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1 pp. β AD β Aβ Aβ AD AD Aβ AD Aβ Aβ AD Aβ AD AD AD AD NMDA N - -D- AD Amyloidogenicity and pathogenicity of Aβ in Alzheimer s disease Takashi Saito Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Hirosawa, Wako-shi, Saitama, Japan AD AD AD β Aβ Aβ AD Aβ AD AD Aβ APP APP Aβ γ- Aβ AD Aβ

2 Aβ APP β- γ- A Aβ Aβ Aβ Aβ AD Aβ Aβ Aβ AD Aβ Aβ C longer Aβ Aβ Aβ B longer Aβ longer Aβ γ- Aβ Aβ longer Aβ Aβ Aβ AβAD Aβ Aβ γ- Aβ Aβ C γ- - PS AD Aβ A Aβ β- γ- APP Aβ B Aβ Aβ longer Aβ Aβ Aβ PS -R I Aβ Aβ

AD AD Aβ Aβ Aβ P One-way ANOVA Scheffe s Fμm PS Aβ Aβ Aβ Aβ Aβ PS -R I Aβ AD

-KO Notch B PS -R I KI PS - R I KI R I wt Aβ Aβ Aβ C PS -R I KI Aβ Aβ D Aβ

Aβ PS - R I KI MEF in vitro PS -R I KI MEF Aβ in vivo R I wt Aβ R I R I Aβ

3 AD AD Aβ Aβ Aβ P One-way ANOVA Scheffe s Fμm PS Aβ Aβ Aβ Aβ Aβ PS -R I Aβ AD Aβ in vivo Aβ PS - R I KI PS PS -R I KI R I R IA PS KO Notch PS -R I KI PS -KO Notch B PS -R I KI PS - R I KI R I wt Aβ Aβ Aβ C PS -R I KI Aβ Aβ D Aβ Aβ in vivo Aβ PS -R I Aβ Aβ C γ- Aβ Aβ Aβ Aβ Aβ Aβ Aβ Aβ B Aβ γ- PS -R I KI Aβ PS - R I KI MEF in vitro PS -R I KI MEF Aβ in vivo R I wt Aβ R I R I Aβ Aβ A PS -R I PS -KO R I KO MEF Aβ R I wt PS Aβ Aβ PS -R I Aβ PS - R I Aβ Aβ Aβ Aβ

4 PS -R I KI A PS -R I KI R I R I E mm B Notch PS -R I PS -R I KI PS -KO MEF Notch R I R I PS -KO Notch NICD C D PS -R I KI PS -R I wt Aβ C Aβ Aβ P Student-t D Aβ Aβ P Student-t Aβ B PS -R I KI Aβ Aβ PS PS -R I Aβ PS Aβ Aβ PS

5 APP APP Tg APP Tg PS -R I KI APP Tg A B PS -R I KI APP Tg Aβ APP Tg PS -R I KI APP Tg Aβ B C Aβ Aβ APP Tg PS -R I KI D PS -R I APP Tg Aβ Aβ PS -R I Aβ A PS -R I KI PS -R I PS -KO MEF Aβ PS -R I KI R I R I PS -R I KI PS -KO R I KO Aβ P One-way ANOVA, Scheffe s F B PS -R I Aβ PS -R I PS -R I KI MEF APP Aβ PS -R I in vivo Aβ AD AD Aβ Aβ Aβ Aβ μm Aβ Aβ A T Aβ B Aβ Aβ C APP Tg PS -R I KI Aβ D AD Aβ E APP Tg Aβ APP Tg Aβ Aβ AD Aβ AD AD Aβ Aβ Aβ Aβ Aβ Aβ Aβ

6 APP Tg PS -R I A Aβ APP Tg PS - R I KI APP Tg μm B C APP Tg APP Tg PS -R I KI Aβ P Student-t APP Tg PS -R I KI Aβ APP Tg B APP Tg PS -R I KI APP Tg APP Tg Aβ C D Y APP Tg PS -R I KI P One-way ANOVA Scheffe s F

7 β μ β β β β β μ β β β μ μ β μ β β β β β μ β β β μ

8 APP Tg Aβ A APP Tg Aβ TS GuHCl Aβ B APP Tg Aβ Aβ Aβ Aβ AD PS AD Aβ Aβ AD PS Aβ PS -R I PS Aβ Aβ A C AD Aβ Aβ Aβ B D Aβ Aβ Aβ C D Aβ AD AD Aβ Aβ

9 AD Aβ PS Aβ A C Aβ AD B D Aβ PS Aβ Aβ Christine Van Broeckhoven John Q. Trojanowski Virginia M.-Y. Lee University College London Martin N. Rossor Raphael Kopan Blennow, K., de Leon, M.J., & Zetterberg, H. Lancet,,. Qi-Takahara, Y., Morishima-Kawashima, M., Tanimura, Y., Dolios, G., Hirotani, N., Horikoshi, Y., Kametani, F., Maeda, M., Saido, T.C., Wang, R., & Ihara, Y. J. Neurosci.,,. Takami, M., Nagashima, Y., Sano, Y., Ishihara, S., Morishima- Kawashima,M.,Funamoto,S.,&Ihara,Y. J. Neurosci.,,. Miravalle, L., Calero, M., Takao, M., Roher, A.E., Ghetti, B., &Vidal,R. Biochemistry,,. Van Vickle, G.D., Esh, C.L., Kalback, W.M., Patton, R.L., Luehrs, D.C., Kokjohn, T.A., Fifield, F.G., Fraser, P.E., Westaway, D., McLaurin, J., Lopez, J., Brune, D., Newel, A.J., Poston, M., Beach, T.G., & Rpher, A.E. Biochemistry,,. Iizuka, T., Shoji, M., Harigaya, Y., Kawarabayashi, T., Watanabe, M., Kanai, M., & Hirai, S. Brain Res.,,. Parvathy, S., Davies, P., Haroutunian, V., Purohit, D.P., Mohs, R.C., Park, H., Moran, T.M., Chan, J.Y., & Buxbaum, J.D. Arch. Neurol.,,. Welander, H., Franberg, J., Graff, C., Sundstrom, E., Winblad, B.,&Tjernberg,L.O. J. Neurochem.,,. Keller, L., Welander, H., Chiang, H.H., Tjernberg, L.O., Nennesmo, I., Wallin, A.K., & Graff, C. Euro.J.Hum. Genet.,,. Saito, T., Suemoto, T., Brouwers, N., Sleegers, K., Funamoto, S., Mihira, N., Matsuba, Y., Yamada, K., Nilsson, P., Takano, J., Nishimura, M., Iwata, N., Van Broeckhoven, C., Ihara, Y., & Saido, T.C. Nat. Neurosci.,,. Nakaya, Y., Yamane, T., Shiraishi, H., Wang, H.Q., Matsubara, E., Sato, T., Dolios, G., Wang, R., De Strooper, B., Shoji, M., Komano, H., Yanagisawa, K., Ihara, Y., Fraser, P., St George- Hyslop, P., & Nishimura, M. J. Biol. Chem.,,. Shen, J., Bronson, R.T., Chen, D.F., Xia, W., Selkoe, D.J., & Tonegawa, S. Cell,,.

10 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., & Sisodia, S. Nature,,. Sturchler-Pierrat, C., Abramowski, D., Duke, M., Wiederhold, K.H., Misti, C., Rothacher, S., Ledermann, B., Burki, K., Frey, P., Paganetti, P.A., Waridel, C., Calhoun, M.E., Jucker, M., Probst, A., Staufenbiel, M., & Sommer, B. Proc. Natl. Acad. Sci. USA,,. Mouri, A., Noda, Y., Hara, H., Mizoguchi, H., Tabira, T., & Nabeshima, T. FASEB J.,,. Zou, K., Liu, J., Watanabe, A., Hiraga, S., Liu, S., Tanabe, C., Maeda, T., Terayama, Y., Takahashi, S., Michikawa, M., & Komano, H. Am. J. Pathol., in press. Kumar-Singh, S., Theuns, J., Van Broeck, B., Pirici, D., Vennekens, K., Corsmit, E., Cruts, M., Dermaut, B., Wang, R., Van Broeckhoven, C. Human Mutation,,. Zou, K., Liu, S., Liu, J., Tanabe, C., Maeda, T., Terayama, Y., Takahashi, S., & Komano, H. Trans. Medic.,,.