QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, January 12, 2005, 25(2):436-445; doi:10.1523/JNEUROSCI.1575-04.2005

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (75) Citing Articles via Google Scholar Google Scholar Articles by Qi-Takahara, Y. Articles by Ihara, Y. Search for Related Content PubMed PubMed Citation Articles by Qi-Takahara, Y. Articles by Ihara, Y.

 Previous Article  |  Next Article 

Neurobiology of Disease
Longer Forms of Amyloid Protein: Implications for the Mechanism of Intramembrane Cleavage by -Secretase

Yue Qi-Takahara,¹ Maho Morishima-Kawashima,¹ Yu Tanimura,¹ Georgia Dolios,² Naoko Hirotani,³ Yuko Horikoshi,⁵ Fuyuki Kametani,⁶ Masahiro Maeda,⁵ Takaomi C. Saido,⁴ Rong Wang,² and Yasuo Ihara¹

¹Department of Neuropathology, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan, ²Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029-6574, ³Resources Center and ⁴Laboratory for Proteolytic Neuroscience, Brain Science Institute, RIKEN, Saitama 351-0198, Japan, ⁵Immuno-Biological Laboratories Company, Ltd., Gunma 375-0005, Japan, and ⁶Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo 156-8585, Japan

-Cleavage of -amyloid precursor protein (APP) in the middle of the cell membrane generates amyloid protein (A), and -cleavage, 10 residues downstream of the -cleavage site, releases the APP intracellular domain (AICD). A significant link between generation of A and AICD and failure to detect AICD41-99 led us to hypothesize that -cleavage generates longer As, which are then processed to A40/42. Using newly developed gel systems and an N-end-specific monoclonal antibody, we have identified the longer As (A1-43, A1-45, A1-46, and A1-48) within the cells and in brain tissues. The production of these longer As as well as A40/42 is presenilin dependent and is suppressed by {1S-benzyl-4R-[1S-carbamoyl-2-phenylethylcarbamoyl-1S-3-methylbutylcarbamoyl]-2R-hydroxy-5-phenylpentyl}carbamic acid tert-butyl ester, a transition state analog inhibitor for aspartyl protease. In contrast, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, a potent dipeptide -secretase inhibitor, builds up A1-43 and A1-46 intracellularly, which was also confirmed by mass spectrometry. Notably, suppression of A40 appeared to lead to an increase in A43, which in turn brings an increase in A46, in a dose-dependent manner. We therefore propose an -helical model in which longer A species generated by -cleavage is cleaved at every three residues in its carboxyl portion.

Key words: amyloid -protein; APP; -secretase; intramembrane cleavage; presenilin; Alzheimer's disease

---

Received April 25, 2004; revised November 26, 2004; accepted November 29, 2004.

This article has been cited by other articles:

				D. R. Dries, S. Shah, Y.-H. Han, C. Yu, S. Yu, M. S. Shearman, and G. Yu Glu-333 of Nicastrin Directly Participates in {gamma}-Secretase Activity J. Biol. Chem., October 23, 2009; 284(43): 29714 - 29724. [Abstract] [Full Text] [PDF]

				S. Eggert, B. Midthune, B. Cottrell, and E. H. Koo Induced Dimerization of the Amyloid Precursor Protein Leads to Decreased Amyloid-{beta} Protein Production J. Biol. Chem., October 16, 2009; 284(42): 28943 - 28952. [Abstract] [Full Text] [PDF]

				R. Pardossi-Piquard, C. Bohm, F. Chen, S. Kanemoto, F. Checler, G. Schmitt-Ulms, P. St. George-Hyslop, and P. E. Fraser TMP21 Transmembrane Domain Regulates {gamma}-Secretase Cleavage J. Biol. Chem., October 16, 2009; 284(42): 28634 - 28641. [Abstract] [Full Text] [PDF]

				M. Takami, Y. Nagashima, Y. Sano, S. Ishihara, M. Morishima-Kawashima, S. Funamoto, and Y. Ihara {gamma}-Secretase: Successive Tripeptide and Tetrapeptide Release from the Transmembrane Domain of {beta}-Carboxyl Terminal Fragment J. Neurosci., October 14, 2009; 29(41): 13042 - 13052. [Abstract] [Full Text] [PDF]

				A. Harmeier, C. Wozny, B. R. Rost, L.-M. Munter, H. Hua, O. Georgiev, M. Beyermann, P. W. Hildebrand, C. Weise, W. Schaffner, et al. Role of Amyloid-{beta} Glycine 33 in Oligomerization, Toxicity, and Neuronal Plasticity J. Neurosci., June 10, 2009; 29(23): 7582 - 7590. [Abstract] [Full Text] [PDF]

				T. Sato, T.-c. Tang, G. Reubins, J. Z. Fei, T. Fujimoto, P. Kienlen-Campard, S. N. Constantinescu, J.-N. Octave, S. Aimoto, and S. O. Smith A helix-to-coil transition at the {varepsilon}-cut site in the transmembrane dimer of the amyloid precursor protein is required for proteolysis PNAS, February 3, 2009; 106(5): 1421 - 1426. [Abstract] [Full Text] [PDF]

				H. Steiner, E. Winkler, and C. Haass Chemical Cross-linking Provides a Model of the {gamma}-Secretase Complex Subunit Architecture and Evidence for Close Proximity of the C-terminal Fragment of Presenilin with APH-1 J. Biol. Chem., December 12, 2008; 283(50): 34677 - 34686. [Abstract] [Full Text] [PDF]

				T. Suzuki and T. Nakaya Regulation of Amyloid {beta}-Protein Precursor by Phosphorylation and Protein Interactions J. Biol. Chem., October 31, 2008; 283(44): 29633 - 29637. [Abstract] [Full Text] [PDF]

				H. Steiner, R. Fluhrer, and C. Haass Intramembrane Proteolysis by {gamma}-Secretase J. Biol. Chem., October 31, 2008; 283(44): 29627 - 29631. [Abstract] [Full Text] [PDF]

				R. Fluhrer, A. Fukumori, L. Martin, G. Grammer, M. Haug-Kroper, B. Klier, E. Winkler, E. Kremmer, M. M. Condron, D. B. Teplow, et al. Intramembrane Proteolysis of GXGD-type Aspartyl Proteases Is Slowed by a Familial Alzheimer Disease-like Mutation J. Biol. Chem., October 31, 2008; 283(44): 30121 - 30128. [Abstract] [Full Text] [PDF]

				C. R. Burton, J. E. Meredith, D. M. Barten, M. E. Goldstein, C. M. Krause, C. J. Kieras, L. Sisk, L. G. Iben, C. Polson, M. W. Thompson, et al. The Amyloid-{beta} Rise and {gamma}-Secretase Inhibitor Potency Depend on the Level of Substrate Expression J. Biol. Chem., August 22, 2008; 283(34): 22992 - 23003. [Abstract] [Full Text] [PDF]

				S. Osawa, S. Funamoto, M. Nobuhara, S. Wada-Kakuda, M. Shimojo, S. Yagishita, and Y. Ihara Phosphoinositides Suppress {gamma}-Secretase in Both the Detergent-soluble and -insoluble States J. Biol. Chem., July 11, 2008; 283(28): 19283 - 19292. [Abstract] [Full Text] [PDF]

				A. Tolia, K. Horre, and B. De Strooper Transmembrane Domain 9 of Presenilin Determines the Dynamic Conformation of the Catalytic Site of {gamma}-Secretase J. Biol. Chem., July 11, 2008; 283(28): 19793 - 19803. [Abstract] [Full Text] [PDF]

				E. Czirr, B. A. Cottrell, S. Leuchtenberger, T. Kukar, T. B. Ladd, H. Esselmann, S. Paul, R. Schubenel, J. W. Torpey, C. U. Pietrzik, et al. Independent Generation of A{beta}42 and A{beta}38 Peptide Species by {gamma}-Secretase J. Biol. Chem., June 20, 2008; 283(25): 17049 - 17054. [Abstract] [Full Text] [PDF]

				M. Shimojo, N. Sahara, T. Mizoroki, S. Funamoto, M. Morishima-Kawashima, T. Kudo, M. Takeda, Y. Ihara, H. Ichinose, and A. Takashima Enzymatic Characteristics of I213T Mutant Presenilin-1/{gamma}-Secretase in Cell Models and Knock-in Mouse Brains: FAMILIAL ALZHEIMER DISEASE-LINKED MUTATION IMPAIRS {gamma}-SITE CLEAVAGE OF AMYLOID PRECURSOR PROTEIN C-TERMINAL FRAGMENT {beta} J. Biol. Chem., June 13, 2008; 283(24): 16488 - 16496. [Abstract] [Full Text] [PDF]

				S. Yagishita, M. Morishima-Kawashima, S. Ishiura, and Y. Ihara A 46 Is Processed to A 40 and A 43, but Not to A 42, in the Low Density Membrane Domains J. Biol. Chem., January 11, 2008; 283(2): 733 - 738. [Abstract] [Full Text] [PDF]

				S. Tagami, M. Okochi, K. Yanagida, A. Ikuta, A. Fukumori, N. Matsumoto, Y. Ishizuka-Katsura, T. Nakayama, N. Itoh, J. Jiang, et al. Regulation of Notch Signaling by Dynamic Changes in the Precision of S3 Cleavage of Notch-1 Mol. Cell. Biol., January 1, 2008; 28(1): 165 - 176. [Abstract] [Full Text] [PDF]

				L. G. Iben, R. E. Olson, L. A. Balanda, S. Jayachandra, B. J. Robertson, V. Hay, J. Corradi, C. V. C. Prasad, R. Zaczek, C. F. Albright, et al. Signal Peptide Peptidase and {gamma}-Secretase Share Equivalent Inhibitor Binding Pharmacology J. Biol. Chem., December 21, 2007; 282(51): 36829 - 36836. [Abstract] [Full Text] [PDF]

				Z. Ren, D. Schenk, G. S. Basi, and I. P. Shapiro Amyloid -Protein Precursor Juxtamembrane Domain Regulates Specificity of {gamma}-Secretase-dependent Cleavages J. Biol. Chem., November 30, 2007; 282(48): 35350 - 35360. [Abstract] [Full Text] [PDF]

				M. E. Goldstein, Y. Cao, T. Fiedler, J. Toyn, L. Iben, D. M. Barten, M. Pierdomenico, J. Corsa, C. V. C. Prasad, R. E. Olson, et al. Ex Vivo Occupancy of {gamma}-Secretase Inhibitors Correlates with Brain beta-Amyloid Peptide Reduction in Tg2576 Mice J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 102 - 108. [Abstract] [Full Text] [PDF]

				K. Zou, H. Yamaguchi, H. Akatsu, T. Sakamoto, M. Ko, K. Mizoguchi, J.-S. Gong, W. Yu, T. Yamamoto, K. Kosaka, et al. Angiotensin-Converting Enzyme Converts Amyloid {beta}-Protein 1 42 (A{beta}1 42) to A{beta}1 40, and Its Inhibition Enhances Brain A{beta} Deposition J. Neurosci., August 8, 2007; 27(32): 8628 - 8635. [Abstract] [Full Text] [PDF]

				P. Du, K. M. Wood, M. H. Rosner, D. Cunningham, B. Tate, and K. F. Geoghegan Dominance of Amyloid Precursor Protein Sequence over Host Cell Secretases in Determining beta-Amyloid Profiles Studies of Interspecies Variation and Drug Action by Internally Standardized Immunoprecipitation/Mass Spectrometry J. Pharmacol. Exp. Ther., March 1, 2007; 320(3): 1144 - 1152. [Abstract] [Full Text] [PDF]

				T. A. Lanz, M. J. Karmilowicz, K. M. Wood, N. Pozdnyakov, P. Du, M. A. Piotrowski, T. M. Brown, C. E. Nolan, K. E. G. Richter, J. E. Finley, et al. Concentration-Dependent Modulation of Amyloid-beta in Vivo and in Vitro Using the {gamma}-Secretase Inhibitor, LY-450139 J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 924 - 933. [Abstract] [Full Text] [PDF]

				Y. Morohashi, T. Kan, Y. Tominari, H. Fuwa, Y. Okamura, N. Watanabe, C. Sato, H. Natsugari, T. Fukuyama, T. Iwatsubo, et al. C-terminal Fragment of Presenilin Is the Molecular Target of a Dipeptidic {gamma}-Secretase-specific Inhibitor DAPT (N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-Butyl Ester) J. Biol. Chem., May 26, 2006; 281(21): 14670 - 14676. [Abstract] [Full Text] [PDF]

				N. Kakuda, S. Funamoto, S. Yagishita, M. Takami, S. Osawa, N. Dohmae, and Y. Ihara Equimolar Production of Amyloid beta-Protein and Amyloid Precursor Protein Intracellular Domain from beta-Carboxyl-terminal Fragment by {gamma}-Secretase J. Biol. Chem., May 26, 2006; 281(21): 14776 - 14786. [Abstract] [Full Text] [PDF]

				G. Zhao, M.-Z. Cui, G. Mao, Y. Dong, J. Tan, L. Sun, and X. Xu {gamma}-Cleavage Is Dependent on {zeta}-Cleavage during the Proteolytic Processing of Amyloid Precursor Protein within Its Transmembrane Domain J. Biol. Chem., November 11, 2005; 280(45): 37689 - 37697. [Abstract] [Full Text] [PDF]

				D. Dominguez, J. Tournoy, D. Hartmann, T. Huth, K. Cryns, S. Deforce, L. Serneels, I. E. Camacho, E. Marjaux, K. Craessaerts, et al. Phenotypic and Biochemical Analyses of BACE1- and BACE2-deficient Mice J. Biol. Chem., September 2, 2005; 280(35): 30797 - 30806. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help