[en] The Swedish mutation within the amyloid precursor protein (APP) causes early-onset Alzheimer's disease due to increased cleavage of APP by BACE1. While beta-secretase shedding of Swedish APP (APPswe) largely results from an activity localized in the late secretory pathway, cleavage of wild-type APP occurs mainly in endocytic compartments. However, we show that liberation of Abeta from APPswe is still dependent on functional internalization from the cell surface. Inspite the unchanged overall beta-secretase cleaved soluble APP released from APP(swe) secretion, mutations of the APPswe internalization motif strongly reduced C99 levels and substantially decreased Abeta secretion. We point out that alpha-secretase activity-mediated conversion of C99 to C83 is the main cause of this Abeta reduction. Furthermore, we demonstrate that alpha-secretase cleavage of C99 even contributes to the reduction of Abeta secretion of internalization deficient wild-type APP. Therefore, inhibition of alpha-secretase cleavage increased Abeta secretion through diminished conversion of C99 to C83 in APP695, APP695swe or C99 expressing cells.
Disciplines :
Neurology
Author, co-author :
Jäger, Sebastian; Molecular Neurodegeneration Group, Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg-University Mainz, Mainz, Germany
Leuchtenberger, Stefanie; Molecular Neuropathology Group, Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany
Martin, Anne; Institute of Physiological Chemistry and Pathobiochemistry, Molecular Neurodegeneration, Johannes-Gutenberg-University Mainz, D-55099 Mainz, Germany
Czirr, Eva; Molecular Neuropathology Group, Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany
Wesselowski, Johanna; Institute of Physiological Chemistry and Pathobiochemistry, Molecular Neurodegeneration, Johannes-Gutenberg-University Mainz, D-55099 Mainz, Germany
Dieckmann, Marco; Molecular Neuropathology Group, Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany
Waldron, Elaine; Institute of Physiological Chemistry and Pathobiochemistry, Molecular Neurodegeneration, Johannes-Gutenberg-University Mainz, D-55099 Mainz, Germany
Korth, Carsten; Institute of Neuropathology, Heinrich Heine University, Düsseldorf, Germany
Koo, Edward H; Department of Neurosciences, University of California, United States
HENEKA, Michael ; Department of Neurology, Clinical Neuroscience, University of Bonn, Bonn, Germany
Weggen, Sascha; Molecular Neuropathology Group, Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany
Pietrzik, Claus U; Institute of Physiological Chemistry and Pathobiochemistry, Molecular Neurodegeneration, Johannes-Gutenberg-University Mainz, D-55099 Mainz, Germany
External co-authors :
yes
Language :
English
Title :
alpha-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Abeta generation.
Bueler H., Fischer M., Lang Y., Bluethmann H., Lipp H. P., DeArmond S. J., Prusiner S. B., Aguet M. Weissmann C. (1992) Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356, 577 582.
Buxbaum J. D., Liu K. N., Luo Y., Slack J. L., Stocking K. L., Peschon J. J., Johnson R. S., Castner B. J., Cerretti D. P. Black R. A. (1998) Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J. Biol. Chem. 273, 27765 27767.
Caporaso G. L., Gandy S. E., Buxbaum J. D. Greengard P. (1992) Chloroquine inhibits intracellular degradation but not secretion of Alzheimer beta/A4 amyloid precursor protein. Proc. Natl. Acad. Sci. USA 89, 2252 2256.
Chen W. J., Goldstein J. L. Brown M. S. (1990) NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. J. Biol. Chem. 265, 3116 3123.
Chyung J. H. Selkoe D. J. (2003) Inhibition of receptor-mediated endocytosis demonstrates generation of amyloid beta-protein at the cell surface. J. Biol. Chem. 278, 51035 51043.
Chyung J. H., Raper D. M. Selkoe D. J. (2005) Gamma-secretase exists on the plasma membrane as an intact complex that accepts substrates and effects intramembrane cleavage. J. Biol. Chem. 280, 4383 4392.
Cirrito J. R., Kang J. E., Lee J., Stewart F. R., Verges D. K., Silverio L. M., Bu G., Mennerick S. Holtzman D. M. (2008) Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 58, 42 51.
Citron M., Oltersdorf T., Haass C., McConlogue L., Hung A. Y., Seubert P., Vigo-Pelfrey C., Lieberburg I. Selkoe D. J. (1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 360, 672 674.
Citron M., Teplow D. B. Selkoe D. J. (1995) Generation of amyloid beta protein from its precursor is sequence specific. Neuron 14, 661 670.
Cook D. G., Forman M. S., Sung J. C., Leight S., Kolson D. L., Iwatsubo T., Lee V. M. Doms R. W. (1997) Alzheimer's A beta(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nat. Med. 3, 1021 1023.
De Strooper B., Umans L., Van Leuven F. Van Den Berghe H. (1993) Study of the synthesis and secretion of normal and artificial mutants of murine amyloid precursor protein (APP): cleavage of APP occurs in a late compartment of the default secretion pathway. J. Cell Biol. 121, 295 304.
Edbauer D., Winkler E., Regula J. T., Pesold B., Steiner H. Haass C. (2003) Reconstitution of gamma-secretase activity. Nat. Cell Biol. 5, 486 488.
Esch F. S., Keim P. S., Beattie E. C., Blacher R. W., Culwell A. R., Oltersdorf T., McClure D. Ward P. J. (1990) Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science 248, 1122 1124.
Felsenstein K. M., Hunihan L. W. Roberts S. B. (1994) Altered cleavage and secretion of a recombinant beta-APP bearing the Swedish familial Alzheimer's disease mutation. Nat. Genet. 6, 251 255.
Haass C. (2004) Take five - BACE and the gamma-secretase quartet conduct Alzheimer's amyloid beta-peptide generation. EMBO J. 23, 483 488.
Haass C., Koo E. H., Mellon A., Hung A. Y. Selkoe D. J. (1992) Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 357, 500 503.
Haass C., Hung A. Y., Schlossmacher M. G., Teplow D. B. Selkoe D. J. (1993) Beta-amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms. J. Biol. Chem. 268, 3021 3024.
Haass C., Hung A. Y., Selkoe D. J. Teplow D. B. (1994) Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid beta-protein precursor. J. Biol. Chem. 269, 17741 17748.
Haass C., Lemere C. A., Capell A., Citron M., Seubert P., Schenk D., Lannfelt L. Selkoe D. J. (1995) The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway. Nat. Med. 1, 1291 1296.
Hartmann T., Bieger S. C., Bruhl B. et al. (1997) Distinct sites of intracellular production for Alzheimer's disease A beta40/42 amyloid peptides. Nat. Med. 3, 1016 1020.
Hsiao K., Chapman P., Nilsen S., Eckman C., Harigaya Y., Younkin S., Yang F. Cole G. (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274, 99 102.
Huse J. T., Pijak D. S., Leslie G. J., Lee V. M. Doms R. W. (2000) Maturation and endosomal targeting of beta-site amyloid precursor protein-cleaving enzyme. The Alzheimer's disease beta-secretase. J. Biol. Chem. 275, 33729 33737.
Hussain I., Powell D., Howlett D. R. et al. (1999) Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol. Cell. Neurosci. 14, 419 427.
Kaether C., Schmitt S., Willem M. Haass C. (2006) Amyloid precursor protein and Notch intracellular domains are generated after transport of their precursors to the cell surface. Traffic 7, 408 415.
King G. D., Perez R. G., Steinhilb M. L., Gaut J. R. Turner R. S. (2003) X11alpha modulates secretory and endocytic trafficking and metabolism of amyloid precursor protein: mutational analysis of the YENPTY sequence. Neuroscience 120, 143 154.
Koike H., Tomioka S., Sorimachi H., Saido T. C., Maruyama K., Okuyama A., Fujisawa-Sehara A., Ohno S., Suzuki K. Ishiura S. (1999) Membrane-anchored metalloprotease MDC9 has an alpha-secretase activity responsible for processing the amyloid precursor protein. Biochem. J. 343 (Pt 2 371 375.
Koo E. H. Squazzo S. L. (1994) Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J. Biol. Chem. 269, 17386 17389.
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 (Pt 5 991 998.
Lai A., Sisodia S. S. Trowbridge I. S. (1995) Characterization of sorting signals in the beta-amyloid precursor protein cytoplasmic domain. J. Biol. Chem. 270, 3565 3573.
Lammich S., Kojro E., Postina R., Gilbert S., Pfeiffer R., Jasionowski M., Haass C. Fahrenholz F. (1999) Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl. Acad. Sci. USA 96, 3922 3927.
Leuchtenberger S., Maler J., Czirr E., Ness J., Lichtenthaler S. F., Esselmann H., Pietrzik C. U., Wiltfang J. Weggen S. (2008) Nonsteroidal Anti-Inflammatory Drugs and Ectodomain Shedding of the Amyloid Precursor Protein. Neurodegener. Dis. 6 (1-2 1 6.
Lichtenthaler S. F., Multhaup G., Masters C. L. Beyreuther K. (1999) A novel substrate for analyzing Alzheimer's disease gamma-secretase. FEBS Lett. 453, 288 292.
Perez R. G., Squazzo S. L. Koo E. H. (1996) Enhanced release of amyloid beta-protein from codon 670/671 "Swedish" mutant beta-amyloid precursor protein occurs in both secretory and endocytic pathways. J. Biol. Chem. 271, 9100 9107.
Perez R. G., Soriano S., Hayes J. D., Ostaszewski B., Xia W., Selkoe D. J., Chen X., Stokin G. B. Koo E. H. (1999) Mutagenesis identifies new signals for beta-amyloid precursor protein endocytosis, turnover, and the generation of secreted fragments, including Abeta42. J. Biol. Chem. 274, 18851 18856.
Pietrzik C. U., Busse T., Merriam D. E., Weggen S. Koo E. H. (2002) The cytoplasmic domain of the LDL receptor-related protein regulates multiple steps in APP processing. EMBO J. 21, 5691 5700.
Portelius E., Brinkmalm G., Tran A. J., Zetterberg H., Westman-Brinkmalm A. Blennow K. (2009a) Identification of novel APP/Abeta isoforms in human cerebrospinal fluid. Neurodegener Dis 6, 87 94.
Portelius E., Price E., Brinkmalm G., Stiteler M., Olsson M., Persson R., Westman-Brinkmalm A., Zetterberg H., Simon A. J. Blennow K. (2009b) A novel pathway for amyloid precursor protein processing. Neurobiol. Aging [Epub ahead of print] doi :.
Postina R., Schroeder A., Dewachter I. et al. (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J. Clin. Invest. 113, 1456 1464.
Sambamurti K., Shioi J., Anderson J. P., Pappolla M. A. Robakis N. K. (1992) Evidence for intracellular cleavage of the Alzheimer's amyloid precursor in PC12 cells. J. Neurosci. Res. 33, 319 329.
Sastre M., Steiner H., Fuchs K., Capell A., Multhaup G., Condron M. M., Teplow D. B. Haass C. (2001) Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep 2, 835 841.
Selkoe D. J. (2001) Alzheimer's disease: genes, proteins, and therapy. Physiol. Rev. 81, 741 766.
Seubert P., Oltersdorf T., Lee M. G. et al. (1993) Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide. Nature 361, 260 263.
Sinha S., Anderson J. P., Barbour R. et al. (1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402, 537 540.
Sisodia S. S. (1992) Beta-amyloid precursor protein cleavage by a membrane-bound protease. Proc. Natl. Acad. Sci. USA 89, 6075 6079.
Skovronsky D. M., Moore D. B., Milla M. E., Doms R. W. Lee V. M. (2000) Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in the trans-golgi network. J. Biol. Chem. 275, 2568 2575.
Thinakaran G., Teplow D. B., Siman R., Greenberg B. Sisodia S. S. (1996) Metabolism of the "Swedish" amyloid precursor protein variant in neuro2a (N2a) cells. Evidence that cleavage at the "beta-secretase" site occurs in the golgi apparatus. J. Biol. Chem. 271, 9390 9397.
Vassar R., Bennett B. D., Babu-Khan S. et al. (1999) Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735 741.
Weidemann A., Eggert S., Reinhard F. B., Vogel M., Paliga K., Baier G., Masters C. L., Beyreuther K. Evin G. (2002) A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing. Biochemistry 41, 2825 2835.
Yan R., Bienkowski M. J., Shuck M. E. et al. (1999) Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature 402, 533 537.
