secreted form of Alzheimer's amyloid precursor protein from PC12 cells by nicotine.Mol. Pharmacol. 52,430436.
  • 23
    Kinouchi T., Sorimachi H., Maruyama K., Mizuno K., Ohno S., Ishiura S., Suzuki K. (1995) Conventional protein-kinase-C (Pkc)-alpha and novel Pkc-epsilon, but not Pkc-delta, increase the secretion of an N-terminal fragment of Alzheimers-disease amyloid precursor protein from Pkc cDNA transfected 3Y1 fibroblasts.FEBS Lett. 364,203206.
  • 24
    Kiss Z., Phillips H., Anderson W.H. (1995) The bisindolylmaleimide GF 109203X, a selective inhibitor of protein kinase C, does not inhibit the potentiating effect of phorbol ester on ethanol-induced phospholipase C-mediated hydrolysis of phosphatidyleth-anolamine.Biochim. Biophys. Acta 1265,9395.
  • 25
    Koo E.H., Sisodia S.S., Archer D.R., Martin L.J., Weidemann A., Beyreuther K., Fischer P., Masters C.L., Price D.L. (1990) Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport.Proc. Natl. Acad. Sci. USA 87,15611565.
  • 26
    Koo E.H., Squazzo S.L., Selkoe D.J., Koo C.H. (1996) Trafficking of cell-surface amyloid beta-protein precursor. I. Secretion, endocytosis and recycling as detected by labeled monoclonal antibody.J. Cell Sci. 109,991998.
  • 27
    Marambaud P., Lopez-Perez E., Wilk S., Checler F. (1997) Constitutive and protein kinase C-regulated secretory cleavage of Alzheimer's β-amyloid precursor protein : different control of early and late events by the proteasome. J. Neurochem. 69,25002505.
  • 28
    Marquez-Sterling N.R., Lo A.C.Y., Sisodia S.S., Koo E.H. (1997) Trafficking of cell-surface beta-amyloid precursor protein : evidence that a sorting intermediate participates in synaptic vesicle recycling.J. Neurosci. 17,140151.
  • 29
    Mattson M.P. (1997) Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives.Physiol. Rev. 77,10811132.
  • 30
    Mattson M.P., Cheng B., Culwell A.R., Esch F.S., Lieberberg I., Rydel R.E. (1993) Evidence for excitoprotective and intraneuronal calcium regulating roles for secreted forms of the β-amyloid precursor protein. Neuron 10,243254.
  • 31
    McLaughlin M., Ross B.M., Milligan G., McCulloch J., Knowler J.T. (1991) Robustness of G proteins in Alzheimer's disease : an immunoblot study.J. Neurochem. 57,914.
  • 32
    Mehta N.D., Refolo L.M., Eckman C., Sanders S., Yager D., PerezTur J., Younkin S., Duff K., Hardy J., Hutton M. (1998) Increased A beta 42(43) from cell lines expressing presenilin 1 mutations.Ann. Neurol. 43,256258.
  • 33
    Mills J. & Reiner P.B. (1996) Phorbol esters but not the cholinergic agonists oxotremorine-M and carbachol increase release of the amyloid precursor protein in cultured rat cortical neurons.J. Neurochem. 67,15111518.
  • 34
    Mills J., Charest D.L., Lam F., Beyreuther K., Ida N., Pelech S.L., Reiner P.B. (1997) Regulation of amyloid precursor protein catabolism involves the mitogen-activated protein kinase signal transduction pathway.J. Neurosci. 17,94159422.
  • 35
    Milward E.A., Papadopoulos R., Fuller S.J., Moir R.D., Small D., Beyreuther K., Masters C.L. (1992) The amyloid protein-precursor of Alzheimers-disease is a mediator of the effects of nerve growth-factor on neurite outgrowth.Neuron 9,129137.
  • 36
    Nicholls D.G. (1993) The glutamatergic nerve-terminal.Eur. J. Biochem. 212,613631.
  • 37
    Nitsch R.M., Deng A., Wurtman R.J., Growdon J.H. (1997) Metabotropic glutamate receptor subtype mGluR1α stimulates the secretion of the amyloid β-protein precursor ectodomain. J. Neurochem. 69,704712.
  • 38
    Nitsch R.M., Slack B.E., Wurtman R.J., Growdon J.H. (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors.Science 258,304307.
  • 39
    Nitsch R.M., Deng M.H., Growdon J.H., Wurtman R.J. (1996) Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion.J. Biol. Chem. 271,41884194.
  • 40
    Pahlsson P., Shankin-Eshleman S.H., Spitalnik S.L. (1992) N-linked glycosylation of β-amyloid precursor protein. Biochem. Biophys. Res. Commun. 189,16671673.
  • 41
    Peraus G.C., Masters C.L., Beyreuther K. (1997) Late compartments of amyloid precursor protein transport in SY5Y cells are involved in beta-amyloid secretion.J. Neurosci. 17,77147724.
  • 42
    Petryniak M.A., Wurtman R.J., Slack B.E. (1996) Elevated intracellular calcium concentration increases secretory processing of the amyloid precursor protein by a tyrosine phosphorylation-dependent mechanism.Biochem. J. 320,957963.
  • 43
    Refolo L.M., Wittenberg I.S., Friedrich V.L., Robakis N.K. (1991) The Alzheimer amyloid precursor is associated with the detergent-insoluble cytoskeleton.J. Neurosci. 11,38883897.
  • 44
    Robinson P.J., Liu J.P., Chen W., Wenzel T. (1993) Activation of protein kinase C in vitro and in intact cells or synaptosomes determined by acetic acid extraction of MARCKS.Anal. Biochem. 210,172178.DOI: 10.1006/abio.1993.1169
  • 45
    Sisodia S.S. (1992) Beta-amyloid precursor protein cleavage by a membrane-bound protease.Proc. Natl. Acad. Sci. USA 89,60756079.
  • 46
    Slack B.E., Breu J., Petryniak M.A., Srivastava K., Wurtman R.J. (1995) Tyrosine phosphorylation-dependent stimulation of amyloid precursor protein secretion by the M3 muscarinic acetylcholine receptor.J. Biol. Chem. 270,83378344.
  • 47
    Slack B.E., Breu J., Muchnicki L., Wurtman R.J. (1997) Rapid stimulation of amyloid precursor protein release by epidermal growth factor : role of protein kinase C.Biochem. J. 327,245249.
  • 48
    Uberall F., Giselbrecht S., Hellbert K., Fresser F., Bauer B., Gschwendt M., Grunicke H.H., Baier G. (1997) Conventional PKC-alpha, novel PKC-epsilon and PKC-theta, but not atypical PKC-lambda are MARCKS kinases in intact NIH 3T3 fibroblasts.J. Biol. Chem. 272,40724078.
  • 49
    Wild-Bode C., Yamazaki T., Capell A., Leimer U., Steiner H., Ihara Y., Haass C. (1997) Intracellular generation and accumulation of amyloid β peptide terminating at amino acid 42.J. Biol. Chem. 272,1608516088.
  • 50
    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.Y. (1995) Muscarinic regulation of Alzheimer's disease amyloid precursor protein secretion and amyloid beta-protein production in human neuronal NT2N cells.J. Biol. Chem. 270,49164922.
  • 51
    Xu H.X., Greengard P., Gandy S. (1995) Regulated formation of Golgi secretory vesicles containing Alzheimer beta-amyloid precursor protein.J. Biol. Chem. 270,2324323245.
  • 52
    Xu H.X., Sweeney D., Wang R., Thinakaran G., Lo A.C.Y., Sisodia S.S., Greengard P., Gandy S. (1997) Generation of Alzheimer beta-amyloid protein in the trans-Golgi network in the apparent absence of vesicle formation.Proc. Natl. Acad. Sci. USA 94,37483752.