Funktionelle Charakterisierung von BACE, einer für die Alzheimer Krankheit relevanten Protease Anja Capellfür Manfredo Manfredi11.1121.23452#1914420#1481.3567348#4171.3.1474#1158910111.3.212503#2861314577#1891.3.2.115161.3.2.217483#111181.3.2.31920599#4712122539#1681.423426#1862425504#40026271.51.5.128365#155291.5.230479#2381.63122.12.1.1312.1.2322.1.32.1.42.22.2.1332.2.2342.2.2.12.2.2.2566#4012.2.3352.2.3.12.2.42.2.4.1362.32.3.1373839402.3.24142432.3.32.3.4442.3.52.3.6452.3.74647482.3.8492.3.92.3.105051522.3.112.3.12532.42.4.1542.4.1.1552.4.1.256572.4.1.358592.4.1.42.4.22.4.2.1602.4.2.26162632.52.5.12.5.1.164652.5.1.266672.5.268692.5.32.5.3.1702.5.3.2717273742.5.3.375767778798081822.5.3.4832.5.3.58485868788892.5.3.6902.5.3.7912.5.42.5.4.192932.5.4.2942.5.4.39596972.5.4.498992.5.4.51001012.5.52.5.5.11022.5.5.21031042.5.5.31052.5.62.5.6.11061072.5.6.21081091102.5.6.31111121132.5.6.41142.62.6.11151161171181192.6.21201211221232.72.7.12.7.1.11241251262.7.1.21272.7.1.32.7.1.41282.7.2129392#290130131457#3032.7.31321331341352.7.3.113613733.13.1.11371381393.1.2140511#1273.1.3470#306141376#1901421433.23.2.1561#274144555#240145527#1763.2.2146147232#186148300#180149233#1821503.2.33.2.3.1151490#257152522#1671531543.2.3.2539#129155527#1033.31563.3.1157538#1893.3.2402#309158445#524159222#2191603.4161479#344162534#240163490#1351641653.53.5.1166522#168167390#1863.5.2168435#2761693.5.33.5.3.1170317#1863.5.3.2171523#237172173274#963.5.41743.5.4.1175170#203176490#568177528#2083.5.4.2178577#212179528#2053.5.4.3180224#1101813.5.4.4182604#1973.5.4.5183528#343184185190#1293.5.5186489#2533.61873.6.13.6.1.1188440#5701893.6.1.2190535#4993.6.1.3191443#281192443#2793.6.23.6.2.1193610#1943.6.2.2194578#4421953.6.2.3196584#45719744.11974.1.11984.1.21992002014.1.32024.1.4203204205551#4242062072084.1.52092104.1.62112124.1.6.1213214438#2054.1.6.2215523#2324.22162172184.3219AbkürzungsverzeichnisLiteraturverzeichnisDanksagungErklärungLebenslaufPublikationendeInhaltsverzeichnisHilfe Literaturverzeichnis Albach, C.; Klein, R. A. und Schmitz, B. (2001): Do rodent and human brains have different N-glycosylation patterns?, Biol Chem 382) [2], Seite 187-94. Alberts, B.; Johnson, A. ; Lewis, J.; Raff, M.; Roberts, K. und Walter, P. (2002): Molecular biology of the cell, 4th edition. Auflage, Garland Science (Taylor & Francis Group), ISBN 0-8153-4072-9 (pbk.). Allinson, T. M.; Parkin, E. T.; Turner, A. J. und Hooper, N. M. (2003): ADAMs family members as amyloid precursor protein alpha-secretases, J Neurosci Res 74) [3], Seite 342-52. Alzheimer, A. (1907): Über eine eigenartige Erkrankung der Hirnrinde, Allg. Z. Psychiatrie Psychisch-Gerichtl. Med. 64), Seite 146-148. Andrau, David; Dumanchin-Njock, Cecile; Ayral, Erwan; Vizzavona, Jean; Farzan, Mike; Boisbrun, Michel; Fulcrand, Pierre; Hernandez, Jean-Francois; Martinez, Jean; Lefranc-Jullien, Solveig und Checler, Frederic (2003): BACE1- and BACE2-expressing Human Cells: CHARACTERIZATION OF {beta}-AMYLOID PRECURSOR PROTEIN-DERIVED CATABOLITES, DESIGN OF A NOVEL FLUORIMETRIC ASSAY, AND IDENTIFICATION OF NEW IN VITRO INHIBITORS, J. Biol. Chem. 278) [28], Seite 25859-25866. Andreasen, N.; Sjogren, M. und Blennow, K. (2003): CSF markers for Alzheimer's disease: total tau, phospho-tau and Abeta42, World J Biol Psychiatry 4) [4], Seite 147-55. Andreeva, N. S.; Bochkarev, A. und Pechik, I. (1995): A new way of looking at aspartic proteinase structures: a comparison of pepsin structure to other aspartic proteinases in the near active site region, Adv Exp Med Biol 362), Seite 19-32. Ankri, J. und Poupard, M. (2003): [Prevalence and incidence of dementia among the very old. Review of the literature], Rev Epidemiol Sante Publique 51) [3], Seite 349-60. Annaert, W. und De Strooper, B. (1999): Presenilins: molecular switches between proteolysis and signal transduction, Trends Neurosci. 22) [10], Seite 439-43. Annaert, W. G.; Levesque, L.; Craessaerts, K.; Dierinck, I.; Snellings, G.; Westaway, D.; George-Hyslop, P. S.; Cordell, B.; Fraser, P. und De Strooper, B. (1999): Presenilin 1 controls g-secretase processing of amyloid precursor protein in pre-golgi compartments of hippocampal neurons, J. Cell Biol. 147) [2], Seite 277-94. Baek, S. H.; Ohgi, K. A.; Rose, D. W.; Koo, E. H.; Glass, C. K. und Rosenfeld, M. G. (2002): Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kB and b-amyloid precursor protein, Cell 110), Seite 55-67. Bard, F.; Cannon, C.; Barbour, R.; Burke, R. L.; Games, D.; Grajeda, H.; Guido, T.; Hu, K.; Huang, J.; Johnson-Wood, K.; Khan, K.; Kholodenko, D.; Lee, M.; Lieberburg, I.; Motter, R.; Nguyen, M.; Soriano, F.; Vasquez, N.; Weiss, K.; Welch, B.; Seubert, P.; Schenk, D. und Yednock, T. (2000): Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease, Nat Med 6) [8], Seite 916-9. Barrow, C. J. und Zagorski, M. G. (1991): Solution structures of beta peptide and its constituent fragments: relation to amyloid deposition, Science 253) [5016], Seite 179-82. Baxter, J. D.; Duncan, K.; Chu, W.; James, M. N.; Russell, R. B.; Haidar, M. A.; DeNoto, F. M.; Hsueh, W. und Reudelhuber, T. L. (1991): Molecular biology of human renin and its gene, Recent Prog Horm Res 47), Seite 211-57. Benjannet, S.; Elagoz, A.; Wickham, L.; Mamarbachi, M.; Munzer, J. S.; Basak, A.; Lazure, C.; Cromlish, J. A.; Sisodia, S.; Checler, F.; Chretien, M. und Seidah, N. G. (2001): Post-translational processing of beta-secretase (beta-amyloid- converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid-beta production, J Biol Chem 276) [14], Seite 10879-87.. Bennett, B. D.; Babu-Khan, S.; Loeloff, R.; Louis, J. C.; Curran, E.; Citron, M. und Vassar, R. (2000): Expression analysis of BACE2 in brain and peripheral tissues, J Biol Chem 275) [27], Seite 20647-51. Bennett, B. D.; Denis, P.; Haniu, M.; Teplow, D. B.; Kahn, S.; Louis, J. C.; Citron, M. und Vassar, R. (2000): A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's beta -secretase, J Biol Chem 275) [48], Seite 37712-7.. Benting, J. H.; Rietveld, A. G. und Simons, K. (1999): N-Glycans mediate the apical sorting of a GPI-anchored, raft-associated protein in Madin-Darby canine kidney cells, J Cell Biol 146) [2], Seite 313-20. Birnboim, H. C. und Doly, J. (1979): A rapid alkaline extraction procedure for screening recombinant plasmid DNA, Nucleic Acids Res 7) [6], Seite 1513-23.. Black, R. A.; Rauch, C. T.; Kozlosky, C. J.; Peschon, J. J.; Slack, J. L.; Wolfson, M. F.; Castner, B. J.; Stocking, K. L.; Reddy, P.; Srinivasan, S.; Nelson, N.; Boiani, N.; Schooley, K. A.; Gerhart, M.; Davis, R.; Fitzner, J. N.; Johnson, R. S.; Paxton, R. J.; March, C. J. und Cerretti, D. P. (1997): A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells, Nature 385) [6618], Seite 729-33. Blacker, M.; Noe, M. C.; Carty, T. J.; Goodyer, C. G. und LeBlanc, A. C. (2002): Effect of tumor necrosis factor-alpha converting enzyme (TACE) and metalloprotease inhibitor on amyloid precursor protein metabolism in human neurons, J Neurochem 83) [6], Seite 1349-57. Blennow, K. und Hampel, H. (2003): CSF markers for incipient Alzheimer's disease, Lancet Neurol 2) [10], Seite 605-13. Bondareff, W.; Harrington, C. R.; McDaniel, S. W.; Wischik, C. M. und Roth, M. (1994): Presence of axonal paired helical filament-tau in Alzheimer's disease: submicroscopic localization, J Neurosci Res 38) [6], Seite 664-9. Bonifacino, J. S. (2004): The GGA proteins: adaptors on the move, Nat Rev Mol Cell Biol 5) [1], Seite 23-32. Bonifacino, J. S. und Lippincott-Schwartz, J. (1991): Degradation of proteins within the endoplasmic reticulum, Curr Opin Cell Biol 3) [4], Seite 592-600. Borchelt, D. R.; Thinakaran, G.; Eckman, C. B.; Lee, M. K.; Davenport, F.; Ratovitsky, T.; Prada, C. M.; Kim, G.; Seekins, S.; Yager, D.; Slunt, H. H.; Wang, R.; Seeger, M.; Levey, A. I.; Gandy, S. E.; Copeland, N. G.; Jenkins, N. A.; Price, D. L.; Younkin, S. G. und Sisodia, S. S. (1996): Familial Alzheimer's disease-linked presenilin 1 variants elevate Ab1-42/1-40 ratio in vitro and in vivo, Neuron 17) [5], Seite 1005-13. Bothwell, M. und Giniger, E. (2000): Alzheimer's disease: neurodevelopment converges with neurodegeneration, Cell 102) [3], Seite 271-3. Bott, R.; Subramanian, E. und Davies, D. R. (1982): Three-dimensional structure of the complex of the Rhizopus chinensis carboxyl proteinase and pepstatin at 2.5-A resolution, Biochemistry 21) [26], Seite 6956-62.. Braak, H.; Braak, E.; Yilmazer, D.; de Vos, R. A.; Jansen, E. N. und Bohl, J. (1996): Pattern of brain destruction in Parkinson's and Alzheimer's diseases, J Neural Transm 103) [4], Seite 455-90. Bradford, M. M. (1976): A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding, Anal Biochem 72), Seite 248-54. Bresnahan, P. A.; Leduc, R.; Thomas, L.; Thorner, J.; Gibson, H. L.; Brake, A. J.; Barr, P. J. und Thomas, G. (1990): Human fur gene encodes a yeast KEX2-like endoprotease that cleaves pro-beta-NGF in vivo, J Cell Biol 111) [6 Pt 2], Seite 2851-9. Brown, D. A. und London, E. (1998): Functions of lipid rafts in biological membranes, Annu Rev Cell Dev Biol 14), Seite 111-36. Bursavich, M. G.; West, C. W. und Rich, D. H. (2001): From peptides to non-peptide peptidomimetics: design and synthesis of new piperidine inhibitors of aspartic peptidases, Org Lett 3) [15], Seite 2317-20.. Busciglio, J.; Gabuzda, D. H.; Matsudaira, P. und Yankner, B. A. (1993): Generation of b-amyloid in the secretory pathway in neuronal and nonneuronal cells, Proc. Natl. Acad. Sci. USA 90) [5], Seite 2092-6. Bush, A. I.; Multhaup, G.; Moir, R. D.; Williamson, T. G.; Small, D. H.; Rumble, B.; Pollwein, P.; Beyreuther, K. und Masters, C. L. (1993): A novel zinc(II) binding site modulates the function of the beta A4 amyloid protein precursor of Alzheimer's disease, J Biol Chem 268) [22], Seite 16109-12. Bush, A. I.; Pettingell, W. H.; Multhaup, G.; d Paradis, M.; Vonsattel, J. P.; Gusella, J. F.; Beyreuther, K.; Masters, C. L. und Tanzi, R. E. (1994): Rapid induction of Alzheimer A beta amyloid formation by zinc, Science 265) [5177], Seite 1464-7. Buxbaum, J. D.; Koo, E. H. und Greengard, P. (1993): Protein phosphorylation inhibits production of Alzheimer amyloid beta/A4 peptide, Proc Natl Acad Sci U S A 90) [19], Seite 9195-8.. 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. und Black, R. A. (1998): Evidence that tumor necrosis factor a converting enzyme is involved in regulated a-secretase cleavage of the Alzheimer amyloid protein precursor, J. Biol. Chem. 273) [43], Seite 27765-7. Buxbaum, J. D.; Oishi, M.; Chen, H. I.; Pinkas-Kramarski, R.; Jaffe, E. A.; Gandy, S. E. und Greengard, P. (1992): Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor, Proc Natl Acad Sci U S A 89) [21], Seite 10075-8. Buxbaum, J. D.; Thinakaran, G.; Koliatsos, V.; O'Callahan, J.; Slunt, H. H.; Price, D. L. und Sisodia, S. S. (1998): Alzheimer amyloid protein precursor in the rat hippocampus: transport and processing through the perforant path, J Neurosci 18) [23], Seite 9629-37. Cai, H.; Wang, Y.; McCarthy, D.; Wen, H.; Borchelt, D. R.; Price, D. L. und Wong, P. C. (2001): BACE1 is the major beta-secretase for generation of Abeta peptides by neurons, Nat Neurosci 4) [3], Seite 233-4.. Cai, X. D.; Golde, T. E. und Younkin, S. G. (1993): Release of excess amyloid b protein from a mutant amyloid b protein precursor, Science 259) [5094], Seite 514-6. Cao, X. und Sudhof, T. C. (2004): Dissection of amyloid-beta precursor protein-dependent transcriptional transactivation, J Biol Chem 279) [23], Seite 24601-11. Cao, X. und Südhof, T. C. (2001): A transcriptionally active complex of APP with Fe65 and histone acetyltransferase Tip60, Science 293) [5527], Seite 115-20.. Capell, A.; Grunberg, J.; Pesold, B.; Diehlmann, A.; Citron, M.; Nixon, R.; Beyreuther, K.; Selkoe, D. J. und Haass, C. (1998): The proteolytic fragments of the Alzheimer's disease-associated presenilin-1 form heterodimers and occur as a 100-150-kDa molecular mass complex, J. Biol. Chem. 273) [6], Seite 3205-11. Capell, A.; Kaether, C.; Edbauer, D.; Shirotani, K.; Merkl, S.; Steiner, H. und Haass, C. (2003): Nicastrin interacts with gamma-secretase complex components via the N-terminal part of its transmembrane domain, J Biol Chem 278) [52], Seite 52519-23. Capell, A.; Meyn, L.; Fluhrer, R.; Teplow, D. B.; Walter, J. und Haass, C. (2002): Apical sorting of beta-secretase limits amyloid beta-peptide production, J Biol Chem 277) [7], Seite 5637-43.. Capell, A.; Saffrich, R.; Olivo, J. C.; Meyn, L.; Walter, J.; Grunberg, J.; Mathews, P.; Nixon, R.; Dotti, C. und Haass, C. (1997): Cellular expression and proteolytic processing of presenilin proteins is developmentally regulated during neuronal differentiation, J. Neurochem. 69) [6], Seite 2432-40. Capell, A.; Steiner, H.; Romig, H.; Keck, S.; Baader, M.; Grim, M. G.; Baumeister, R. und Haass, C. (2000): Presenilin-1 differentially facilitates endoproteolysis of the b-amyloid precursor protein and Notch, Nat. Cell Biol. 2) [4], Seite 205-211. Capell, A.; Steiner, H.; Willem, M.; Kaiser, H.; Meyer, C.; Walter, J.; Lammich, S.; Multhaup, G. und Haass, C. (2000): Maturation and pro-peptide cleavage of beta-secretase, J Biol Chem 275) [40], Seite 30849-54.. Chaiet, G. und Wolf, F.J. (1964): The properties of strepavidin, a biotin-binding protein produced by Streptomycetes, Arch. Biochem. Biophys. 106), Seite 1-5. Chandra, V.; Pandav, R.; Dodge, H. H.; Johnston, J. M.; Belle, S. H.; DeKosky, S. T. und Ganguli, M. (2001): Incidence of Alzheimer's disease in a rural community in India: the Indo-US study, Neurology 57) [6], Seite 985-9. Chang, W. P.; Koelsch, G.; Wong, S.; Downs, D.; Da, H.; Weerasena, V.; Gordon, B.; Devasamudram, T.; Bilcer, G.; Ghosh, A. K. und Tang, J. (2004): In vivo inhibition of Abeta production by memapsin 2 (beta-secretase) inhibitors, J Neurochem 89) [6], Seite 1409-16. Chantry, A.; Gregson, N. A. und Glynn, P. (1989): A novel metalloproteinase associated with brain myelin membranes. Isolation and characterization, J Biol Chem 264) [36], Seite 21603-7. Charlwood, J.; Dingwall, C.; Matico, R.; Hussain, I.; Johanson, K.; Moore, S.; Powell, D. J.; Skehel, J. M.; Ratcliffe, S.; Clarke, B.; Trill, J.; Sweitzer, S. und Camilleri, P. (2001): Characterization of the glycosylation profiles of Alzheimer's beta - secretase protein Asp-2 expressed in a variety of cell lines, J Biol Chem 276) [20], Seite 16739-48.. Chartier-Harlin, M. C.; Crawford, F.; Houlden, H.; Warren, A.; Hughes, D.; Fidani, L.; Goate, A.; Rossor, M.; Roques, P.; Hardy, J. und et al. (1991): Early-onset Alzheimer's disease caused by mutations at codon 717 of the b-amyloid precursor protein gene, Nature 353) [6347], Seite 844-6.. Cherny, R. A.; Atwood, C. S.; Xilinas, M. E.; Gray, D. N.; Jones, W. D.; McLean, C. A.; Barnham, K. J.; Volitakis, I.; Fraser, F. W.; Kim, Y.; Huang, X.; Goldstein, L. E.; Moir, R. D.; Lim, J. T.; Beyreuther, K.; Zheng, H.; Tanzi, R. E.; Masters, C. L. und Bush, A. I. (2001): Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice, Neuron 30) [3], Seite 665-76. Chou, K. C. und Howe, W. J. (2002): Prediction of the tertiary structure of the beta-secretase zymogen, Biochem Biophys Res Commun 292) [3], Seite 702-8.. Christensen, M. A.; Zhou, W.; Qing, H.; Lehman, A.; Philipsen, S. und Song, W. (2004): Transcriptional regulation of BACE1, the beta-amyloid precursor protein beta-secretase, by Sp1, Mol Cell Biol 24) [2], Seite 865-74. Chyung, A. S.; Greenberg, B. D.; Cook, D. G.; Doms, R. W. und Lee, V. M. (1997): Novel beta-secretase cleavage of beta-amyloid precursor protein in the endoplasmic reticulum/intermediate compartment of NT2N cells, J Cell Biol 138) [3], Seite 671-80.. Chyung, J. H. und Selkoe, D. J. (2003): Inhibition of receptor-mediated endocytosis demonstrates generation of amyloid beta-protein at the cell surface, J Biol Chem 278) [51], Seite 51035-43. Citron, M. (2004): Beta-secretase inhibition for the treatment of Alzheimer's disease--promise and challenge, Trends Pharmacol Sci 25) [2], Seite 92-7. Citron, M. (2004): Strategies for disease modification in Alzheimer's disease, Nat Rev Neurosci 5) [9], Seite 677-85. Citron, M.; Diehl, T. S.; Capell, A.; Haass, C.; Teplow, D. B. und Selkoe, D. J. (1996): Inhibition of amyloid beta-protein production in neural cells by the serine protease inhibitor AEBSF, Neuron 17) [1], Seite 171-9.. Citron, M.; Oltersdorf, T.; Haass, C.; McConlogue, L.; Hung, A. Y.; Seubert, P.; Vigo-Pelfrey, C.; Lieberburg, I. und Selkoe, D. J. (1992): Mutation of the b-amyloid precursor protein in familial Alzheimer's disease increases b-protein production, Nature 360) [6405], Seite 672-4. Citron, M.; Teplow, DB. und Selkoe, DJ (1995): Generation of amyloid beta protein from its precursor is sequence specific., Neuron 14) [3], Seite 661-670. Citron, M.; Westaway, D.; Xia, W.; Carlson, G.; Diehl, T.; Levesque, G.; Johnson-Wood, K.; Lee, M.; Seubert, P.; Davis, A.; Kholodenko, D.; Motter, R.; Sherrington, R.; Perry, B.; Yao, H.; Strome, R.; Lieberburg, I.; Rommens, J.; Kim, S.; Schenk, D.; Fraser, P.; St George Hyslop, P. und Selkoe, D. J. (1997): Mutant presenilins of Alzheimer's disease increase production of 42- residue amyloid b-protein in both transfected cells and transgenic mice, Nat. Med. 3) [1], Seite 67-72. Cook, D. G.; Forman, M. S.; Sung, J. C.; Leight, S.; Kolson, D. L.; Iwatsubo, T.; Lee, V. M. und Doms, R. W. (1997): Alzheimer's A beta(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells, Nat Med 3) [9], Seite 1021-3. Corder, E. H.; Saunders, A. M.; Risch, N. J.; Strittmatter, W. J.; Schmechel, D. E.; Gaskell, P. C., Jr.; Rimmler, J. B.; Locke, P. A.; Conneally, P. M.; Schmader, K. E. und et al. (1994): Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease, Nat Genet 7) [2], Seite 180-4. Creemers, J. W.; Ines Dominguez, D.; Plets, E.; Serneels, L.; Taylor, N. A.; Multhaup, G.; Craessaerts, K.; Annaert, W. und De Strooper, B. (2001): Processing of beta-secretase by furin and other members of the proprotein convertase family, J Biol Chem 276) [6], Seite 4211-7.. Crowther, R. A. und Goedert, M. (2000): Abnormal tau-containing filaments in neurodegenerative diseases, J Struct Biol 130) [2-3], Seite 271-9. Cupers, P.; Bentahir, M.; Craessaerts, K.; Orlans, I.; Vanderstichele, H.; Saftig, P.; De Strooper, B. und Annaert, W. (2001): The discrepancy between presenilin subcellular localization and g-secretase processing of amyloid precursor protein, J. Cell Biol. 154) [4], Seite 731-40. De Strooper, B. (2003): Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex, Neuron 38) [1], Seite 9-12. De Strooper, B. und Annaert, W. (2000): Proteolytic processing and cell biological functions of the amyloid precursor protein, J Cell Sci 113 ( Pt 11)), Seite 1857-70. De Strooper, B.; Annaert, W.; Cupers, P.; Saftig, P.; Craessaerts, K.; Mumm, J. S.; Schroeter, E. H.; Schrijvers, V.; Wolfe, M. S.; Ray, W. J.; Goate, A. und Kopan, R. (1999): A presenilin-1-dependent g-secretase-like protease mediates release of Notch intracellular domain, Nature 398) [6727], Seite 518-22. De Strooper, B.; Beullens, M.; Contreras, B.; Levesque, L.; Craessaerts, K.; Cordell, B.; Moechars, D.; Bollen, M.; Fraser, P.; George-Hyslop, P. S. und Van Leuven, F. (1997): Phosphorylation, subcellular localization, and membrane orientation of the Alzheimer's disease-associated presenilins, J Biol Chem 272) [6], Seite 3590-8. De Strooper, B.; Craessaerts, K.; Dewachter, I.; Moechars, D.; Greenberg, B.; Van Leuven, F. und Van den Berghe, H. (1995): Basolateral secretion of amyloid precursor protein in Madin-Darby canine kidney cells is disturbed by alterations of intracellular pH and by introducing a mutation associated with familial Alzheimer's disease, J Biol Chem 270) [8], Seite 4058-65. De Strooper, B.; Saftig, P.; Craessaerts, K.; Vanderstichele, H.; Guhde, G.; Annaert, W.; Von Figura, K. und Van Leuven, F. (1998): Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein, Nature 391) [6665], Seite 387-90. De Strooper, B.; Simons, M.; Multhaup, G.; Van Leuven, F.; Beyreuther, K. und Dotti, C. G. (1995): Production of intracellular amyloid-containing fragments in hippocampal neurons expressing human amyloid precursor protein and protection against amyloidogenesis by subtle amino acid substitutions in the rodent sequence, Embo J 14) [20], Seite 4932-8. De Strooper, B.; Umans, L.; Van Leuven, F. und 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) [2], Seite 295-304. DeKosky, S. T. und Marek, K. (2003): Looking backward to move forward: early detection of neurodegenerative disorders, Science 302) [5646], Seite 830-4. Demetriades, A. K. (2002): Functional neuroimaging in Alzheimer's type dementia, J Neurol Sci 203-204), Seite 247-51. Dickson, D. W. (1997): The pathogenesis of senile plaques, J Neuropathol Exp Neurol 56) [4], Seite 321-39. Dingwall, C. (2001): Spotlight on BACE: the secretases as targets for treatment in Alzheimer disease, J Clin Invest 108) [9], Seite 1243-6.. Dinter, A. und Berger, E. G. (1998): Golgi-disturbing agents, Histochem Cell Biol 109) [5-6], Seite 571-90. Doan, A.; Thinakaran, G.; Borchelt, D. R.; Slunt, H. H.; Ratovitsky, T.; Podlisny, M.; Selkoe, D. J.; Seeger, M.; Gandy, S. E.; Price, D. L. und Sisodia, S. S. (1996): Protein topology of presenilin 1, Neuron 17) [5], Seite 1023-30. Dodart, J. C.; Bales, K. R.; Gannon, K. S.; Greene, S. J.; DeMattos, R. B.; Mathis, C.; DeLong, C. A.; Wu, S.; Wu, X.; Holtzman, D. M. und Paul, S. M. (2002): Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model, Nat Neurosci 5) [5], Seite 452-7. Dotti, C. G. und Simons, K. (1990): Polarized sorting of viral glycoproteins to the axon and dendrites of hippocampal neurons in culture, Cell 62) [1], Seite 63-72. Duff, K.; Eckman, C.; Zehr, C.; Yu, X.; Prada, C. M.; Perez-Tur, J.; Hutton, M.; Buee, L.; Harigaya, Y.; Yager, D.; Morgan, D.; Gordon, M. N.; Holcomb, L.; Refolo, L.; Zenk, B.; Hardy, J. und Younkin, S. (1996): Increased amyloid-b42(43) in brains of mice expressing mutant presenilin 1, Nature 383) [6602], Seite 710-3. Dunn, B. M. (2002): Structure and mechanism of the pepsin-like family of aspartic peptidases, Chem Rev 102) [12], Seite 4431-58. Ebinu, J. O. und Yankner, B. A. (2002): A RIP tide in neuronal signal transduction, Neuron 34) [4], Seite 499-502. Edbauer, D.; Willem, M.; Lammich, S.; Steiner, H. und Haass, C. (2002): Insulin-degrading enzyme rapidly removes the beta-amyloid precursor protein intracellular domain (AICD), J Biol Chem 277) [16], Seite 13389-93.. Edbauer, D.; Winkler, E.; Haass, C. und Steiner, H. (2002): Presenilin and nicastrin regulate each other and determine amyloid b-peptide production via complex formation, Proc. Natl. Acad. Sci. USA 99) [13], Seite 8666-71. Edbauer, D.; Winkler, E.; Regula, J. T.; Pesold, B.; Steiner, H. und Haass, C. (2003): Reconstitution of gamma-secretase activity, Nat Cell Biol 5) [5], Seite 486-8.. Ehehalt, R.; Keller, P.; Haass, C.; Thiele, C. und Simons, K. (2003): Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts, J Cell Biol 160) [1], Seite 113-23. Ermolieff, J.; Loy, J. A.; Koelsch, G. und Tang, J. (2000): Proteolytic activation of recombinant pro-memapsin 2 (pro-beta-secretase) studied with new fluorogenic substrates, Biochemistry 39) [40], Seite 12450-6. Esch, F. S.; Keim, P. S.; Beattie, E. C.; Blacher, R. W.; Culwell, A. R.; Oltersdorf, T.; McClure, D. und Ward, P. J. (1990): Cleavage of amyloid beta peptide during constitutive processing of its precursor, Science 248) [4959], Seite 1122-4.. Esler, W. P. und Wolfe, M. S. (2001): A portrait of Alzheimer secretases--new features and familiar faces, Science 293) [5534], Seite 1449-54. Esler, W.P.; Kimberly, W.T.; Ostaszewski, B.L.; Diehl, T.S.; Moore, C.L.; Tsai, J-Y.; Rahmati, T.; Xia, W.; Selkoe, D.J. und Wolfe, M.S. (2000): Transition-state analogue inhibitors of g-secretase bind directly to presenilin-1, Nat. Cell Biol. 2), Seite 428-433. Esteban, J. A. (2004): Living with the enemy: a physiological role for the beta-amyloid peptide, Trends Neurosci 27) [1], Seite 1-3. Farzan, M.; Schnitzler, C. E.; Vasilieva, N.; Leung, D. und Choe, H. (2000): BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein, Proc Natl Acad Sci U S A 97) [17], Seite 9712-7.. Fluhrer, R.; Capell, A.; Westmeyer, G.; Willem, M.; Hartung, B.; Condron, M. M.; Teplow, D. B.; Haass, C. und Walter, J. (2002): A non-amyloidogenic function of BACE-2 in the secretory pathway, J Neurochem 81) [5], Seite 1011-20.. Fox, N. C.; Crum, W. R.; Scahill, R. I.; Stevens, J. M.; Janssen, J. C. und Rossor, M. N. (2001): Imaging of onset and progression of Alzheimer's disease with voxel-compression mapping of serial magnetic resonance images, Lancet 358) [9277], Seite 201-5. Fraering, P. C.; Ye, W.; Strub, J. M.; Dolios, G.; LaVoie, M. J.; Ostaszewski, B. L.; van Dorsselaer, A.; Wang, R.; Selkoe, D. J. und Wolfe, M. S. (2004): Purification and characterization of the human gamma-secretase complex, Biochemistry 43) [30], Seite 9774-89. Francis, R.; McGrath, G.; Zhang, J.; Ruddy, D. A.; Sym, M.; Apfeld, J.; Nicoll, M.; Maxwell, M.; Hai, B.; Ellis, M. C.; Parks, A. L.; Xu, W.; Li, J.; Gurney, M.; Myers, R. L.; Himes, C. S.; Hiebsch, R.D; Ruble, C.; Nye, J. S. und Curtis, D. (2002): aph-1 and pen-2 are required for Notch pathway signaling, g-secretase cleavage of bAPP, and presenilin protein accumulation, Dev. Cell 3) [1], Seite 85-97. Fraser, M. E.; Strynadka, N. C.; Bartlett, P. A.; Hanson, J. E. und James, M. N. (1992): Crystallographic analysis of transition-state mimics bound to penicillopepsin: phosphorus-containing peptide analogues, Biochemistry 31) [22], Seite 5201-14.. Friedhoff, P.; von Bergen, M.; Mandelkow, E. M. und Mandelkow, E. (2000): Structure of tau protein and assembly into paired helical filaments, Biochim Biophys Acta 1502) [1], Seite 122-32. Fukumoto, H.; Cheung, B. S.; Hyman, B. T. und Irizarry, M. C. (2002): beta-Secretase Protein and Activity Are Increased in the Neocortex in Alzheimer Disease, Arch Neurol 59) [9], Seite 1381-9.. Fullekrug, J. und Simons, K. (2004): Lipid rafts and apical membrane traffic, Ann N Y Acad Sci 1014), Seite 164-9. Gan, Y.; McGraw, T. E. und Rodriguez-Boulan, E. (2002): The epithelial-specific adaptor AP1B mediates post-endocytic recycling to the basolateral membrane, Nat Cell Biol 4) [8], Seite 605-9. Gandy, S. E.; Caporaso, G. L.; Buxbaum, J. D.; de Cruz Silva, O.; Iverfeldt, K.; Nordstedt, C.; Suzuki, T.; Czernik, A. J.; Nairn, A. C. und Greengard, P. (1993): Protein phosphorylation regulates relative utilization of processing pathways for Alzheimer beta/A4 amyloid precursor protein, Ann N Y Acad Sci 695), Seite 117-21.. Garten, W.; Hallenberger, S.; Ortmann, D.; Schafer, W.; Vey, M.; Angliker, H.; Shaw, E. und Klenk, H. D. (1994): Processing of viral glycoproteins by the subtilisin-like endoprotease furin and its inhibition by specific peptidylchloroalkylketones, Biochimie 76) [3-4], Seite 217-25. Ge, Y. W.; Maloney, B.; Sambamurti, K. und Lahiri, D. K. (2004): Functional characterization of the 5' flanking region of the BACE gene: identification of a 91 bp fragment involved in basal level of BACE promoter expression, Faseb J 18) [9], Seite 1037-9. Georgakopoulos, A.; Marambaud, P.; Efthimiopoulos, S.; Shioi, J.; Cui, W.; Li, H. C.; Schutte, M.; Gordon, R.; Holstein, G. R.; Martinelli, G.; Mehta, P.; Friedrich, V. L., Jr. und Robakis, N. K. (1999): Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system and is recruited to intercellular and synaptic contacts, Mol. Cell 4) [6], Seite 893-902. Gervais, F. G.; Xu, D.; Robertson, G. S.; Vaillancourt, J. P.; Zhu, Y.; Huang, J.; LeBlanc, A.; Smith, D.; Rigby, M.; Shearman, M. S.; Clarke, E. E.; Zheng, H.; Van Der Ploeg, L. H.; Ruffolo, S. C.; Thornberry, N. A.; Xanthoudakis, S.; Zamboni, R. J.; Roy, S. und Nicholson, D. W. (1999): Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation, Cell 97) [3], Seite 395-406. Ghosh, A. K.; Bilcer, G.; Harwood, C.; Kawahama, R.; Shin, D.; Hussain, K. A.; Hong, L.; Loy, J. A.; Nguyen, C.; Koelsch, G.; Ermolieff, J. und Tang, J. (2001): Structure-based design: potent inhibitors of human brain memapsin 2 (beta-secretase), J Med Chem 44) [18], Seite 2865-8. Ghosh, A. K.; Hong, L. und Tang, J. (2002): beta-Secretase as a Therapeutic Target for Inhibitor Drugs, Curr Med Chem 9) [11], Seite 1135-44.. Glabe, C. (2001): Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer's disease, J Mol Neurosci 17) [2], Seite 137-45.. Glenner, G. G. und Wong, C. W. (1984): Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochem Biophys Res Commun 120) [3], Seite 885-90. Goate, A.; Chartier-Harlin, M. C.; Mullan, M.; Brown, J.; Crawford, F.; Fidani, L.; Giuffra, L.; Haynes, A.; Irving, N.; James, L. und et al. (1991): Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease, Nature 349) [6311], Seite 704-6. Goedert, M.; Jakes, R.; Spillantini, M. G.; Hasegawa, M.; Smith, M. J. und Crowther, R. A. (1996): Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans, Nature 383) [6600], Seite 550-3. Golde, T. E.; Estus, S.; Younkin, L. H.; Selkoe, D. J. und Younkin, S. G. (1992): Processing of the amyloid protein precursor to potentially amyloidogenic derivatives, Science 255) [5045], Seite 728-30.. Gottlieb, T. A.; Beaudry, G.; Rizzolo, L.; Colman, A.; Rindler, M.; Adesnik, M. und Sabatini, D. D. (1986): Secretion of endogenous and exogenous proteins from polarized MDCK cell monolayers, Proc Natl Acad Sci U S A 83) [7], Seite 2100-4. Gotz, J.; Chen, F.; van Dorpe, J. und Nitsch, R. M. (2001): Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils, Science 293) [5534], Seite 1491-5. Gouras, G. K.; Xu, H.; Jovanovic, J. N.; Buxbaum, J. D.; Wang, R.; Greengard, P.; Relkin, N. R. und Gandy, S. (1998): Generation and regulation of beta-amyloid peptide variants by neurons, J Neurochem 71) [5], Seite 1920-5. Goutte, C. (2002): Genetics leads the way to the accomplices of presenilins, Dev Cell 3) [1], Seite 6-7. Goutte, C.; Tsunozaki, M.; Hale, V. A. und Priess, J. R. (2002): APH-1 is a multipass membrane protein essential for the Notch signaling pathway in embryos, Proc. Natl. Acad. Sci. USA 99) [2], Seite 775-779. Green, N. M.; Konieczny, L.; Toms, E. J. und Valentine, R. C. (1971): The use of bifunctional biotinyl compounds to determine the arrangement of subunits in avidin, Biochem J 125) [3], Seite 781-91.. Grundke-Iqbal, I.; Iqbal, K.; Tung, Y. C.; Quinlan, M.; Wisniewski, H. M. und Binder, L. I. (1986): Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology, Proc Natl Acad Sci U S A 83) [13], Seite 4913-7. Gruninger-Leitch, F.; Schlatter, D.; Kung, E.; Nelbock, P. und Dobeli, H. (2002): Substrate and inhibitor profile of BACE (beta-secretase) and comparison with other mammalian aspartic proteases, J Biol Chem 277) [7], Seite 4687-93.. Haass, C. (2004): Take five-BACE and the gamma-secretase quartet conduct Alzheimer's amyloid beta-peptide generation, Embo J 23) [3], Seite 483-8. Haass, C.; Capell, A.; Citron, M.; Teplow, D. B. und Selkoe, D. J. (1995): The vacuolar H(+)-ATPase inhibitor bafilomycin A1 differentially affects proteolytic processing of mutant and wild-type beta-amyloid precursor protein, J Biol Chem 270) [11], Seite 6186-92. Haass, C.; Hung, A. Y.; Schlossmacher, M. G.; Oltersdorf, T.; Teplow, D. B. und Selkoe, D. J. (1993): Normal cellular processing of the beta-amyloid precursor protein results in the secretion of the amyloid beta peptide and related molecules, Ann N Y Acad Sci 695), Seite 109-16. Haass, C.; Hung, A. Y.; Schlossmacher, M. G.; Teplow, D. B. und Selkoe, D. J. (1993): beta-Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms, J Biol Chem 268) [5], Seite 3021-4. Haass, C.; Hung, A. Y.; Selkoe, D. J. und 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) [26], Seite 17741-8. Haass, C.; Koo, E. H.; Capell, A.; Teplow, D. B. und Selkoe, D. J. (1995): Polarized sorting of beta-amyloid precursor protein and its proteolytic products in MDCK cells is regulated by two independent signals, J Cell Biol 128) [4], Seite 537-47. Haass, C.; Koo, E. H.; Mellon, A.; Hung, A. Y. und Selkoe, D. J. (1992): Targeting of cell-surface b-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments, Nature 357) [6378], Seite 500-3. Haass, C.; Koo, E. H.; Teplow, D. B. und Selkoe, D. J. (1994): Polarized secretion of beta-amyloid precursor protein and amyloid beta- peptide in MDCK cells, Proc Natl Acad Sci U S A 91) [4], Seite 1564-8. Haass, C.; Lemere, C. A.; Capell, A.; Citron, M.; Seubert, P.; Schenk, D.; Lannfelt, L. und Selkoe, D. J. (1995): The Swedish mutation causes early-onset Alzheimer's disease by beta- secretase cleavage within the secretory pathway, Nat Med 1) [12], Seite 1291-6. Haass, C.; Schlossmacher, M. G.; Hung, A. Y.; Vigo-Pelfrey, C.; Mellon, A.; Ostaszewski, B. L.; Lieberburg, I.; Koo, E. H.; Schenk, D.; Teplow, D. B. und et al. (1992): Amyloid b-peptide is produced by cultured cells during normal metabolism, Nature 359) [6393], Seite 322-5. Haass, C. und Selkoe, D. J. (1993): Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide, Cell 75) [6], Seite 1039-42. Haass, C. und Steiner, H. (2002): Alzheimer disease gamma-secretase: a complex story of GxGD-type presenilin proteases, Trends Cell Biol 12) [12], Seite 556-62. Hadland, B.; Manley, N.; Su, D. M.; Longmore, G.; Moore, C.; Wolfe, M.; Schroeter, E. und Kopan, R. (2001): g-Secretase inhibitors repress thymocyte development, Proc. Natl. Acad. Sci. USA 98), Seite 7487-7491. Hallenberger, S.; Bosch, V.; Angliker, H.; Shaw, E.; Klenk, H. D. und Garten, W. (1992): Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160, Nature 360) [6402], Seite 358-61. Hampel, H.; Mitchell, A.; Blennow, K.; Frank, R. A.; Brettschneider, S.; Weller, L. und Moller, H. J. (2004): Core biological marker candidates of Alzheimer's disease - perspectives for diagnosis, prediction of outcome and reflection of biological activity, J Neural Transm 111) [3], Seite 247-72. Haniu, M.; Denis, P.; Young, Y.; Mendiaz, E. A.; Fuller, J.; Hui, J. O.; Bennett, B. D.; Kahn, S.; Ross, S.; Burgess, T.; Katta, V.; Rogers, G.; Vassar, R. und Citron, M. (2000): Characterization of Alzheimer's beta -secretase protein BACE. A pepsin family member with unusual properties, J Biol Chem 275) [28], Seite 21099-106.. Hardy, J. (1997): The Alzheimer family of diseases: many etiologies, one pathogenesis?, Proc Natl Acad Sci U S A 94) [6], Seite 2095-7. Hardy, J. (1997): Amyloid, the presenilins and Alzheimer's disease [see comments], Trends Neurosci 20) [4], Seite 154-9. Hardy, J. und Allsop, D. (1991): Amyloid deposition as the central event in the aetiology of Alzheimer's disease, Trends Pharmacol Sci 12) [10], Seite 383-8. Hardy, J.; Duff, K.; Hardy, K. G.; Perez-Tur, J. und Hutton, M. (1998): Genetic dissection of Alzheimer's disease and related dementias: amyloid and its relationship to tau, Nat Neurosci 1) [5], Seite 355-8. Hardy, J. und Selkoe, D. J. (2002): The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics, Science 297) [5580], Seite 353-6. Harris, B. Z. und Lim, W. A. (2001): Mechanism and role of PDZ domains in signaling complex assembly, J Cell Sci 114) [Pt 18], Seite 3219-31. Harrison, T. M.; Chidgey, M. A.; Brammar, W. J. und Adams, G. J. (1989): The pro-peptide is not necessary for active renin secretion from transfected mammalian cells, Proteins 5) [4], Seite 259-65. Hartmann, D.; de Strooper, B.; Serneels, L.; Craessaerts, K.; Herreman, A.; Annaert, W.; Umans, L.; Lubke, T.; Lena Illert, A.; von Figura, K. und Saftig, P. (2002): The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts, Hum Mol Genet 11) [21], Seite 2615-24. Hartmann, T.; Bieger, S. C.; Bruhl, B.; Tienari, P. J.; Ida, N.; Allsop, D.; Roberts, G. W.; Masters, C. L.; Dotti, C. G.; Unsicker, K. und Beyreuther, K. (1997): Distinct sites of intracellular production for Alzheimer's disease A beta40/42 amyloid peptides, Nat Med 3) [9], Seite 1016-20. Hatsuzawa, K.; Nagahama, M.; Takahashi, S.; Takada, K.; Murakami, K. und Nakayama, K. (1992): Purification and characterization of furin, a Kex2-like processing endoprotease, produced in Chinese hamster ovary cells, J Biol Chem 267) [23], Seite 16094-9. Hayashi, I.; Urano, Y.; Fukuda, R.; Isoo, N.; Kodama, T.; Hamakubo, T.; Tomita, T. und Iwatsubo, T. (2004): Selective reconstitution and recovery of functional gamma-secretase complex on budded baculovirus particles, J Biol Chem 279) [36], Seite 38040-6. He, X.; Chang, W. P.; Koelsch, G. und Tang, J. (2002): Memapsin 2 (beta-secretase) cytosolic domain binds to the VHS domains of GGA1 and GGA2: implications on the endocytosis mechanism of memapsin 2, FEBS Lett 524) [1-3], Seite 183-7. Heber, S.; Herms, J.; Gajic, V.; Hainfellner, J.; Aguzzi, A.; Rulicke, T.; von Kretzschmar, H.; von Koch, C.; Sisodia, S.; Tremml, P.; Lipp, H. P.; Wolfer, D. P. und Muller, U. (2000): Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members, J Neurosci 20) [21], Seite 7951-63. Helenius, A. (1994): How N-linked oligosaccharides affect glycoprotein folding in the endoplasmic reticulum, Mol Biol Cell 5) [3], Seite 253-65. Helenius, A. und Aebi, M. (2001): Intracellular functions of N-linked glycans, Science 291) [5512], Seite 2364-9. Hendrie, H. C.; Ogunniyi, A.; Hall, K. S.; Baiyewu, O.; Unverzagt, F. W.; Gureje, O.; Gao, S.; Evans, R. M.; Ogunseyinde, A. O.; Adeyinka, A. O.; Musick, B. und Hui, S. L. (2001): Incidence of dementia and Alzheimer disease in 2 communities: Yoruba residing in Ibadan, Nigeria, and African Americans residing in Indianapolis, Indiana, Jama 285) [6], Seite 739-47. Hendriks, L. und Van Broeckhoven, C. (1996): A beta A4 amyloid precursor protein gene and Alzheimer's disease, Eur J Biochem 237) [1], Seite 6-15. Hendriks, L.; van Duijn, C. M.; Cras, P.; Cruts, M.; Van Hul, W.; van Harskamp, F.; Warren, A.; McInnis, M. G.; Antonarakis, S. E.; Martin, J. J. und et al. (1992): Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene, Nat Genet 1) [3], Seite 218-21. Herreman, A.; Hartmann, D.; Annaert, W.; Saftig, P.; Craessaerts, K.; Serneels, L.; Umans, L.; Schrijvers, V.; Checler, F.; Vanderstichele, H.; Baekelandt, V.; Dressel, R.; Cupers, P.; Huylebroeck, D.; Zwijsen, A.; Van Leuven, F. und De Strooper, B. (1999): Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency, Proc. Natl. Acad. Sci. USA 96) [21], Seite 11872-7. Herreman, A.; Serneels, L.; Annaert, W.; Collen, D.; Schoonjans, L. und De Strooper, B. (2000): Total inactivation of g-secretase activity in presenilin-deficient embryonic stem cells, Nat. Cell Biol. 2), Seite 461-2. Herreman, A.; Van Gassen, G.; Bentahir, M.; Nyabi, O.; Craessaerts, K.; Mueller, U.; Annaert, W. und De Strooper, B. (2003): gamma-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation, J Cell Sci 116) [Pt 6], Seite 1127-36. Holsinger, R. M.; McLean, C. A.; Beyreuther, K.; Masters, C. L. und Evin, G. (2002): Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease, Ann Neurol 51) [6], Seite 783-6. Hong, L.; Koelsch, G.; Lin, X.; Wu, S.; Terzyan, S.; Ghosh, A. K.; Zhang, X. C. und Tang, J. (2000): Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor, Science 290) [5489], Seite 150-3.. Hong, L.; Turner, R. T., 3rd; Koelsch, G.; Ghosh, A. K. und Tang, J. (2002): Memapsin 2 (beta-secretase) as a therapeutic target, Biochem Soc Trans 30) [4], Seite 530-4. Hosaka, M.; Nagahama, M.; Kim, W. S.; Watanabe, T.; Hatsuzawa, K.; Ikemizu, J.; Murakami, K. und Nakayama, K. (1991): Arg-X-Lys/Arg-Arg motif as a signal for precursor cleavage catalyzed by furin within the constitutive secretory pathway, J Biol Chem 266) [19], Seite 12127-30. Hu, Y. und Fortini, M. E. (2003): Different cofactor activities in gamma-secretase assembly: evidence for a nicastrin-Aph-1 subcomplex, J Cell Biol 161) [4], Seite 685-90. Hung, A. Y.; Haass, C.; Nitsch, R. M.; Qiu, W. Q.; Citron, M.; Wurtman, R. J.; Growdon, J. H. und Selkoe, D. J. (1993): Activation of protein kinase C inhibits cellular production of the amyloid beta-protein, J Biol Chem 268) [31], Seite 22959-62.. Hung, A. Y. und Selkoe, D. J. (1994): Selective ectodomain phosphorylation and regulated cleavage of beta-amyloid precursor protein, Embo J 13) [3], Seite 534-42. Huse, J. T. und Doms, R. W. (2001): Neurotoxic traffic: uncovering the mechanics of amyloid production in Alzheimer's disease, Traffic 2) [2], Seite 75-81.. Huse, J. T.; Liu, K.; Pijak, D. S.; Carlin, D.; Lee, V. M. und Doms, R. W. (2002): Beta-secretase processing in the trans-Golgi network preferentially generates truncated amyloid species that accumulate in Alzheimer's disease brain, J Biol Chem 277) [18], Seite 16278-84.. Huse, J. T.; Pijak, D. S.; Leslie, G. J.; Lee, V. M. und 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) [43], Seite 33729-37.. Hussain, I.; Hawkins, J.; Shikotra, A.; Riddell, D. R.; Faller, A. und Dingwall, C. (2003): Characterization of the ectodomain shedding of the beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1), J Biol Chem 278) [38], Seite 36264-8. Hussain, I.; Powell, D.; Howlett, D. R.; Tew, D. G.; Meek, T. D.; Chapman, C.; Gloger, I. S.; Murphy, K. E.; Southan, C. D.; Ryan, D. M.; Smith, T. S.; Simmons, D. L.; Walsh, F. S.; Dingwall, C. und Christie, G. (1999): Identification of a novel aspartic protease (Asp 2) as b-secretase, Mol. Cell. Neurosci. 14) [6], Seite 419-27. Hutton, M.; Lendon, C. L.; Rizzu, P.; Baker, M.; Froelich, S.; Houlden, H.; Pickering-Brown, S.; Chakraverty, S.; Isaacs, A.; Grover, A.; Hackett, J.; Adamson, J.; Lincoln, S.; Dickson, D.; Davies, P.; Petersen, R. C.; Stevens, M.; de Graaff, E.; Wauters, E.; van Baren, J.; Hillebrand, M.; Joosse, M.; Kwon, J. M.; Nowotny, P.; Heutink, P. und et al. (1998): Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17, Nature 393) [6686], Seite 702-5. Hyman, B. T. und Tanzi, R. (1995): Molecular epidemiology of Alzheimer's disease, N Engl J Med 333) [19], Seite 1283-4. Ikin, A. F.; Annaert, W. G.; Takei, K.; De Camilli, P.; Jahn, R.; Greengard, P. und 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) [50], Seite 31783-6. Iwatsubo, T.; Odaka, A.; Suzuki, N.; Mizusawa, H.; Nukina, N. und Ihara, Y. (1994): Visualization of Ab42(43) and Ab40 in senile plaques with end-specific A b monoclonals: evidence that an initially deposited species is Ab42(43), Neuron 13) [1], Seite 45-53. Jacob, R. und Naim, H. Y. (2001): Apical membrane proteins are transported in distinct vesicular carriers, Curr Biol 11) [18], Seite 1444-50. James, M. N.; Sielecki, A.; Salituro, F.; Rich, D. H. und Hofmann, T. (1982): Conformational flexibility in the active sites of aspartyl proteinases revealed by a pepstatin fragment binding to penicillopepsin, Proc Natl Acad Sci U S A 79) [20], Seite 6137-41.. Janus, C.; Pearson, J.; McLaurin, J.; Mathews, P. M.; Jiang, Y.; Schmidt, S. D.; Chishti, M. A.; Horne, P.; Heslin, D.; French, J.; Mount, H. T.; Nixon, R. A.; Mercken, M.; Bergeron, C.; Fraser, P. E.; St George-Hyslop, P. und Westaway, D. (2000): A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease, Nature 408) [6815], Seite 979-82. Jarrett, J. T.; Berger, E. P. und Lansbury, P. T., Jr. (1993): The carboxy terminus of the b-amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease, Biochemistry 32) [18], Seite 4693-7.. Jean, F.; Boudreault, A.; Basak, A.; Seidah, N. G. und Lazure, C. (1995): Fluorescent peptidyl substrates as an aid in studying the substrate specificity of human prohormone convertase PC1 and human furin and designing a potent irreversible inhibitor, J Biol Chem 270) [33], Seite 19225-31. Jean, F.; Stella, K.; Thomas, L.; Liu, G.; Xiang, Y.; Reason, A. J. und Thomas, G. (1998): alpha1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: application as an antipathogenic agent, Proc Natl Acad Sci U S A 95) [13], Seite 7293-8. Joachim, C. L. und Selkoe, D. J. (1992): The seminal role of beta-amyloid in the pathogenesis of Alzheimer disease, Alzheimer Dis Assoc Disord 6) [1], Seite 7-34. Jones, B. G.; Thomas, L.; Molloy, S. S.; Thulin, C. D.; Fry, M. D.; Walsh, K. A. und Thomas, G. (1995): Intracellular trafficking of furin is modulated by the phosphorylation state of a casein kinase II site in its cytoplasmic tail, Embo J 14) [23], Seite 5869-83.. Kaether, C.; Lammich, S.; Edbauer, D.; Ertl, M.; Rietdorf, J.; Capell, A.; Steiner, H. und Haass, C. (2002): Presenilin-1 affects trafficking and processing of betaAPP and is targeted in a complex with nicastrin to the plasma membrane, J Cell Biol 158) [3], Seite 551-61.. Kaether, C.; Skehel, P. und Dotti, C. G. (2000): Axonal membrane proteins are transported in distinct carriers: a two-color video microscopy study in cultured hippocampal neurons, Mol Biol Cell 11) [4], Seite 1213-24. Kamal, A.; Almenar-Queralt, A.; LeBlanc, J. F.; Roberts, E. A. und Goldstein, L. S. (2001): Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP, Nature 414) [6864], Seite 643-8.. Kamal, A.; Stokin, G. B.; Yang, Z.; Xia, C. H. und Goldstein, L. S. (2000): Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I, Neuron 28) [2], Seite 449-59. Kamenetz, F.; Tomita, T.; Hsieh, H.; Seabrook, G.; Borchelt, D.; Iwatsubo, T.; Sisodia, S. und Malinow, R. (2003): APP processing and synaptic function, Neuron 37) [6], Seite 925-37. Kang, J.; Lemaire, H. G.; Unterbeck, A.; Salbaum, J. M.; Masters, C. L.; Grzeschik, K. H.; Multhaup, G.; Beyreuther, K. und Muller-Hill, B. (1987): The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor, Nature 325) [6106], Seite 733-6. Kim, D. Y.; Ingano, L. A. und Kovacs, D. M. (2002): Nectin-1alpha, an immunoglobulin-like receptor involved in the formation of synapses, is a substrate for presenilin/gamma-secretase-like cleavage, J Biol Chem 277) [51], Seite 49976-81. Kimberly, W. T.; LaVoie, M. J.; Ostaszewski, B. L.; Ye, W.; Wolfe, M. S. und Selkoe, D. J. (2003): Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2, Proc Natl Acad Sci U S A 100) [11], Seite 6382-7.. Kimberly, W. T.; Xia, W.; Rahmati, T.; Wolfe, M. S. und Selkoe, D. J. (2000): The transmembrane aspartates in presenilin 1 and 2 are obligatory for g-secretase activity and amyloid b-protein generation, J. Biol. Chem. 275) [5], Seite 3173-8. Kimberly, W. T.; Zheng, J. B.; Guenette, S. Y. und Selkoe, D. J. (2001): The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner, J Biol Chem 276) [43], Seite 40288-92. Kinoshita, A.; Fukumoto, H.; Shah, T.; Whelan, C. M.; Irizarry, M. C. und Hyman, B. T. (2003): Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes, J Cell Sci 116) [Pt 16], Seite 3339-46. Kitaguchi, N.; Takahashi, Y.; Tokushima, Y.; Shiojiri, S. und Ito, H. (1988): Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity, Nature 331) [6156], Seite 530-2. Kitazume, S.; Tachida, Y.; Oka, R.; Shirotani, K.; Saido, T. C. und Hashimoto, Y. (2001): Alzheimer's beta-secretase, beta-site amyloid precursor protein- cleaving enzyme, is responsible for cleavage secretion of a Golgi- resident sialyltransferase, Proc Natl Acad Sci U S A 98) [24], Seite 13554-9.. Klausner, R. D.; Donaldson, J. G. und Lippincott-Schwartz, J. (1992): Brefeldin A: insights into the control of membrane traffic and organelle structure, J Cell Biol 116) [5], Seite 1071-80.. Klenk, H. D.; Garten, W. und Rott, R. (1984): Inhibition of proteolytic cleavage of the hemagglutinin of influenza virus by the calcium-specific ionophore A23187, Embo J 3) [12], Seite 2911-5. Knops, J.; Suomensaari, S.; Lee, M.; McConlogue, L.; Seubert, P. und Sinha, S. (1995): Cell-type and amyloid precursor protein-type specific inhibition of A beta release by bafilomycin A1, a selective inhibitor of vacuolar ATPases, J Biol Chem 270) [6], Seite 2419-22. Koelsch, G.; Mares, M.; Metcalf, P. und Fusek, M. (1994): Multiple functions of pro-parts of aspartic proteinase zymogens, FEBS Lett 343) [1], Seite 6-10.. Koike, H.; Tomioka, S.; Sorimachi, H.; Saido, T. C.; Maruyama, K.; Okuyama, A.; Fujisawa-Sehara, A.; Ohno, S.; Suzuki, K. und Ishiura, S. (1999): Membrane-anchored metalloprotease MDC9 has an a-secretase activity responsible for processing the amyloid precursor protein, Biochem. J. 343), Seite 371-375.. Koo, E. H. (2002): The beta-amyloid precursor protein (APP) and Alzheimer's disease: does the tail wag the dog?, Traffic 3) [11], Seite 763-70. Koo, E. H.; Sisodia, S. S.; Archer, D. R.; Martin, L. J.; Weidemann, A.; Beyreuther, K.; Fischer, P.; Masters, C. L. und Price, D. L. (1990): Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport, Proc Natl Acad Sci U S A 87) [4], Seite 1561-5. Koo, E. H. und Squazzo, S. L. (1994): Evidence that production and release of amyloid b-protein involves the endocytic pathway, J. Biol. Chem. 269) [26], Seite 17386-9. Koo, E. H.; Squazzo, S. L.; Selkoe, D. J. und 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)], Seite 991-8. Kopan, R. und Goate, A. (2000): A common enzyme connects notch signaling and Alzheimer's disease, Genes Dev 14) [22], Seite 2799-806. Kopan, R. und Goate, A. (2002): Aph-2/Nicastrin: an essential component of g-secretase and regulator of Notch signaling and Presenilin localization, Neuron 33) [3], Seite 321-4.. Kopan, R. und Ilagan, M. X. (2004): Gamma-secretase: proteasome of the membrane?, Nat Rev Mol Cell Biol 5) [6], Seite 499-504. Kreitzer, G.; Schmoranzer, J.; Low, S. H.; Li, X.; Gan, Y.; Weimbs, T.; Simon, S. M. und Rodriguez-Boulan, E. (2003): Three-dimensional analysis of post-Golgi carrier exocytosis in epithelial cells, Nat Cell Biol 5) [2], Seite 126-36. Krysan, D. J.; Rockwell, N. C. und Fuller, R. S. (1999): Quantitative characterization of furin specificity. Energetics of substrate discrimination using an internally consistent set of hexapeptidyl methylcoumarinamides, J Biol Chem 274) [33], Seite 23229-34. Laemmli, U. K. (1970): Cleavage of structural proteins during the assembly of the head of bacteriophage T4, Nature 227) [259], Seite 680-5.. Lai, A.; Sisodia, S. S. und Trowbridge, I. S. (1995): Characterization of sorting signals in the beta-amyloid precursor protein cytoplasmic domain, J Biol Chem 270) [8], Seite 3565-73. Lai, E. C. (2002): Notch cleavage: Nicastrin helps Presenilin make the final cut, Curr Biol 12) [6], Seite R200-2. Lammich, S.; Kojro, E.; Postina, R.; Gilbert, S.; Pfeiffer, R.; Jasionowski, M.; Haass, C. und Fahrenholz, F. (1999): Constitutive and regulated a-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease, Proc. Natl. Acad. Sci. USA 96) [7], Seite 3922-7. Lammich, S.; Okochi, M.; Takeda, M.; Kaether, C.; Capell, A.; Zimmer, A.-K.; Edbauer, D.; Walter, J.; Steiner, H. und Haass, C. (2002): Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Ab-like peptide, J Biol Chem in press). Lammich, S.; Schobel, S.; Zimmer, A. K.; Lichtenthaler, S. F. und Haass, C. (2004): Expression of the Alzheimer protease BACE1 is suppressed via its 5'-untranslated region, EMBO Rep 5) [6], Seite 620-5. Lapatto, R.; Blundell, T.; Hemmings, A.; Overington, J.; Wilderspin, A.; Wood, S.; Merson, J. R.; Whittle, P. J.; Danley, D. E.; Geoghegan, K. F. und et al. (1989): X-ray analysis of HIV-1 proteinase at 2.7 A resolution confirms structural homology among retroviral enzymes, Nature 342) [6247], Seite 299-302.. LaPointe, C. F. und Taylor, R. K. (2000): The type 4 prepilin peptidases comprise a novel family of aspartic acid proteases, J Biol Chem 275) [2], Seite 1502-10. LaVoie, M. J.; Fraering, P. C.; Ostaszewski, B. L.; Ye, W.; Kimberly, W. T.; Wolfe, M. S. und Selkoe, D. J. (2003): Assembly of the gamma-secretase complex involves early formation of an intermediate subcomplex of Aph-1 and nicastrin, J Biol Chem 278) [39], Seite 37213-22. LaVoie, M. J. und Selkoe, D. J. (2003): The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments, J Biol Chem 278) [36], Seite 34427-37. Leavitt, R.; Schlesinger, S. und Kornfeld, S. (1977): Tunicamycin inhibits glycosylation and multiplication of Sindbis and vesicular stomatitis viruses, J Virol 21) [1], Seite 375-85. Lee, E. B.; Skovronsky, D. M.; Abtahian, F.; Doms, R. W. und Lee, V. M. (2003): Secretion and intracellular generation of truncated Abeta in beta-site amyloid-beta precursor protein-cleaving enzyme expressing human neurons, J Biol Chem 278) [7], Seite 4458-66. Lee, H. J.; Jung, K. M.; Huang, Y. Z.; Bennett, L. B.; Lee, J. S.; Mei, L. und Kim, T. W. (2002): Presenilin-dependent g-secretase-like intramembrane cleavage of ErbB4, J. Biol. Chem. 277) [8], Seite 6318-23. Lee, J. Y.; Cole, T. B.; Palmiter, R. D.; Suh, S. W. und Koh, J. Y. (2002): Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice, Proc Natl Acad Sci U S A 99) [11], Seite 7705-10. Lee, SF; Shah, S. ; Li, H. ; Yu, C.; Han, W. und Yu, G. (2002): Mammalian APH-1 interacts with presenilin and nicastrin, and is required for intramembrane proteolysis of APP and Notch., J Biol Chem. in press). Lee, V. M. und Trojanowski, J. Q. (1999): Neurodegenerative tauopathies: human disease and transgenic mouse models, Neuron 24) [3], Seite 507-10. Leem, J. Y.; Vijayan, S.; Han, P.; Cai, D.; Machura, M.; Lopes, K. O.; Veselits, M. L.; Xu, H. und Thinakaran, G. (2002): Presenilin 1 is required for maturation and cell surface accumulation of nicastrin, J. Biol. Chem. 277) [21], Seite 19236-40. Lemere, C. A.; Blusztajn, J. K.; Yamaguchi, H.; Wisniewski, T.; Saido, T. C. und Selkoe, D. J. (1996): Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation, Neurobiol Dis 3) [1], Seite 16-32. Levy-Lahad, E.; Wasco, W.; Poorkaj, P.; Romano, D. M.; Oshima, J.; Pettingell, W. H.; Yu, C. E.; Jondro, P. D.; Schmidt, S. D.; Wang, K. und et al. (1995): Candidate gene for the chromosome 1 familial Alzheimer's disease locus, Science 269) [5226], Seite 973-7.. Levy-Lahad, E.; Wijsman, E. M.; Nemens, E.; Anderson, L.; Goddard, K. A.; Weber, J. L.; Bird, T. D. und Schellenberg, G. D. (1995): A familial Alzheimer's disease locus on chromosome 1, Science 269) [5226], Seite 970-3.. Levy, E.; Carman, M. D.; Fernandez-Madrid, I. J.; Power, M. D.; Lieberburg, I.; van Duinen, S. G.; Bots, G. T.; Luyendijk, W. und Frangione, B. (1990): Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type, Science 248) [4959], Seite 1124-6. Lewis, J.; McGowan, E.; Rockwood, J.; Melrose, H.; Nacharaju, P.; Van Slegtenhorst, M.; Gwinn-Hardy, K.; Paul Murphy, M.; Baker, M.; Yu, X.; Duff, K.; Hardy, J.; Corral, A.; Lin, W. L.; Yen, S. H.; Dickson, D. W.; Davies, P. und Hutton, M. (2000): Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein, Nat Genet 25) [4], Seite 402-5. Li, J.; Ma, J. und Potter, H. (1995): Identification and expression analysis of a potential familial Alzheimer disease gene on chromosome 1 related to AD3, Proc Natl Acad Sci U S A 92) [26], Seite 12180-4. Li, M.; Phylip, L. H.; Lees, W. E.; Winther, J. R.; Dunn, B. M.; Wlodawer, A.; Kay, J. und Gustchina, A. (2000): The aspartic proteinase from Saccharomyces cerevisiae folds its own inhibitor into a helix, Nat Struct Biol 7) [2], Seite 113-7.. Li, Q. und Sudhof, T. C. (2004): Cleavage of amyloid-beta precursor protein and amyloid-beta precursor-like protein by BACE 1, J Biol Chem 279) [11], Seite 10542-50. Li, X. und Greenwald, I. (1998): Additional evidence for an eight-transmembrane-domain topology for and human presenilins, Proc. Natl. Acad. Sci. USA 95) [12], Seite 7109-14. Li, Y. M.; Lai, M. T.; Xu, M.; Huang, Q.; DiMuzio-Mower, J.; Sardana, M. K.; Shi, X. P.; Yin, K. C.; Shafer, J. A. und Gardell, S. J. (2000): Presenilin 1 is linked with g-secretase activity in the detergent solubilized state, Proc. Natl. Acad. Sci. USA 97) [11], Seite 6138-43. Li, Y. M.; Xu, M.; Lai, M. T.; Huang, Q.; Castro, J. L.; DiMuzio-Mower, J.; Harrison, T.; Lellis, C.; Nadin, A.; Neduvelli, J. G.; Register, R. B.; Sardana, M. K.; Shearman, M. S.; Smith, A. L.; Shi, X. P.; Yin, K. C.; Shafer, J. A. und Gardell, S. J. (2000): Photoactivated g-secretase inhibitors directed to the active site covalently label presenilin 1, Nature 405), Seite 689-94. Lichtenthaler, S. F.; Beher, D.; Grimm, H. S.; Wang, R.; Shearman, M. S.; Masters, C. L. und Beyreuther, K. (2002): The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain, Proc Natl Acad Sci U S A 99) [3], Seite 1365-70. Lichtenthaler, S. F.; Dominguez, D. I.; Westmeyer, G. G.; Reiss, K.; Haass, C.; Saftig, P.; De Strooper, B. und Seed, B. (2003): The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1, J Biol Chem 278) [49], Seite 48713-9. Lichtenthaler, S. F. und Haass, C. (2004): Amyloid at the cutting edge: activation of alpha-secretase prevents amyloidogenesis in an Alzheimer disease mouse model, J Clin Invest 113) [10], Seite 1384-7. Lin, X.; Koelsch, G.; Wu, S.; Downs, D.; Dashti, A. und Tang, J. (2000): Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein, Proc Natl Acad Sci U S A 97) [4], Seite 1456-60.. Linstedt, A. D. und Hauri, H. P. (1993): Giantin, a novel conserved Golgi membrane protein containing a cytoplasmic domain of at least 350 kDa, Mol Biol Cell 4) [7], Seite 679-93.. Lippincott-Schwartz, J.; Yuan, L.; Tipper, C.; Amherdt, M.; Orci, L. und Klausner, R. D. (1991): Brefeldin A's effects on endosomes, lysosomes, and the TGN suggest a general mechanism for regulating organelle structure and membrane traffic, Cell 67) [3], Seite 601-16. Liu, K.; Doms, R. W. und Lee, V. M. (2002): Glu11 site cleavage and N-terminally truncated A beta production upon BACE overexpression, Biochemistry 41) [9], Seite 3128-36.. Lo, A. C.; Haass, C.; Wagner, S. L.; Teplow, D. B. und Sisodia, S. S. (1994): Metabolism of the "Swedish" amyloid precursor protein variant in Madin- Darby canine kidney cells, J Biol Chem 269) [49], Seite 30966-73.. Lobo, A.; Launer, L. J.; Fratiglioni, L.; Andersen, K.; Di Carlo, A.; Breteler, M. M.; Copeland, J. R.; Dartigues, J. F.; Jagger, C.; Martinez-Lage, J.; Soininen, H. und Hofman, A. (2000): Prevalence of dementia and major subtypes in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group, Neurology 54) [11 Suppl 5], Seite S4-9. Löffler, G. und Petrides, P. E. (2003): Biochemie und Pathobiochemie, 7. Auflage. Auflage, Springer - Verlag,

Berlin, Heidelberg, New York

, 3-540-42295-1. Lopez-Perez, E.; Zhang, Y.; Frank, S. J.; Creemers, J.; Seidah, N. und Checler, F. (2001): Constitutive alpha-secretase cleavage of the beta-amyloid precursor protein in the furin-deficient LoVo cell line: involvement of the pro-hormone convertase 7 and the disintegrin metalloprotease ADAM10, J Neurochem 76) [5], Seite 1532-9. Lu, D. C.; Rabizadeh, S.; Chandra, S.; Shayya, R. F.; Ellerby, L. M.; Ye, X.; Salvesen, G. S.; Koo, E. H. und Bredesen, D. E. (2000): A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor, Nat Med 6) [4], Seite 397-404. Luo, W. J.; Wang, H.; Li, H.; Kim, B. S.; Shah, S.; Lee, H. J.; Thinakaran, G.; Kim, T. W.; Yu, G. und Xu, H. (2003): PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1, J Biol Chem. Luo, Y.; Bolon, B.; Kahn, S.; Bennett, B. D.; Babu-Khan, S.; Denis, P.; Fan, W.; Kha, H.; Zhang, J.; Gong, Y.; Martin, L.; Louis, J. C.; Yan, Q.; Richards, W. G.; Citron, M. und Vassar, R. (2001): Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation, Nat Neurosci 4) [3], Seite 231-2.. Machen, T. E.; Leigh, M. J.; Taylor, C.; Kimura, T.; Asano, S. und Moore, H. P. (2003): pH of TGN and recycling endosomes of H+/K+-ATPase-transfected HEK-293 cells: implications for pH regulation in the secretory pathway, Am J Physiol Cell Physiol 285) [1], Seite C205-14.. Mager, P. P. (2001): The active site of HIV-1 protease, Med Res Rev 21) [4], Seite 348-53.. Mahdi, F.; Van Nostrand, W. E. und Schmaier, A. H. (1995): Protease nexin-2/amyloid beta-protein precursor inhibits factor Xa in the prothrombinase complex, J Biol Chem 270) [40], Seite 23468-74. Mallender, W. D.; Yager, D.; Onstead, L.; Nichols, M. R.; Eckman, C.; Sambamurti, K.; Kopcho, L. M.; Marcinkeviciene, J.; Copeland, R. A. und Rosenberry, T. L. (2001): Characterization of recombinant, soluble beta-secretase from an insect cell expression system, Mol Pharmacol 59) [3], Seite 619-26.. http://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/referer?http://www.molpharm.org/cgi/content/full/59/3/619 Mandelkow, E. M. und Mandelkow, E. (1998): Tau in Alzheimer's disease, Trends Cell Biol 8) [11], Seite 425-7.. Marambaud, P.; Shioi, J.; Serban, G.; Georgakopoulos, A.; Sarner, S.; Nagy, V.; Baki, L.; Wen, P.; Efthimiopoulos, S.; Shao, Z.; Wisniewski, T. und Robakis, N. K. (2002): A presenilin-1/g-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions, Embo J. 21) [8], Seite 1948-56. Marambaud, P.; Wen, P. H.; Dutt, A.; Shioi, J.; Takashima, A.; Siman, R. und Robakis, N. K. (2003): A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations, Cell 114) [5], Seite 635-45. Marcinkeviciene, J.; Luo, Y.; Graciani, N. R.; Combs, A. P. und Copeland, R. A. (2001): Mechanism of Inhibition of beta-site amyloid precursor protein-cleaving enzyme (BACE) by a statine-based peptide, J Biol Chem 276) [26], Seite 23790-4.. Marcinkiewicz, M. und Seidah, N. G. (2000): Coordinated expression of beta-amyloid precursor protein and the putative beta-secretase BACE and alpha-secretase ADAM10 in mouse and human brain, J Neurochem 75) [5], Seite 2133-43.. Marlow, L.; Cain, M.; Pappolla, M. A. und Sambamurti, K. (2003): Beta-secretase processing of the Alzheimer's amyloid protein precursor (APP), J Mol Neurosci 20) [3], Seite 233-9. Masliah, E.; Mallory, M.; Alford, M.; DeTeresa, R.; Hansen, L. A.; McKeel, D. W., Jr. und Morris, J. C. (2001): Altered expression of synaptic proteins occurs early during progression of Alzheimer's disease, Neurology 56) [1], Seite 127-9. Masters, C. L.; Multhaup, G.; Simms, G.; Pottgiesser, J.; Martins, R. N. und Beyreuther, K. (1985): Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels, Embo J 4) [11], Seite 2757-63. Masters, C. L.; Simms, G.; Weinman, N. A.; Multhaup, G.; McDonald, B. L. und Beyreuther, K. (1985): Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proc Natl Acad Sci U S A 82) [12], Seite 4245-9. Matsuda, S.; Yasukawa, T.; Homma, Y.; Ito, Y.; Niikura, T.; Hiraki, T.; Hirai, S.; Ohno, S.; Kita, Y.; Kawasumi, M.; Kouyama, K.; Yamamoto, T.; Kyriakis, J. M. und Nishimoto, I. (2001): c-Jun N-terminal kinase (JNK)-interacting protein-1b/islet-brain-1 scaffolds Alzheimer's amyloid precursor protein with JNK, J Neurosci 21) [17], Seite 6597-607. Maurer, K und Maurer, U (1998): Alzheimer. Das Leben eines Arztes und die Karriere einer Krankheit, Piper,

München

, 3492040616. Maxfield, F. R. und McGraw, T. E. (2004): Endocytic recycling, Nat Rev Mol Cell Biol 5) [2], Seite 121-32. May, P.; Reddy, Y. K. und Herz, J. (2002): Proteolytic processing of low density lipoprotein receptor-related protein mediates regulated release of its intracellular domain, J Biol Chem 277) [21], Seite 18736-43. McDowell, W. und Schwarz, R. T. (1988): Dissecting glycoprotein biosynthesis by the use of specific inhibitors, Biochimie 70) [11], Seite 1535-49. McKhann, G.; Drachman, D.; Folstein, M.; Katzman, R.; Price, D. und Stadlan, E. M. (1984): Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease, Neurology 34) [7], Seite 939-44. McPhie, D. L.; Golde, T.; Eckman, C. B.; Yager, D.; Brant, J. B. und Neve, R. L. (2001): beta-Secretase cleavage of the amyloid precursor protein mediates neuronal apoptosis caused by familial Alzheimer's disease mutations, Brain Res Mol Brain Res 97) [1], Seite 103-13.. Mills, J. und Reiner, P. B. (1999): Mitogen-activated protein kinase is involved in N-methyl-D-aspartate receptor regulation of amyloid precursor protein cleavage, Neuroscience 94) [4], Seite 1333-8. Milward, E. A.; Papadopoulos, R.; Fuller, S. J.; Moir, R. D.; Small, D.; Beyreuther, K. und Masters, C. L. (1992): The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowth, Neuron 9) [1], Seite 129-37.. Minopoli, G.; de Candia, P.; Bonetti, A.; Faraonio, R.; Zambrano, N. und Russo, T. (2001): The beta-amyloid precursor protein functions as a cytosolic anchoring site that prevents Fe65 nuclear translocation, J Biol Chem 276) [9], Seite 6545-50. Mizuno, T.; Haass, C.; Michikawa, M. und Yanagisawa, K. (1998): Cholesterol-dependent generation of a unique amyloid beta-protein from apically missorted amyloid precursor protein in MDCK cells, Biochim Biophys Acta 1373) [1], Seite 119-30. Mohan, M. J.; Seaton, T.; Mitchell, J.; Howe, A.; Blackburn, K.; Burkhart, W.; Moyer, M.; Patel, I.; Waitt, G. M.; Becherer, J. D.; Moss, M. L. und Milla, M. E. (2002): The tumor necrosis factor-alpha converting enzyme (TACE): a unique metalloproteinase with highly defined substrate selectivity, Biochemistry 41) [30], Seite 9462-9. Molinari, M.; Calanca, V.; Galli, C.; Lucca, P. und Paganetti, P. (2003): Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle, Science 299) [5611], Seite 1397-400. Molloy, S. S.; Anderson, E. D.; Jean, F. und Thomas, G. (1999): Bi-cycling the furin pathway: from TGN localization to pathogen activation and embryogenesis, Trends Cell Biol 9) [1], Seite 28-35. Molloy, S. S.; Bresnahan, P. A.; Leppla, S. H.; Klimpel, K. R. und Thomas, G. (1992): Human furin is a calcium-dependent serine endoprotease that recognizes the sequence Arg-X-X-Arg and efficiently cleaves anthrax toxin protective antigen, J Biol Chem 267) [23], Seite 16396-402. Molloy, S. S.; Thomas, L.; Kamibayashi, C.; Mumby, M. C. und Thomas, G. (1998): Regulation of endosome sorting by a specific PP2A isoform, J Cell Biol 142) [6], Seite 1399-411.. Morais, V. A.; Crystal, A. S.; Pijak, D. S.; Carlin, D.; Costa, J.; Lee, V. M. und Doms, R. W. (2003): The transmembrane domain region of nicastrin mediates direct interactions with APH-1 and the gamma-secretase complex, J Biol Chem 278) [44], Seite 43284-91. Morgan, D.; Diamond, D. M.; Gottschall, P. E.; Ugen, K. E.; Dickey, C.; Hardy, J.; Duff, K.; Jantzen, P.; DiCarlo, G.; Wilcock, D.; Connor, K.; Hatcher, J.; Hope, C.; Gordon, M. und Arendash, G. W. (2000): A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease, Nature 408) [6815], Seite 982-5. Morris, H. R.; Khan, M. N.; Janssen, J. C.; Brown, J. M.; Perez-Tur, J.; Baker, M.; Ozansoy, M.; Hardy, J.; Hutton, M.; Wood, N. W.; Lees, A. J.; Revesz, T.; Lantos, P. und Rossor, M. N. (2001): The genetic and pathological classification of familial frontotemporal dementia, Arch Neurol 58) [11], Seite 1813-6.. Morris, H. R.; Perez-Tur, J.; Janssen, J. C.; Brown, J.; Lees, A. J.; Wood, N. W.; Hardy, J.; Hutton, M. und Rossor, M. N. (1999): Mutation in the tau exon 10 splice site region in familial frontotemporal dementia, Ann Neurol 45) [2], Seite 270-1.. Morris, R. G. (2003): Long-term potentiation and memory, Philos Trans R Soc Lond B Biol Sci 358) [1432], Seite 643-7. Moss, M. L.; Jin, S. L.; Milla, M. E.; Bickett, D. M.; Burkhart, W.; Carter, H. L.; Chen, W. J.; Clay, W. C.; Didsbury, J. R.; Hassler, D.; Hoffman, C. R.; Kost, T. A.; Lambert, M. H.; Leesnitzer, M. A.; McCauley, P.; McGeehan, G.; Mitchell, J.; Moyer, M.; Pahel, G.; Rocque, W.; Overton, L. K.; Schoenen, F.; Seaton, T.; Su, J. L.; Becherer, J. D. und et al. (1997): Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha, Nature 385) [6618], Seite 733-6. Mostov, K.; Su, T. und ter Beest, M. (2003): Polarized epithelial membrane traffic: conservation and plasticity, Nat Cell Biol 5) [4], Seite 287-93. Mucke, L.; Masliah, E.; Yu, G. Q.; Mallory, M.; Rockenstein, E. M.; Tatsuno, G.; Hu, K.; Kholodenko, D.; Johnson-Wood, K. und McConlogue, L. (2000): High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation, J Neurosci 20) [11], Seite 4050-8. Mullan, M.; Crawford, F.; Axelman, K.; Houlden, H.; Lilius, L.; Winblad, B. und Lannfelt, L. (1992): A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid, Nat Genet 1) [5], Seite 345-7. Müller, U.; Gajic, V.; Steinbach, J.; Aguzzi, A.; Herms, J.Tremml, P.; Sisodia, S.S.; Wolfer, D.P. und Lipp, H.-P. (1998): Single and combined gene deficiencies of APP/APLP-family members, Neurobiol. Aging 16), Seite 1174. Muller, U. und Kins, S. (2002): APP on the move, Trends Mol Med 8) [4], Seite 152-5. Mumm, J. S. und Kopan, R. (2000): Notch signaling: from the outside in, Dev Biol 228) [2], Seite 151-65. Mumm, J. S.; Schroeter, E. H.; Saxena, M. T.; Griesemer, A.; Tian, X.; Pan, D. J.; Ray, W. J. und Kopan, R. (2000): A ligand-induced extracellular cleavage regulates g-secretase-like proteolytic activation of Notch1, Mol. Cell 5) [2], Seite 197-206. Murrell, J.; Farlow, M.; Ghetti, B. und Benson, M. D. (1991): A mutation in the amyloid precursor protein associated with hereditary Alzheimer´s disease, Science 254), Seite 97-99. Nakayama, K. (1997): Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins, Biochem J 327 ( Pt 3)), Seite 625-35. Naruse, S.; Thinakaran, G.; Luo, J. J.; Kusiak, J. W.; Tomita, T.; Iwatsubo, T.; Qian, X.; Ginty, D. D.; Price, D. L.; Borchelt, D. R.; Wong, P. C. und Sisodia, S. S. (1998): Effects of PS1 deficiency on membrane protein trafficking in neurons, Neuron 21) [5], Seite 1213-21. Naslund, J.; Haroutunian, V.; Mohs, R.; Davis, K. L.; Davies, P.; Greengard, P. und Buxbaum, J. D. (2000): Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline, Jama 283) [12], Seite 1571-7. Naslund, J.; Schierhorn, A.; Hellman, U.; Lannfelt, L.; Roses, A. D.; Tjernberg, L. O.; Silberring, J.; Gandy, S. E.; Winblad, B.; Greengard, P. und et al. (1994): Relative abundance of Alzheimer A beta amyloid peptide variants in Alzheimer disease and normal aging, Proc Natl Acad Sci U S A 91) [18], Seite 8378-82. Nelson, W. J. und Yeaman, C. (2001): Protein trafficking in the exocytic pathway of polarized epithelial cells, Trends Cell Biol 11) [12], Seite 483-6. Ng, K. K.; Petersen, J. F.; Cherney, M. M.; Garen, C.; Zalatoris, J. J.; Rao-Naik, C.; Dunn, B. M.; Martzen, M. R.; Peanasky, R. J. und James, M. N. (2000): Structural basis for the inhibition of porcine pepsin by Ascaris pepsin inhibitor-3, Nat Struct Biol 7) [8], Seite 653-7.. Ni, C. Y.; Murphy, M. P.; Golde, T. E. und Carpenter, G. (2001): g-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase, Science 294) [5549], Seite 2179-2181.. Nilsberth, C.; Westlind-Danielsson, A.; Eckman, C. B.; Condron, M. M.; Axelman, K.; Forsell, C.; Stenh, C.; Luthman, J.; Teplow, D. B.; Younkin, S. G.; Naslund, J. und Lannfelt, L. (2001): The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Ab protofibril formation, Nat. Neurosci. 4) [9], Seite 887-93.. Nishimoto, I.; Okamoto, T.; Matsuura, Y.; Takahashi, S.; Murayama, Y. und Ogata, E. (1993): Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o), Nature 362) [6415], Seite 75-9.. Nitsch, R. M.; Farber, S. A.; Growdon, J. H. und Wurtman, R. J. (1993): Release of amyloid beta-protein precursor derivatives by electrical depolarization of rat hippocampal slices, Proc Natl Acad Sci U S A 90) [11], Seite 5191-3. Nitsch, R. M.; Slack, B. E.; Wurtman, R. J. und Growdon, J. H. (1992): Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors, Science 258) [5080], Seite 304-7.. Norman, J. A.; Hadjilambris, O.; Baska, R.; Sharp, D. Y. und Kumar, R. (1992): Stable expression, secretion, and characterization of active human renin in mammalian cells, Mol Pharmacol 41) [1], Seite 53-9.. Oda, K. (1992): Calcium depletion blocks proteolytic cleavages of plasma protein precursors which occur at the Golgi and/or trans-Golgi network. Possible involvement of Ca(2+)-dependent Golgi endoproteases, J Biol Chem 267) [24], Seite 17465-71. Oddo, S.; Billings, L.; Kesslak, J. P.; Cribbs, D. H. und LaFerla, F. M. (2004): Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome, Neuron 43) [3], Seite 321-32. Oddo, S.; Caccamo, A.; Kitazawa, M.; Tseng, B. P. und LaFerla, F. M. (2003): Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease, Neurobiol Aging 24) [8], Seite 1063-70. Ohl, C.; Albach, C.; Altevogt, P. und Schmitz, B. (2003): N-glycosylation patterns of HSA/CD24 from different cell lines and brain homogenates: a comparison, Biochimie 85) [6], Seite 565-73. Okamoto, I.; Tsuiki, H.; Kenyon, L. C.; Godwin, A. K.; Emlet, D. R.; Holgado-Madruga, M.; Lanham, I. S.; Joynes, C. J.; Vo, K. T.; Guha, A.; Matsumoto, M.; Ushio, Y.; Saya, H. und Wong, A. J. (2002): Proteolytic cleavage of the CD44 adhesion molecule in multiple human tumors, Am J Pathol 160) [2], Seite 441-7. Okochi, M.; Steiner, H.; Fukumori, A.; Tanii, H.; Tomita, T.; Tanaka, T.; Iwatsubo, T.; Kudo, T.; Haass, C. und Takeda, M. (2002): Presenilins mediate a dual intramembraneous g-secretase cleavage of Notch, which is required for signaling and removal of the transmembrane domain, EMBO J 21) [20], Seite 5408-16. Okoniewska, M.; Tanaka, T. und Yada, R. Y. (1999): The role of the flap residue, threonine 77, in the activation and catalytic activity of pepsin A, Protein Eng 12) [1], Seite 55-61.. Okoniewska, M.; Tanaka, T. und Yada, R. Y. (2000): The pepsin residue glycine-76 contributes to active-site loop flexibility and participates in catalysis, Biochem J 349) [Pt 1], Seite 169-77.. Oltersdorf, T.; Ward, P. J.; Henriksson, T.; Beattie, E. C.; Neve, R.; Lieberburg, I. und Fritz, L. C. (1990): The Alzheimer amyloid precursor protein. Identification of a stable intermediate in the biosynthetic/degradative pathway, J Biol Chem 265) [8], Seite 4492-7.. Osborn, J. (2002): A review of the suitability of CyDye fluors for use in high-throughput drug screening applications, Bioscience, Amersham, Drug Discovery Technology, Life Science News Online,

Buckinghamshire, England U. K.

. Pastorino, L.; Ikin, A. F.; Lamprianou, S.; Vacaresse, N.; Revelli, J. P.; Platt, K.; Paganetti, P.; Mathews, P. M.; Harroch, S. und Buxbaum, J. D. (2004): BACE (beta-secretase) modulates the processing of APLP2 in vivo, Mol Cell Neurosci 25) [4], Seite 642-9. Pastorino, L.; Ikin, A. F.; Nairn, A. C.; Pursnani, A. und Buxbaum, J. D. (2002): The carboxyl-terminus of BACE contains a sorting signal that regulates BACE trafficking but not the formation of total A(beta), Mol Cell Neurosci 19) [2], Seite 175-85.. Perez, R. G.; Soriano, S.; Hayes, J. D.; Ostaszewski, B.; Xia, W.; Selkoe, D. J.; Chen, X.; Stokin, G. B. und 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) [27], Seite 18851-6. Periz, G. und Fortini, M. E. (2004): Functional reconstitution of gamma-secretase through coordinated expression of presenilin, nicastrin, Aph-1, and Pen-2, J Neurosci Res 77) [3], Seite 309-22. Peschon, J. J.; Slack, J. L.; Reddy, P.; Stocking, K. L.; Sunnarborg, S. W.; Lee, D. C.; Russell, W. E.; Castner, B. J.; Johnson, R. S.; Fitzner, J. N.; Boyce, R. W.; Nelson, N.; Kozlosky, C. J.; Wolfson, M. F.; Rauch, C. T.; Cerretti, D. P.; Paxton, R. J.; March, C. J. und Black, R. A. (1998): An essential role for ectodomain shedding in mammalian development, Science 282) [5392], Seite 1281-4. Phylip, L. H.; Lees, W. E.; Brownsey, B. G.; Bur, D.; Dunn, B. M.; Winther, J. R.; Gustchina, A.; Li, M.; Copeland, T.; Wlodawer, A. und Kay, J. (2001): The potency and specificity of the interaction between the IA3 inhibitor and its target aspartic proteinase from Saccharomyces cerevisiae, J Biol Chem 276) [3], Seite 2023-30.. Pike, C. J.; Cummings, B. J.; Monzavi, R. und Cotman, C. W. (1994): Beta-amyloid-induced changes in cultured astrocytes parallel reactive astrocytosis associated with senile plaques in Alzheimer's disease, Neuroscience 63) [2], Seite 517-31. Pike, C. J.; Overman, M. J. und Cotman, C. W. (1995): Amino-terminal deletions enhance aggregation of beta-amyloid peptides in vitro, J Biol Chem 270) [41], Seite 23895-8. Pinnix, I.; Council, J. E.; Roseberry, B.; Onstead, L.; Mallender, W.; Sucic, J. und Sambamurti, K. (2001): Convertases other than furin cleave beta-secretase to its mature form, Faseb J 15) [10], Seite 1810-2.. Polishchuk, R.; Di Pentima, A. und Lippincott-Schwartz, J. (2004): Delivery of raft-associated, GPI-anchored proteins to the apical surface of polarized MDCK cells by a transcytotic pathway, Nat Cell Biol 6) [4], Seite 297-307. Ponte, P.; Gonzalez-DeWhitt, P.; Schilling, J.; Miller, J.; Hsu, D.; Greenberg, B.; Davis, K.; Wallace, W.; Lieberburg, I. und Fuller, F. (1988): A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors, Nature 331) [6156], Seite 525-7. Ponting, C. P.; Hutton, M.; Nyborg, A.; Baker, M.; Jansen, K. und Golde, T. E. (2002): Identification of a novel family of presenilin homologues, Hum. Mol. Genet. 11) [9], Seite 1037-44. Postina, R.; Schroeder, A.; Dewachter, I.; Bohl, J.; Schmitt, U.; Kojro, E.; Prinzen, C.; Endres, K.; Hiemke, C.; Blessing, M.; Flamez, P.; Dequenne, A.; Godaux, E.; van Leuven, F. und Fahrenholz, F. (2004): A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model, J Clin Invest 113) [10], Seite 1456-64. Potter, B. A.; Ihrke, G.; Bruns, J. R.; Weixel, K. M. und Weisz, O. A. (2004): Specific N-glycans direct apical delivery of transmembrane, but not soluble or glycosylphosphatidylinositol-anchored forms of endolyn in Madin-Darby canine kidney cells, Mol Biol Cell 15) [3], Seite 1407-16. Prencipe, M.; Casini, A. R.; Ferretti, C.; Lattanzio, M. T.; Fiorelli, M. und Culasso, F. (1996): Prevalence of dementia in an elderly rural population: effects of age, sex, and education, J Neurol Neurosurg Psychiatry 60) [6], Seite 628-33. Prokop, S.; Shirotani, K.; Edbauer, D.; Haass, C. und Steiner, H. (2004): Requirement of PEN-2 for stabilization of the presenilin N-/C-terminal fragment heterodimer within the gamma-secretase complex, J Biol Chem 279) [22], Seite 23255-61. Ratovitski, T.; Slunt, H. H.; Thinakaran, G.; Price, D. L.; Sisodia, S. S. und Borchelt, D. R. (1997): Endoproteolytic processing and stabilization of wild-type and mutant presenilin, J. Biol. Chem. 272) [39], Seite 24536-41. Ray, W. J.; Yao, M.; Mumm, J.; Schroeter, E. H.; Saftig, P.; Wolfe, M.; Selkoe, D. J.; Kopan, R. und Goate, A. M. (1999): Cell surface presenilin-1 participates in the g-secretase-like proteolysis of Notch, J. Biol. Chem. 274) [51], Seite 36801-7. Rebeck, G. W.; Reiter, J. S.; Strickland, D. K. und Hyman, B. T. (1993): Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions, Neuron 11) [4], Seite 575-80. Rich, D. H.; Bernatowicz, M. S.; Agarwal, N. S.; Kawai, M.; Salituro, F. G. und Schmidt, P. G. (1985): Inhibition of aspartic proteases by pepstatin and 3-methylstatine derivatives of pepstatin. Evidence for collected-substrate enzyme inhibition, Biochemistry 24) [13], Seite 3165-73.. Riddell, D. R.; Christie, G.; Hussain, I. und Dingwall, C. (2001): Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts, Curr Biol 11) [16], Seite 1288-93.. Riedel-Heller, S. G.; Busse, A.; Aurich, C.; Matschinger, H. und Angermeyer, M. C. (2001): Prevalence of dementia according to DSM-III-R and ICD-10: results of the Leipzig Longitudinal Study of the Aged (LEILA75+) Part 1, Br J Psychiatry 179), Seite 250-4. Roberds, S. L.; Anderson, J.; Basi, G.; Bienkowski, M. J.; Branstetter, D. G.; Chen, K. S.; Freedman, S. B.; Frigon, N. L.; Games, D.; Hu, K.; Johnson-Wood, K.; Kappenman, K. E.; Kawabe, T. T.; Kola, I.; Kuehn, R.; Lee, M.; Liu, W.; Motter, R.; Nichols, N. F.; Power, M.; Robertson, D. W.; Schenk, D.; Schoor, M.; Shopp, G. M.; Shuck, M. E.; Sinha, S.; Svensson, K. A.; Tatsuno, G.; Tintrup, H.; Wijsman, J.; Wright, S. und McConlogue, L. (2001): BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics, Hum Mol Genet 10) [12], Seite 1317-24. Rodriguez-Boulan, E. und Gonzalez, A. (1999): Glycans in post-Golgi apical targeting: sorting signals or structural props?, Trends Cell Biol 9) [8], Seite 291-4. Rogaev, E. I.; Sherrington, R.; Rogaeva, E. A.; Levesque, G.; Ikeda, M.; Liang, Y.; Chi, H.; Lin, C.; Holman, K.; Tsuda, T. und et al. (1995): Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene, Nature 376) [6543], Seite 775-8.. Rosa, P.; Mantovani, S.; Rosboch, R. und Huttner, W. B. (1992): Monensin and brefeldin A differentially affect the phosphorylation and sulfation of secretory proteins, J Biol Chem 267) [17], Seite 12227-32.. Roth, J. (2002): Protein N-glycosylation along the secretory pathway: relationship to organelle topography and function, protein quality control, and cell interactions, Chem Rev 102) [2], Seite 285-303. Sabo, S. L.; Ikin, A. F.; Buxbaum, J. D. und Greengard, P. (2001): The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement, J Cell Biol 153) [7], Seite 1403-14. Sambamurti, K.; Kinsey, R.; Maloney, B.; Ge, Y. W. und Lahiri, D. K. (2004): Gene structure and organization of the human beta-secretase (BACE) promoter, Faseb J 18) [9], Seite 1034-6. Sambrook, J. und Russel, D.W. (2001): Molecular cloning: A laboratory manual, 3nd. Auflage, Cold Spring Harbor Press,

Cold Spring Habor, New York

. Samuels, S. C. und Davis, K. L. (1998): Experimental approaches to cognitive disturbance in Alzheimer's disease, Harv Rev Psychiatry 6) [1], Seite 11-22. Sandbrink, R.; Masters, C. L. und Beyreuther, K. (1994): Similar alternative splicing of a non-homologous domain in beta A4- amyloid protein precursor-like proteins, J Biol Chem 269) [19], Seite 14227-34.. Sastre, M.; Steiner, H.; Fuchs, K.; Capell, A.; Multhaup, G.; Condron, M. M.; Teplow, D. B. und 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) [9], Seite 835-41.. Sauder, J. M.; Arthur, J. W. und Dunbrack, R. L., Jr. (2000): Modeling of substrate specificity of the Alzheimer's disease amyloid precursor protein beta-secretase, J Mol Biol 300) [2], Seite 241-8.. Saunders, A.; Kim, T-W. und Tanzi, R. (1999): BACE Maps to Chromosome 11 and a BACE Homolog, BACE2, Reside in the Obligate Down Syndrome Region of Chromosome 21, Science 286), Seite 1255a. Saunders, A. M.; Strittmatter, W. J.; Schmechel, D.; George-Hyslop, P. H.; Pericak-Vance, M. A.; Joo, S. H.; Rosi, B. L.; Gusella, J. F.; Crapper-MacLachlan, D. R.; Alberts, M. J. und et al. (1993): Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease, Neurology 43) [8], Seite 1467-72. Saura, C. A.; Choi, S. Y.; Beglopoulos, V.; Malkani, S.; Zhang, D.; Shankaranarayana Rao, B. S.; Chattarji, S.; Kelleher, R. J., 3rd; Kandel, E. R.; Duff, K.; Kirkwood, A. und Shen, J. (2004): Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration, Neuron 42) [1], Seite 23-36. Saxena, M. T.; Schroeter, E. H.; Mumm, J. S. und Kopan, R. (2001): Murine Notch homologs (N1-4) undergo presenilin-dependent proteolysis, J. Biol. Chem. 276) [43], Seite 40268-73.. Schägger, H. und von Jagow, G. (1987): Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa, Anal Biochem 166) [2], Seite 368-79.. Schenk, D.; Barbour, R.; Dunn, W.; Gordon, G.; Grajeda, H.; Guido, T.; Hu, K.; Huang, J.; Johnson-Wood, K.; Khan, K.; Kholodenko, D.; Lee, M.; Liao, Z.; Lieberburg, I.; Motter, R.; Mutter, L.; Soriano, F.; Shopp, G.; Vasquez, N.; Vandevert, C.; Walker, S.; Wogulis, M.; Yednock, T.; Games, D. und Seubert, P. (1999): Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse [see comments], Nature 400) [6740], Seite 173-7. Scheuner, D.; Eckman, C.; Jensen, M.; Song, X.; Citron, M.; Suzuki, N.; Bird, T. D.; Hardy, J.; Hutton, M.; Kukull, W.; Larson, E.; Levy-Lahad, E.; Viitanen, M.; Peskind, E.; Poorkaj, P.; Schellenberg, G.; Tanzi, R.; Wasco, W.; Lannfelt, L.; Selkoe, D. und Younkin, S. (1996): Secreted amyloid b-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nat. Med. 2) [8], Seite 864-70. Schmaier, A. H.; Dahl, L. D.; Rozemuller, A. J.; Roos, R. A.; Wagner, S. L.; Chung, R. und Van Nostrand, W. E. (1993): Protease nexin-2/amyloid beta protein precursor. A tight-binding inhibitor of coagulation factor IXa, J Clin Invest 92) [5], Seite 2540-5. Schmechel, D. E.; Saunders, A. M.; Strittmatter, W. J.; Crain, B. J.; Hulette, C. M.; Joo, S. H.; Pericak-Vance, M. A.; Goldgaber, D. und Roses, A. D. (1993): Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease, Proc Natl Acad Sci U S A 90) [20], Seite 9649-53. Schuck, S. und Simons, K. (2004): Polarized sorting in epithelial cells: raft clustering and the biogenesis of the apical membrane, J Cell Sci 117) [Pt 25], Seite 5955-64. Seals, D. F. und Courtneidge, S. A. (2003): The ADAMs family of metalloproteases: multidomain proteins with multiple functions, Genes Dev 17) [1], Seite 7-30. Seelmeier, S.; Schmidt, H.; Turk, V. und von der Helm, K. (1988): Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A, Proc Natl Acad Sci U S A 85) [18], Seite 6612-6.. Seidah, N. G. und Chretien, M. (1997): Eukaryotic protein processing: endoproteolysis of precursor proteins, Curr Opin Biotechnol 8) [5], Seite 602-7. Selkoe, D. J. (1994): Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer's disease, Annu Rev Cell Biol 10), Seite 373-403. Selkoe, D. J. (1996): Amyloid beta-protein and the genetics of Alzheimer's disease, J Biol Chem 271) [31], Seite 18295-8. Selkoe, D. J. (1999): Translating cell biology into therapeutic advances in Alzheimer's disease, Nature 399) [6738 Suppl], Seite A23-31. Selkoe, D. J. (2001): Alzheimer's disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein, J Alzheimers Dis 3) [1], Seite 75-80. Selkoe, D. J. (2001): Alzheimer's disease: genes, proteins, and therapy, Physiol. Rev. 81) [2], Seite 741-66. Selkoe, D. J. (2002): Alzheimer's disease is a synaptic failure, Science 298) [5594], Seite 789-91. Selkoe, D. J.; Podlisny, M. B.; Joachim, C. L.; Vickers, E. A.; Lee, G.; Fritz, L. C. und Oltersdorf, T. (1988): Beta-amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues, Proc Natl Acad Sci U S A 85) [19], Seite 7341-5.. Selkoe, D. und Kopan, R. (2003): Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration, Annu Rev Neurosci 26), Seite 565-97. Seubert, P.; Oltersdorf, T.; Lee, M. G.; Barbour, R.; Blomquist, C.; Davis, D. L.; Bryant, K.; Fritz, L. C.; Galasko, D.; Thal, L. J. und et al. (1993): Secretion of b-amyloid precursor protein cleaved at the amino terminus of the b-amyloid peptide, Nature 361) [6409], Seite 260-3. Seubert, P.; Vigo-Pelfrey, C.; Esch, F.; Lee, M.; Dovey, H.; Davis, D.; Sinha, S.; Schlossmacher, M.; Whaley, J.; Swindlehurst, C. und et al. (1992): Isolation and quantification of soluble Alzheimer's b-peptide from biological fluids, Nature 359) [6393], Seite 325-7. Shearman, M. S.; Beher, D.; Clarke, E. E.; Lewis, H. D.; Harrison, T.; Hunt, P.; Nadin, A.; Smith, A. L.; Stevenson, G. und Castro, J. L. (2000): L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid b-protein precursor g-secretase activity, Biochemistry 39) [30], Seite 8698-704.. Shen, J.; Bronson, R. T.; Chen, D. F.; Xia, W.; Selkoe, D. J. und Tonegawa, S. (1997): Skeletal and CNS defects in Presenilin-1-deficient mice, Cell 89) [4], Seite 629-39. Sheng, J. G.; Price, D. L. und Koliatsos, V. E. (2003): The beta-amyloid-related proteins presenilin 1 and BACE1 are axonally transported to nerve terminals in the brain, Exp Neurol 184) [2], Seite 1053-7. Sherrington, R.; Rogaev, E. I.; Liang, Y.; Rogaeva, E. A.; Levesque, G.; Ikeda, M.; Chi, H.; Lin, C.; Li, G.; Holman, K. und et al. (1995): Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease, Nature 375) [6534], Seite 754-60. Shi, Xiao-Ping; Chen, Elizabeth; Yin, Kuo-Chang; Na, Sang; Garsky, Victor M.; Lai, Ming-Tain; Li, Yue-Ming; Platchek, Michael; Register, R. Bruce; Sardana, Mohinder K.; Tang, Mei-Jy; Thiebeau, James; Wood, Theresa; Shafer, Jules A. und Gardell, Stephen J. (2001): The Pro Domain of beta -Secretase Does Not Confer Strict Zymogen-like Properties but Does Assist Proper Folding of the Protease Domain, J. Biol. Chem. 276) [13], Seite 10366-10373. Shiba, T.; Kametaka, S.; Kawasaki, M.; Shibata, M.; Waguri, S.; Uchiyama, Y. und Wakatsuki, S. (2004): Insights into the phosphoregulation of beta-secretase sorting signal by the VHS domain of GGA1, Traffic 5) [6], Seite 437-48. Shirotani, K.; Edbauer, D.; Prokop, S.; Haass, C. und Steiner, H. (2004): Identification of distinct gamma-secretase complexes with different APH-1 variants, J Biol Chem 279) [40], Seite 41340-5. Shoji, M.; Golde, T. E.; Ghiso, J.; Cheung, T. T.; Estus, S.; Shaffer, L. M.; Cai, X. D.; McKay, D. M.; Tintner, R.; Frangione, B. und et al. (1992): Production of the Alzheimer amyloid b-protein by normal proteolytic processing, Science 258) [5079], Seite 126-9. Sielecki, A. R.; Fedorov, A. A.; Boodhoo, A.; Andreeva, N. S. und James, M. N. (1990): Molecular and crystal structures of monoclinic porcine pepsin refined at 1.8 A resolution, J Mol Biol 214) [1], Seite 143-70.. Simmen, T.; Honing, S.; Icking, A.; Tikkanen, R. und Hunziker, W. (2002): AP-4 binds basolateral signals and participates in basolateral sorting in epithelial MDCK cells, Nat Cell Biol 4) [2], Seite 154-9. Simons, K. und Ikonen, E. (2000): How cells handle cholesterol, Science 290) [5497], Seite 1721-6. Simons, K. und Toomre, D. (2000): Lipid rafts and signal transduction, Nat Rev Mol Cell Biol 1) [1], Seite 31-9. Simons, M.; de Strooper, B.; Multhaup, G.; Tienari, P. J.; Dotti, C. G. und Beyreuther, K. (1996): Amyloidogenic processing of the human amyloid precursor protein in primary cultures of rat hippocampal neurons, J Neurosci 16) [3], Seite 899-908. Sinha, S.; Anderson, J. P.; Barbour, R.; Basi, G. S.; Caccavello, R.; Davis, D.; Doan, M.; Dovey, H. F.; Frigon, N.; Hong, J.; Jacobson-Croak, K.; Jewett, N.; Keim, P.; Knops, J.; Lieberburg, I.; Power, M.; Tan, H.; Tatsuno, G.; Tung, J.; Schenk, D.; Seubert, P.; Suomensaari, S. M.; Wang, S.; Walker, D.; John, V. und et al. (1999): Purification and cloning of amyloid precursor protein b-secretase from human brain, Nature 402) [6761], Seite 537-40. Sinha, S. und Lieberburg, I. (1999): Cellular mechanisms of beta-amyloid production and secretion, Proc Natl Acad Sci U S A 96) [20], Seite 11049-53. Sisodia, S. S. (1992): Beta-amyloid precursor protein cleavage by a membrane-bound protease, Proc Natl Acad Sci U S A 89) [13], Seite 6075-9. Sisodia, S. S.; Koo, E. H.; Hoffman, P. N.; Perry, G. und Price, D. L. (1993): Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system, J Neurosci 13) [7], Seite 3136-42. Sisodia, S. S. und St George-Hyslop, P. H. (2002): gamma-Secretase, Notch, Abeta and Alzheimer's disease: where do the presenilins fit in?, Nat Rev Neurosci 3) [4], Seite 281-90. Six, E.; Ndiaye, D.; Laabi, Y.; Brou, C.; Gupta-Rossi, N.; Israel, A. und Logeat, F. (2003): The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase, Proc Natl Acad Sci U S A 100) [13], Seite 7638-43. Skovronsky, D. M.; Fath, S.; Lee, V. M. und Milla, M. E. (2001): Neuronal localization of the TNFalpha converting enzyme (TACE) in brain tissue and its correlation to amyloid plaques, J Neurobiol 49) [1], Seite 40-6. Skovronsky, D. M.; Moore, D. B.; Milla, M. E.; Doms, R. W. und 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) [4], Seite 2568-75. Small, D. H.; Mok, S. S. und Bornstein, J. C. (2001): Alzheimer's disease and Abeta toxicity: from top to bottom, Nat Rev Neurosci 2) [8], Seite 595-8. Solans, A.; Estivill, X. und de La Luna, S. (2000): A new aspartyl protease on 21q22.3, BACE2, is highly similar to Alzheimer's amyloid precursor protein beta-secretase, Cytogenet Cell Genet 89) [3-4], Seite 177-84. Sopher, B. L.; Fukuchi, K.; Smith, A. C.; Leppig, K. A.; Furlong, C. E. und Martin, G. M. (1994): Cytotoxicity mediated by conditional expression of a carboxyl-terminal derivative of the beta-amyloid precursor protein, Brain Res Mol Brain Res 26) [1-2], Seite 207-17. Sprecher, C. A.; Grant, F. J.; Grimm, G.; O'Hara, P. J.; Norris, F.; Norris, K. und Foster, D. C. (1993): Molecular cloning of the cDNA for a human amyloid precursor protein homolog: evidence for a multigene family, Biochemistry 32) [17], Seite 4481-6. Steiner, H.; Duff, K.; Capell, A.; Romig, H.; Grim, M. G.; Lincoln, S.; Hardy, J.; Yu, X.; Picciano, M.; Fechteler, K.; Citron, M.; Kopan, R.; Pesold, B.; Keck, S.; Baader, M.; Tomita, T.; Iwatsubo, T.; Baumeister, R. und Haass, C. (1999): A loss of function mutation of presenilin-2 interferes with amyloid beta-peptide production and notch signaling, J Biol Chem 274) [40], Seite 28669-73.. Steiner, H.; Kostka, M.; Romig, H.; Basset, G.; Pesold, B.; Hardy, J.; Capell, A.; Meyn, L.; Grim, M.G.; Baumeister, R.; Fechteler, K. und Haass, C. (2000): Glycine 384 is required for presenilin-1 function and is conserved in polytopic bacterial aspartyl proteases, Nat. Cell Biol. 2), Seite 848-51. Steiner, H.; Romig, H.; Grim, M. G.; Philipp, U.; Pesold, B.; Citron, M.; Baumeister, R. und Haass, C. (1999): The biological and pathological function of the presenilin-1 Deltaexon 9 mutation is independent of its defect to undergo proteolytic processing, J Biol Chem 274) [12], Seite 7615-8.. Steiner, H.; Romig, H.; Pesold, B.; Philipp, U.; Baader, M.; Citron, M.; Loetscher, H.; Jacobsen, H. und Haass, C. (1999): Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis, Biochemistry 38) [44], Seite 14600-5.. Steiner, H.; Winkler, E.; Edbauer, D.; Prokop, S.; Basset, G.; Yamasaki, A.; Kostka, M. und Haass, C. (2002): PEN-2 is an integral component of the gamma -secretase complex required for coordinated expression of presenilin and nicastrin, J Biol Chem 277) [42], Seite 39062-65. Steinhilb, M. L.; Turner, R. S. und Gaut, J. R. (2002): ELISA analysis of beta-secretase cleavage of the Swedish amyloid precursor protein in the secretory and endocytic pathways, J Neurochem 80) [6], Seite 1019-28. Storey, E.; Beyreuther, K. und Masters, C. L. (1996): Alzheimer's disease amyloid precursor protein on the surface of cortical neurons in primary culture co-localizes with adhesion patch components, Brain Res 735) [2], Seite 217-31. Strittmatter, W. J.; Saunders, A. M.; Schmechel, D.; Pericak-Vance, M.; Enghild, J.; Salvesen, G. S. und Roses, A. D. (1993): Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease, Proc Natl Acad Sci U S A 90) [5], Seite 1977-81. Struhl, G. und Adachi, A. (2000): Requirements for presenilin-dependent cleavage of Notch and other transmembrane proteins, Mol. Cell 6), Seite 625-636. Suzuki, N.; Cheung, T. T.; Cai, X. D.; Odaka, A.; Otvos, L., Jr.; Eckman, C.; Golde, T. E. und Younkin, S. G. (1994): An increased percentage of long amyloid b-protein secreted by familial amyloid b-protein precursor (bAPP717) mutants, Science 264) [5163], Seite 1336-40. Sze, C. I.; Bi, H.; Kleinschmidt-DeMasters, B. K.; Filley, C. M. und Martin, L. J. (2000): Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer's disease brains, J Neurol Sci 175) [2], Seite 81-90. Takasugi, N.; Tomita, T.; Hayashi, I.; Tsuruoka, M.; Niimura, M.; Takahashi, Y.; Thinakaran, G. und Iwatsubo, T. (2003): The role of presenilin cofactors in the gamma-secretase complex, Nature 422) [6930], Seite 438-41. Tang, J. und Wong, R. N. (1987): Evolution in the structure and function of aspartic proteases, J Cell Biochem 33) [1], Seite 53-63. Tang, M. X.; Cross, P.; Andrews, H.; Jacobs, D. M.; Small, S.; Bell, K.; Merchant, C.; Lantigua, R.; Costa, R.; Stern, Y. und Mayeux, R. (2001): Incidence of AD in African-Americans, Caribbean Hispanics, and Caucasians in northern Manhattan, Neurology 56) [1], Seite 49-56. Tanzi, R. E.; Gusella, J. F.; Watkins, P. C.; Bruns, G. A.; St George-Hyslop, P.; Van Keuren, M. L.; Patterson, D.; Pagan, S.; Kurnit, D. M. und Neve, R. L. (1987): Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus, Science 235) [4791], Seite 880-4. Tanzi, R. E.; McClatchey, A. I.; Lamperti, E. D.; Villa-Komaroff, L.; Gusella, J. F. und Neve, R. L. (1988): Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease, Nature 331) [6156], Seite 528-30.. Tarentino, A. L.; Gomez, C. M. und Plummer, T. H., Jr. (1985): Deglycosylation of asparagine-linked glycans by peptide:N-glycosidase F, Biochemistry 24) [17], Seite 4665-71.. Tarentino, A. L. und Maley, F. (1974): Purification and properties of an endo-beta-N-acetylglucosaminidase from Streptomyces griseus, J Biol Chem 249) [3], Seite 811-7.. Terry, R. D.; Gonatas, N. K. und Weiss, M. (1964): The ultrastructure of the cerebral cortex in Alzheimer's disease, Trans Am Neurol Assoc 89), Seite 12. Thinakaran, G.; Borchelt, D. R.; Lee, M. K.; Slunt, H. H.; Spitzer, L.; Kim, G.; Ratovitsky, T.; Davenport, F.; Nordstedt, C.; Seeger, M.; Hardy, J.; Levey, A. I.; Gandy, S. E.; Jenkins, N. A.; Copeland, N. G.; Price, D. L. und Sisodia, S. S. (1996): Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo, Neuron 17) [1], Seite 181-90. Thinakaran, G.; Harris, C. L.; Ratovitski, T.; Davenport, F.; Slunt, H. H.; Price, D. L.; Borchelt, D. R. und Sisodia, S. S. (1997): Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors, J. Biol. Chem. 272) [45], Seite 28415-22. Thinakaran, G.; Teplow, D. B.; Siman, R.; Greenberg, B. und 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) [16], Seite 9390-7. Thomas, G. (2002): Furin at the cutting edge: from protein traffic to embryogenesis and disease, Nat Rev Mol Cell Biol 3) [10], Seite 753-66. Thorsett, E. D. und Latimer, L. H. (2000): Therapeutic approaches to Alzheimer's disease, Curr Opin Chem Biol 4) [4], Seite 377-82. Tienari, P. J.; De Strooper, B.; Ikonen, E.; Simons, M.; Weidemann, A.; Czech, C.; Hartmann, T.; Ida, N.; Multhaup, G.; Masters, C. L.; Van Leuven, F.; Beyreuther, K. und Dotti, C. G. (1996): The beta-amyloid domain is essential for axonal sorting of amyloid precursor protein, Embo J 15) [19], Seite 5218-29. Tilley, L.; Morgan, K. und Kalsheker, N. (1998): Genetic risk factors in Alzheimer's disease, Mol Pathol 51) [6], Seite 293-304. Toulokhonova, Larisa; Metzler, William J.; Witmer, Mark R.; Copeland, Robert A. und Marcinkeviciene, Jovita (2003): Kinetic Studies on beta -Site Amyloid Precursor Protein-cleaving Enzyme (BACE). CONFIRMATION OF AN ISO-MECHANISM, J. Biol. Chem. 278) [7], Seite 4582-4589. Tsai, B.; Ye, Y. und Rapoport, T. A. (2002): Retro-translocation of proteins from the endoplasmic reticulum into the cytosol, Nat Rev Mol Cell Biol 3) [4], Seite 246-55. Vassar, R. (2002): beta-Secretase (BACE) as a drug target for alzheimer's disease, Adv Drug Deliv Rev 54) [12], Seite 1589-602. Vassar, R.; Bennett, B. D.; Babu-Khan, S.; Kahn, S.; Mendiaz, E. A.; Denis, P.; Teplow, D. B.; Ross, S.; Amarante, P.; Loeloff, R.; Luo, Y.; Fisher, S.; Fuller, J.; Edenson, S.; Lile, J.; Jarosinski, M. A.; Biere, A. L.; Curran, E.; Burgess, T.; Louis, J. C.; Collins, F.; Treanor, J.; Rogers, G. und Citron, M. (1999): Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE, Science 286) [5440], Seite 735-41.. Verkade, P.; Harder, T.; Lafont, F. und Simons, K. (2000): Induction of caveolae in the apical plasma membrane of Madin-Darby canine kidney cells, J Cell Biol 148) [4], Seite 727-39. Vetrivel, K. S.; Cheng, H.; Lin, W.; Sakurai, T.; Li, T.; Nukina, N.; Wong, P. C.; Xu, H. und Thinakaran, G. (2004): Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes, J Biol Chem 279) [43], Seite 44945-54. Vey, M; Schafer, W; Berghofer, S; Klenk, HD und Garten, W (1994): Maturation of the trans-Golgi network protease furin: compartmentalization of propeptide removal, substrate cleavage, and COOH-terminal truncation, J. Cell Biol. 127) [6], Seite 1829-1842. von Arnim, C. A.; Tangredi, M. M.; Peltan, I. D.; Lee, B. M.; Irizarry, M. C.; Kinoshita, A. und Hyman, B. T. (2004): Demonstration of BACE (beta-secretase) phosphorylation and its interaction with GGA1 in cells by fluorescence-lifetime imaging microscopy, J Cell Sci 117) [Pt 22], Seite 5437-45. von Koch, C. S.; Zheng, H.; Chen, H.; Trumbauer, M.; Thinakaran, G.; van der Ploeg, L. H.; Price, D. L. und Sisodia, S. S. (1997): Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice, Neurobiol Aging 18) [6], Seite 661-9. Walsh, D. M.; Fadeeva, J. V.; LaVoie, M. J.; Paliga, K.; Eggert, S.; Kimberly, W. T.; Wasco, W. und Selkoe, D. J. (2003): gamma-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteins, Biochemistry 42) [22], Seite 6664-73. Walsh, D. M.; Klyubin, I.; Fadeeva, J. V.; Cullen, W. K.; Anwyl, R.; Wolfe, M. S.; Rowan, M. J. und Selkoe, D. J. (2002): Naturally secreted oligomers of amyloid b protein potently inhibit hippocampal long-term potentiation , Nature 416) [6880], Seite 535-9.. Walter, J.; Capell, A.; Hung, A. Y.; Langen, H.; Schnolzer, M.; Thinakaran, G.; Sisodia, S. S.; Selkoe, D. J. und Haass, C. (1997): Ectodomain phosphorylation of beta-amyloid precursor protein at two distinct cellular locations, J Biol Chem 272) [3], Seite 1896-903. Walter, J.; Fluhrer, R.; Hartung, B.; Willem, M.; Kaether, C.; Capell, A.; Lammich, S.; Multhaup, G. und Haass, C. (2001): Phosphorylation regulates intracellular trafficking of beta-secretase, J Biol Chem 276) [18], Seite 14634-41.. Walter, J.; Schindzielorz, A.; Hartung, B. und Haass, C. (2000): Phosphorylation of the beta-amyloid precursor protein at the cell surface by ectocasein kinases 1 and 2, J Biol Chem 275) [31], Seite 23523-9.. Wang, J.; Dickson, D. W.; Trojanowski, J. Q. und Lee, V. M. (1999): The levels of soluble versus insoluble brain Abeta distinguish Alzheimer's disease from normal and pathologic aging, Exp Neurol 158) [2], Seite 328-37. Wang, R.; Sweeney, D.; Gandy, S. E. und Sisodia, S. S. (1996): The profile of soluble amyloid beta protein in cultured cell media. Detection and quantification of amyloid beta protein and variants by immunoprecipitation-mass spectrometry, J Biol Chem 271) [50], Seite 31894-902.. Wang, Y.; Haughey, N. J.; Mattson, M. P. und Furukawa, K. (2004): Dual effects of ATP on rat hippocampal synaptic plasticity, Neuroreport 15) [4], Seite 633-6. Wasco, W.; Bupp, K.; Magendantz, M.; Gusella, J. F.; Tanzi, R. E. und Solomon, F. (1992): Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursor, Proc Natl Acad Sci U S A 89) [22], Seite 10758-62. Wasco, W.; Gurubhagavatula, S.; Paradis, M. D.; Romano, D. M.; Sisodia, S. S.; Hyman, B. T.; Neve, R. L. und Tanzi, R. E. (1993): Isolation and characterization of APLP2 encoding a homologue of the Alzheimer's associated amyloid beta protein precursor, Nat Genet 5) [1], Seite 95-100. Weidemann, A.; Eggert, S.; Reinhard, F. B.; Vogel, M.; Paliga, K.; Baier, G.; Masters, C. L.; Beyreuther, K. und Evin, G. (2002): A novel e-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing, Biochemistry 41) [8], Seite 2825-35. Weidemann, A.; Konig, G.; Bunke, D.; Fischer, P.; Salbaum, J. M.; Masters, C. L. und Beyreuther, K. (1989): Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein, Cell 57) [1], Seite 115-26. Weihofen, A.; Binns, K.; Lemberg, M. K.; Ashman, K. und Martoglio, B. (2002): Identification of signal peptide peptidase, a presenilin-type aspartic protease, Science 296) [5576], Seite 2215-8. Weihofen, A. und Martoglio, B. (2003): Intramembrane-cleaving proteases: controlled liberation of proteins and bioactive peptides, Trends Cell Biol 13) [2], Seite 71-8.. Wertkin, A. M.; Turner, R. S.; Pleasure, S. J.; Golde, T. E.; Younkin, S. G.; Trojanowski, J. Q. und Lee, V. M. (1993): Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides, Proc Natl Acad Sci U S A 90) [20], Seite 9513-7. Wilcheck M. und Bayer E.A. (1990): Avidin-biotin technology, Methods in Enzymology 184). Wild-Bode, C.; Yamazaki, T.; Capell, A.; Leimer, U.; Steiner, H.; Ihara, Y. und Haass, C. (1997): Intracellular generation and accumulation of amyloid b-peptide terminating at amino acid 42, J. Biol. Chem. 272) [26], Seite 16085-8. Winckler, B. und Mellman, I. (1999): Neuronal polarity: controlling the sorting and diffusion of membrane components, Neuron 23) [4], Seite 637-40. Wolfe, M. S.; Xia, W.; Moore, C. L.; Leatherwood, D. D.; Ostaszewski, B.; Rahmati, T.; Donkor, I. O. und Selkoe, D. J. (1999): Peptidomimetic probes and molecular modeling suggest that Alzheimer's g-secretase is an intramembrane-cleaving aspartyl protease, Biochemistry 38) [15], Seite 4720-7. Wolfe, M. S.; Xia, W.; Ostaszewski, B. L.; Diehl, T. S.; Kimberly, W. T. und Selkoe, D. J. (1999): Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and g-secretase activity, Nature 398) [6727], Seite 513-7. Wong, P. C.; Zheng, H.; Chen, H.; Becher, M. W.; Sirinathsinghji, D. J.; Trumbauer, M. E.; Chen, H. Y.; Price, D. L.; Van der Ploeg, L. H. und Sisodia, S. S. (1997): Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm, Nature 387) [6630], Seite 288-92. Xia, W.; Ray, W. J.; Ostaszewski, B. L.; Rahmati, T.; Kimberly, W. T.; Wolfe, M. S.; Zhang, J.; Goate, A. M. und Selkoe, D. J. (2000): Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid b-protein generation, Proc. Natl. Acad. Sci. USA 97), Seite 9299-9304. Xia, W. und Wolfe, M. S. (2003): Intramembrane proteolysis by presenilin and presenilin-like proteases, J Cell Sci 116) [Pt 14], Seite 2839-44. Yamaguchi, H.; Nakazato, Y.; Hirai, S.; Shoji, M. und Harigaya, Y. (1989): Electron micrograph of diffuse plaques. Initial stage of senile plaque formation in the Alzheimer brain, Am J Pathol 135) [4], Seite 593-7. Yamazaki, T.; Koo, E. H. und Selkoe, D. J. (1996): Trafficking of cell-surface amyloid beta-protein precursor. II. Endocytosis, recycling and lysosomal targeting detected by immunolocalization, J Cell Sci 109 ( Pt 5)), Seite 999-1008. Yamazaki, T.; Koo, E. H. und Selkoe, D. J. (1997): Cell surface amyloid beta-protein precursor colocalizes with beta 1 integrins at substrate contact sites in neural cells, J Neurosci 17) [3], Seite 1004-10. Yamazaki, T.; Selkoe, D. J. und Koo, E. H. (1995): Trafficking of cell surface beta-amyloid precursor protein: retrograde and transcytotic transport in cultured neurons, J Cell Biol 129) [2], Seite 431-42. Yan, R.; Bienkowski, M. J.; Shuck, M. E.; Miao, H.; Tory, M. C.; Pauley, A. M.; Brashier, J. R.; Stratman, N. C.; Mathews, W. R.; Buhl, A. E.; Carter, D. B.; Tomasselli, A. G.; Parodi, L. A.; Heinrikson, R. L. und Gurney, M. E. (1999): Membrane-anchored aspartyl protease with Alzheimer's disease b- secretase activity, Nature 402) [6761], Seite 533-7. Yan, R.; Han, P.; Miao, H.; Greengard, P. und Xu, H. (2001): The transmembrane domain of the Alzheimer's beta-secretase (BACE1) determines its late Golgi localization and access to beta -amyloid precursor protein (APP) substrate, J Biol Chem 276) [39], Seite 36788-96.. Yan, R.; Munzner, J. B.; Shuck, M. E. und Bienkowski, M. J. (2001): BACE2 functions as an alternative alpha-secretase in cells, J Biol Chem 276) [36], Seite 34019-27.. Yang, D. S.; Tandon, A.; Chen, F.; Yu, G.; Yu, H.; Arawaka, S.; Hasegawa, H.; Duthie, M.; Schmidt, S. D.; Ramabhadran, T. V.; Nixon, R. A.; Mathews, P. M.; Gandy, S. E.; Mount, H. T.; St George-Hyslop, P. und Fraser, P. E. (2002): Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins, J Biol Chem 277) [31], Seite 28135-42. Yang, J. M.; Lee, J.; Southern, J. F.; Warshaw, A. L.; Dhanak, E. und Lewandrowski, K. B. (1998): Measurement of pS2 protein in pancreatic cyst fluids. Evidence for a potential role of pS2 protein in the pathogenesis of mucinous cystic tumors, Int J Pancreatol 24) [3], Seite 181-6. Yang, L. B.; Lindholm, K.; Yan, R.; Citron, M.; Xia, W.; Yang, X. L.; Beach, T.; Sue, L.; Wong, P.; Price, D.; Li, R. und Shen, Y. (2003): Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease, Nat Med 9) [1], Seite 3-4. Yankner, B. A. (1996): Mechanisms of neuronal degeneration in Alzheimer's disease, Neuron 16) [5], Seite 921-32.. Yao, P. J. (2004): Synaptic frailty and clathrin-mediated synaptic vesicle trafficking in Alzheimer's disease, Trends Neurosci 27) [1], Seite 24-9. Younkin, S. G. (1998): The role of A beta 42 in Alzheimer's disease, J Physiol Paris 92) [3-4], Seite 289-92. Yu, C.; Kim, S. H.; Ikeuchi, T.; Xu, H.; Gasparini, L.; Wang, R. und Sisodia, S. S. (2001): Characterization of a presenilin-mediated APP carboxyl terminal fragment CTFg: evidence for distinct mechanisms involved in g-secretase processing of the APP and Notch1 transmembrane domains, J. Biol. Chem. 276), Seite 43756-43760. Yu, G.; Chen, F.; Levesque, G.; Nishimura, M.; Zhang, D. M.; Levesque, L.; Rogaeva, E.; Xu, D.; Liang, Y.; Duthie, M.; St George-Hyslop, P. H. und Fraser, P. E. (1998): The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains b-catenin, J. Biol. Chem. 273) [26], Seite 16470-5. Yu, G.; Nishimura, M.; Arawaka, S.; Levitan, D.; Zhang, L.; Tandon, A.; Song, Y. Q.; Rogaeva, E.; Chen, F.; Kawarai, T.; Supala, A.; Levesque, L.; Yu, H.; Yang, D. S.; Holmes, E.; Milman, P.; Liang, Y.; Zhang, D. M.; Xu, D. H.; Sato, C.; Rogaev, E.; Smith, M.; Janus, C.; Zhang, Y.; Aebersold, R.; Farrer, L. S.; Sorbi, S.; Bruni, A.; Fraser, P. und St George-Hyslop, P. (2000): Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and bAPP processing, Nature 407) [6800], Seite 48-54. Zhang, Z.; Nadeau, P.; Song, W.; Donoviel, D.; Yuan, M.; Bernstein, A. und Yankner, B. A. (2000): Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1, Nat Cell Biol 2) [7], Seite 463-5. Zheng, H.; Jiang, M.; Trumbauer, M. E.; Sirinathsinghji, D. J.; Hopkins, R.; Smith, D. W.; Heavens, R. P.; Dawson, G. R.; Boyce, S.; Conner, M. W. und et al. (1995): beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity, Cell 81) [4], Seite 525-31. Zhou, C.; Yang, Y. und Jong, A. Y. (1990): Mini-prep in ten minutes, Biotechniques 8) [2], Seite 172-3.