Analysis of presenilin gamma-secretase function on Abeta and NICD generation

• Project/Area Number: 23591703
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Osaka University
• Principal Investigator: TAGAMI Shinji 大阪大学, 医学(系)研究科(研究院), 助教 (40362735)
• Co-Investigator(Kenkyū-buntansha): OKOCHI Masayasu 大阪大学, 大学院医学系研究科, 講師 (90335357)
• Co-Investigator(Renkei-kenkyūsha): TAKEDA Masatoshi 大阪大学, 大学院医学系研究科, 教授 (00179649)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: アルツハイマー病 / アミロイドβ / γセクレターゼ / Notchシグナル / プレセニリン / Alzheimer disease / gamma secretase / amyloid beta / presenilin / Notch-1 / GSM / APLP1 / βAPP

Research Abstract

Amyloid beta42 is a highly aggregatable and pathogenic molecule which triggers Alzheimer disease. Amyloid beta42 is generated by gamma-secretase. In this study, we performed in vitro study in which purified gamma secretase and substrates including amyloid beta42 are mixed. We performed enzyme kinetics study and elucidated how amyloid beta is generated. We also analyzed how amyloid beta42 inhibiting compounds (gamma secretase modulators) function. We also investigated NICD generating process by gamma secretase.

Research Products

• [Journal Article] Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-βaccumulation modifier (2014)
  • Author(s): Morihara T, Hayashi N, Yokokoji M, Akatsu H, Silverman MA, Kimura N, Sato M, Saito Y, Suzuki T, Yanagida K, Kodama TS, Tanaka T, Okochi M, Tagami S, Kazui H, Kudo T, Hashimoto R, Itoh N, Nishitomi K, Yamaguchi-Kabata Y, Tsunoda T, Takamura H, Katayama T, Kimura R, Kamino K, Hashizume Y, Takeda M
  • Journal Title: Proc Natl Acad Sci U S A Volume: Vol.111 Pages: 2638-2643
• [Journal Article] γ-Secretase associated with lipid rafts : multiple interactive pathways in the stepwise processing ofβ-carboxyl-terminal fragment (2014)
  • Author(s): Matsumura N, Takami M, Okochi M, Wada-Kakuda S, Fujiwara H, Tagami S, Funamoto S, Ihara Y, Morishima-Kawashima M
  • Journal Title: J Biol Chem Volume: Vol.289 Pages: 5109-5121
• [Journal Article] Absolute Quantitation of Low Abundance Plasma APL1βpeptides at Sub-fmol/mL Level by SRM/MRM without Immunoaffinity Enrichment (2014)
  • Author(s): Sano S, Tagami S, Hashimoto Y, Yoshizawa-Kumagaye K, Tsunemi M, Okochi M, Tomonaga T
  • Journal Title: J Proteome Res Volume: Vol.13 Pages: 1012-1020
• [Journal Article] Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as as amyloid beta accumulation modifier (2014)
  • Author(s): Morihara, T., Hayashi, N., Yokokoji, M., Akatsu, H., Silverman, MA., Kimura, N., Saito, Y., Suzuki, T., Yanagida, K., Tanaka, T., Kazui, H., Kudo, T., Kodama, TS., Sato, M., Hashimoto, R., Tagami, S., Okochi, M., Ytoh, N., Nishitomi, K., Takamura, H., Katayama, T., Hashizumi, Y., Kimura, R., Kamino, K., Takeda, M
  • Journal Title: Proc. Acad. Natl. Sci. USA Volume: 111 Issue: 7 Pages: 2638-2643
  • DOI: 10.1073/pnas.1307345111
  • Peer Reviewed / Open Access
• [Journal Article] γ-Secretase associated with lipid rafts: multiple interactive pathways in the stepwise processing of β-carboxyl-terminal fragment. (2014)
  • Author(s): Matsumura N, Takami M, Okochi M, Wada-Kakuda S, Fujiwara H, Tagami S, Funamoto S, Ihara Y, Morishima-Kawashima M.
  • Journal Title: J Biol Chem. Volume: 289 Issue: 8 Pages: 51095121-51095121
  • DOI: 10.1074/jbc.m113.510131
  • Peer Reviewed
• [Journal Article] γ-Secretase Modulators and Presenilin 1 Mutants Act Differently on Presenilin/γ-Secretase Function to Cleave Aβ42 and Aβ43 (2013)
  • Author(s): Okochi M, Tagami S, Yanagida K, Takami M, Kodama TS, Mori K, Nakayama T, Ihara Y, Takeda M
  • Journal Title: Cell Reports Volume: Vol.3 Pages: 42-51
• [Journal Article] γ-Secretase Modulators and Presenilin 1 Mutants Act Differently on Presenilin/γ-Secretase Function to Cleave Aβ42 and Aβ43. (2013)
  • Author(s): Okochi M, Tagami S, Yanagida K, Takami M, Kodama TS, Mori K, Nakayama T, Ihara Y, Takeda M.
  • Journal Title: Cell Reports Volume: 3 Pages: 4251-4251
  • Peer Reviewed
• [Journal Article] Absolute Quantitation of Low Abundance Plasma APL1β peptides at Sub-fmol/mL Level by SRM/MRM without Immunoaffinity Enrichment. (2013)
  • Author(s): Sano S, Tagami S, Hashimoto Y, Yoshizawa-Kumagaye K, Tsunemi M, Okochi M, Tomonaga T.
  • Journal Title: J Proteome Res. Volume: 13 Issue: 2 Pages: 10121020-10121020
  • DOI: 10.1021/pr4010103
  • Peer Reviewed
• [Journal Article] Sigma-1Rs are upregulated via PERK/eIF2α/ATF4 pathway and execute protective function in ER stress (2011)
  • Author(s): Mitsuda T, Omi T, Tanimukai H, Sakagami Y, Tagami S, Okochi M, Kudo T, Takeda M
  • Journal Title: Biochem Biophys Res Commun Volume: Vol.415 Pages: 519-525
• [Journal Article] Protein kinase C stabilizes X-linked inhibitor of apoptosis protein (XIAP) through phosphorylation at Ser(87) to suppress apoptotic cell death (2011)
  • Author(s): Kato K, Tanaka T, Sadik G, Baba M, Maruyama D, Yanagida K, Kodama T, Morihara T, Tagami S, Okochi M, Kudo T, Takeda M
  • Journal Title: Psychogeriatrics Volume: Vol.11 Pages: 90-97
• [Journal Article] Different characteristics of cognitive impairment in elderly schizophrenia and Alzheimer's disease in the mild cognitive impairment stage (2011)
  • Author(s): Kazui H, Yoshida T, Takaya M, Sugiyama H, Yamamoto D, Kito Y, Wada T, Nomura K, Yasuda Y, Yamamori H, Ohi K, Fukumoto M, Iike N, Iwase M, Morihara T, Tagami S, Shimosegawa E, Hatazawa J, Ikeda Y, Uchida E, Tanaka T, Kudo T, Hashimoto R, Takeda M
  • Journal Title: Dement Geriatr Cogn Dis Extra Volume: Vol.1 Pages: 20-30
• [Journal Article] Different characteristics of cognitive impairment in elderly schizophrenia and Alzheimer' s disease in the mild cognitive impairment stage (2011)
  • Author(s): Kazui H, Yoshida T, Takaya M, Sugiyama H, Yamamoto D, Kito Y, Wada T, Nomura K, Yasuda Y, Yamamori H, Ohi K, Fukumoto M, Iike N, Iwase M, Morihara T, Tagami S, Shimosegawa E, Hatazawa J, Ikeda Y, Uchida E, Tanaka T, Kudo T, Hashimoto R, Takeda M.
  • Journal Title: Dement Geriatr Cogn Disord Extra Volume: 1 Issue: 1 Pages: 20-30
  • DOI: 10.1159/000323561
  • Peer Reviewed
• [Journal Article] Sigma-1Rs are upregulated via PERK/eIF2α/ATF4 pathway and execute protective function in ER stress. (2011)
  • Author(s): Mitsuda T, Omi T, Tanimukai H, Sakagami Y, Tagami S, Okochi M, Kudo T, Takeda M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 415 Issue: 3 Pages: 519-525
  • DOI: 10.1016/j.bbrc.2011.10.113
  • Peer Reviewed
• [Journal Article] Protein kinase C stabilizes X-linked inhibitor of apoptosis protein (XIAP) through phosphorylation at Ser(87) to suppress apoptotic cell death. (2011)
  • Author(s): Kato K, Tanaka T, Sadik G, Baba M, Maruyama D, Yanagida K, Kodama T, Morihara T, Tagami S, Okochi M, Kudo T, Takeda M.
  • Journal Title: Psychogeriatrics. Volume: 11 Issue: 2 Pages: 90-97
  • DOI: 10.1111/j.1479-8301.2011.00355.x
  • Peer Reviewed
• [Presentation] Degradation of extracellular Aβ42/43 in human brain and cultured cells (2013)
  • Author(s): Naoki Mizuta, Masayasu Okochi, Shinji Tagami, Kanta Yanagida, Takashi Kodama, Mako Takami, Yasuo Ihara, Daisuke Kanayama, Takashi Morihara, Takashi Kudo, Toshihisa Tanaka, Masatoshi Takeda
  • Organizer: CTAD2013
  • Place of Presentation: San Diego
  • Year and Date: 2013-11-14
• [Presentation] Elucidation of the mechanism underlying the alteration of Aβ42 ratio by g-secretase modulators (2013)
  • Author(s): Tagami S, Okochi M, Takeda M
  • Organizer: Neuroscience 2013 Nanosymposium
  • Place of Presentation: San Diego, California
  • Year and Date: 2013-11-11
• [Presentation] Identification and quantitative analysis of short peptides derived from amyloid-beta peptides in living cell (2013)
  • Author(s): Kodama T.S., Okochi M., Tagami S., Yanagida K., Mizuta N., Tanaka T., Morihara T., Kudo T., Takami M., Ihara Y., Takeda M.
  • Organizer: IPA's 16th International Congress
  • Place of Presentation: Seoul Korea, COEX
  • Year and Date: 2013-10-02
• [Presentation] Identification of APLP2-derived Ab-like peptides from human Cerebrospinal fluid (2013)
  • Author(s): 柳田寛太、 大河内正康、田上真次、児玉高志、武田雅俊
  • Organizer: 11th World Congress of Biological Psychiatry
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2013-06-27
• [Presentation] Identification and quantitative analysis of APL1ß peptides in human cerebrospinal fluid (CSF) (2013)
  • Author(s): Takashi. S. Kodama, Masayasu Okochi, Sinji Tagami, Kanta Yanagida, Naoki Mizuta, Toshihisa Tanaka, Takashi Morihara, Takashi Kudo, Masatoshi Takeda
  • Organizer: 11th World Congress of Biological Psychiatry
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2013-06-27
• [Presentation] Regulation of presenilin/gamma-secretase function; towards intervention of Alzheimer disease in future (2013)
  • Author(s): Tagami S, Okochi M, Takeda M
  • Organizer: 11th World Congress of Biological Psychiatry
  • Place of Presentation: Kyoto, Japan (Symposium)
  • Year and Date: 2013-06-26
• [Presentation] APL1β28, a new candidate biomarker for Alzheimer disease (2013)
  • Author(s): Naoki Mizuta, Masayasu Okochi, Shinji Tagami, Kanta Yanagida, Takashi Kodama, Toshihisa Tanaka, Takashi Morihara, Takashi Kudo, Masatoshi Takeda
  • Organizer: 11th World Congress of Biological Psychiatry
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2013-06-24
• [Presentation] CSF APL1β28 is a possible surrogate marker for Aβ42 production in human brains (2013)
  • Author(s): Naoki Mizuta, Masayasu Okochi, Shinji Tagami,Kanta Yanagida, Takashi Kodama,Toshihisa Tanaka, Takashi Morihara, Takashi Kudo, Masatoshi Takeda
  • Organizer: Neuro2013
  • Place of Presentation: Kyoto
  • Year and Date: 2013-06-21
• [Presentation] Determination of APL1ß Peptide Concentration in Cerebrospinal Fluid (CSF) by ELISA (2013)
  • Author(s): Takashi. S. Kodama, Masayasu Okochi, Sinji Tagami, Kanta Yanagida, Naoki Mizuta, Toshihisa Tanaka, Takashi Morihara, Takashi Kudo, Masatoshi Takeda
  • Organizer: Neuro2013
  • Place of Presentation: Kyoto, International Conference Center
  • Year and Date: 2013-06-21
• [Presentation] Regulation of presenilin/gamma-secretase function; towards intervention of Alzheimer disease in future (2013)
  • Author(s): Tagami S, Okochi M, Takeda M.
  • Organizer: 11th World Congress of Biological Psychiatry
  • Place of Presentation: 京都国際会議場 京都
  • Invited
• [Presentation] Elucidation of the mechanism underlying the alteration of Aβ42 ratio by g-secretase modulators. (2013)
  • Author(s): Tagami S, Okochi M, Takeda M.
  • Organizer: Neuroscience 2013
  • Place of Presentation: San Diego, California(USA)
• [Presentation] γセクレターゼ修飾薬のアルツハイマー病予防薬としての理論と実際 (2012)
  • Author(s): 大河内正康, 田上真次, 柳田寛太, 児玉高志, 武田雅俊
  • Organizer: 第31回日本認知症学会学術集会
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2012-10-28
• [Presentation] APL2βの産生メカニズムの解析(1)APLP2はプレセニリン1と2で異なる切断を受ける (2012)
  • Author(s): 柳田寛太, 大河内正康, 田上真次, 児玉高志, 森原剛史, 田中稔久, 工藤喬, 武田雅俊
  • Organizer: 第31回日本認知症学会学術集会
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2012-10-27
• [Presentation] APL2βの産生メカニズムの解析(2)APLP2はプレセニリン1と2で異なる切断を受ける (2012)
  • Author(s): 柳田寛太, 大河内正康, 田上真次, 児玉高志, 森原剛史, 田中稔久, 工藤喬, 武田雅俊
  • Organizer: 第31回日本認知症学会学術集会
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2012-10-27
• [Presentation] ヒト脳脊髄液中APL1βペプチドの高感度定量 (2012)
  • Author(s): 児玉高志, 大河内正康, 田上真次, 柳田寛太, 森原剛史, 田中稔久, 工藤喬, 朝長毅, 武田雅俊
  • Organizer: 第31回日本認知症学会学術集会
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2012-10-26
• [Presentation] ラフトのγセクレターゼによるAPP膜内段階的切断機構 (2012)
  • Author(s): 松村展敬, 高見真子, 田上真次, 大河内正康, 井原康夫, 森島真帆
  • Organizer: 第31回日本認知症学会学術集会
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2012-10-26
• [Presentation] Chracterization of brain APL2β, an Aβ-like peptide produced from APLP2 (2012)
  • Author(s): Masayasu Okochi, Kanta Yanagida, Shinji Tagami, Takashi Kodama, Shozo Sano,Takeshi Tomonaga, Takaomi C.Saido, Masatoshi Takeda
  • Organizer: Alzheimer's Association International Conference 2012
  • Place of Presentation: Vancouver Convention & Exhibition Centre
  • Year and Date: 2012-06-20
• [Presentation] Decrease in major amyloid beta species may trigger amyloidogenesis in vivo (2011)
  • Author(s): Shinji Tagami, Masayasu Okochi, Kanta Yanagida, Takashi Kodama, Takeshi Ikeuchi Takashi Morihara, Hitoshi Tanimukai, Hiroaki Kazui, Toshihisa Tanaka, Takashi Kudo, Masatoshi Takeda
  • Organizer: 10th World Congress of Biological Psychiatry, Prague
  • Place of Presentation: Czech Republic
  • Year and Date: 2011-05-30
• [Presentation] Absolute quantitation of plasma biomarker peptides for Alzheimer disease at pM level using SRM coupled with stable isotope standards and capture by anti-peptide antibodies (2011)
  • Author(s): Shio Watanabe, Shinji Tagami, Shozo Sano, Kumiko Yoshizawa-Kumagaye, Masahiko Tsunemi, Masayasu Okochi and Takeshi Tomonaga
  • Organizer: 日本ヒトプロテオーム機構第9回大会
  • Place of Presentation: 新潟市朱鷺メッセ
• [Presentation] Comparison of pretreatment methods for SISCAPA-SRM quantitation of Alzheimer disease biomaker peptide APL1beta in plasma (2011)
  • Author(s): Shozo Sano, Shinji Tagami, Masayasu Okochi, Kumiko Yoshizawa-Kumagaye, Masahiko Tsunemi, Yoshio Kodera and Takeshi Tomonaga
  • Organizer: 日本ヒトプロテオーム機構第9回大会
  • Place of Presentation: 新潟市朱鷺メッセ
• [Presentation] BACEとγセクレターゼによって産生される脳内Abeta様ペプチドを末梢血中で検出・同定する (2011)
  • Author(s): 田上真次, 大河内正康, 柳田寛太, 児玉高志, 池内健, 佐野聖, 三渡邊史, 生数井裕光, 森原剛史, 谷向仁, 田中稔久, 工藤喬, 朝長毅, 武田雅俊
  • Organizer: 第30回日本認知症学会学術集会
  • Place of Presentation: タワーホール船堀
• [Presentation] βAPPファミリー蛋白は脳内では主にBACEによってsheddingを受けるが培養細胞に過剰発現させるとα-セクレターゼによる切断が増加する (2011)
  • Author(s): 柳田寛太, 大河内正康, 田上真次, 児玉高志, 森原剛史, 田中稔久, 工藤喬, 武田雅俊
  • Organizer: 第30回日本認知症学会学術集会
  • Place of Presentation: タワーホール船堀
• [Presentation] Immuno-SRM/MRMを用いた新規アルツハイマー病血漿マーカーペプチドAPL1βの絶対定量法の確立と臨床応用 (2011)
  • Author(s): 渡邊史生, 田上真次, 佐野聖, 三熊谷久美子, 常見雅彦, 大河内正康, 朝長毅
  • Organizer: 第34回日本分子生物学会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Decrease in major amyloid beta species may trigger amyloidogenesis in vivo. (2011)
  • Author(s): Shinji Tagami, Masayasu Okochi, Kanta Yanagida, Takashi Kodama, Takeshi Ikeuchi Takashi Morihara, Hitoshi Tanimukai, Hiroaki Kazui, Toshihisa Tanaka, Takashi Kudo, Masatoshi Takeda
  • Organizer: 10th World Congress of Biological Psychiatry
  • Place of Presentation: Prague, Czech Republic
• [Presentation] Comparison of pretreatment methods for SISCAPA-SRM quantitation of Alzheimer disease biomaker peptide APL1beta in plasma. (2011)
  • Author(s): Shozo Sano, Shinji Tagami, Masayasu Okochi, Kumiko Yoshizawa-Kumagaye, Masahiko Tsunemi, Yoshio Kodera and Takeshi Tomonaga
  • Organizer: 日本ヒトプロテオーム機構第9回大会
  • Place of Presentation: 新潟市朱鷺メッセ
• [Presentation] "βAPPファミリー蛋白は脳内では主にBACEによってsheddingを受けるが培養細胞に過剰発現させるとα－セクレターゼによる切断が増加する (2011)
  • Author(s): 柳田 寛太 大河内 正康 田上 真次 児玉 高志 森原 剛史 田中 稔久 工藤 喬 武田 雅俊
  • Organizer: 第30回日本認知症学会学術集会
  • Place of Presentation: タワーホール船堀
• [Presentation] "Abeta蓄積修飾遺伝子KLC1 splicing variantの同定（１） APPTgマウスを用いた網羅的解析 (2011)
  • Author(s): 林 紀行 横小路 美貴子 森原 剛史 田上 真次 大河内 正康 田中 稔久 工藤 喬 武田 雅俊
  • Organizer: 第30回日本認知症学会学術集会
  • Place of Presentation: タワーホール船堀
• [Presentation] γセクレターゼ修飾薬のアルツハイマー病予防薬としての理論と実際
  • Author(s): 大河内 正康 田上 真次 柳田 寛太 児玉 高志 武田 雅俊
  • Organizer: 第３１回日本認知症学会学術集会
  • Place of Presentation: つくば国際会議場
• [Presentation] ヒト脳脊髄液中APL1βペプチドの高感度定量
  • Author(s): 児玉 高志 大河内 正康 田上 真次 柳田 寛太 森原 剛史 田中 稔久 工藤 喬 朝長 毅 武田 雅俊
  • Organizer: 第３１回日本認知症学会学術集会
  • Place of Presentation: つくば国際会議場
• [Presentation] APL2βの産生メカニズムの解析（１）APLP2はプレセニリン１と２で異なる切断を受ける
  • Author(s): 柳田 寛太 大河内 正康 田上 真次 児玉 高志 森原 剛史 田中 稔久 工藤 喬 武田 雅俊
  • Organizer: 第３１回日本認知症学会学術集会
  • Place of Presentation: つくば国際会議場
• [Presentation] APL2βの産生メカニズムの解析（２）APLP2はプレセニリン１と２で異なる切断を受ける
  • Author(s): 柳田 寛太 大河内 正康 田上 真次 児玉 高志 森原 剛史 田中 稔久 工藤 喬 武田 雅俊
  • Organizer: 第３１回日本認知症学会学術集会
  • Place of Presentation: つくば国際会議場
• [Presentation] ラフトのγセクレターゼによるAPP膜内段階的切断機構
  • Author(s): 松村 展敬 高見 真子 田上 真次 大河内 正康 井原 康夫 森島 真帆
  • Organizer: 第３１回日本認知症学会学術集会
  • Place of Presentation: つくば国際会議場
• [Remarks]
  • URL: http://www.osaka-u.ac.jp/en/research/annual-report/volume-9/100_select_paper/biology02.html
• [Remarks]
  • URL: http://www.osaka-u.ac.jp/en/research/annual-report/volume-11/100_select_paper/copy6_of_science02.html
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/psy/www/jp/labo/kagaku.html
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/psy/www/jp/labo/kagaku.html
• [Remarks]
  • URL: http://www.osaka-u.ac.jp/en/research/annual-report/volume-9/100_select_paper/biology02.html