Analysis of the mechanism of pathological synaptic alterations in Alzheimer's disease

• Project/Area Number: 20300124
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Kyoto University
• Principal Investigator: KINOSHITA Ayae Kyoto University, 大学院・医学研究科, 教授 (80321610)
• Co-Investigator(Kenkyū-buntansha): KUBOTA Masakazu 京都大学, 大学院・医学研究科, 助教 (80452267) ; 植村 健吾 京都大学, 医学研究科, 助教 (00378663)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥19,760,000 (Direct Cost: ¥15,200,000、Indirect Cost: ¥4,560,000); Fiscal Year 2010: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2009: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2008: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
• Keywords: アルツハイマー病 / 老化 / 神経変性 / シナプス / 認知症 / N-cadherin / インスリン / プレセニリン

Research Abstract

We investigated the pathological mechanisms caused by mutations of Presenilin 1, a responsible protein for familial Alzheimer's disease(AD). We focused on insulin signaling as an influential factor of PS1 and revealed its effect on the localization and conformation of PS1. Our result showed that insulin inhibited GSK3 beta activation, thus leading to inhibition of PS1 phosphorylation and that insulin signaling is involved in the translocation of PS1 to the cell surface and its cleavage functions. Furthermore, we found that insulin receptor, IR, is cleaved by PS1, then its intracellular domain translocates to the nucleus, which activates transcription of Akt. Taken together, we conclude that insulin signaling is modulated by PS1. Next, we created a novel AD model mouse with diabetic condition by giving high fat diet to APP Tg mouse. This mouse showed a marked impairment of short-term memory, suggesting that diabetes is an aggravating factor for AD.

Research Products

• [Journal Article] N-cadherin regulates p38 MAPK signaling via association with JNK-associated leucine zipper protein : implications for neurodegeneration in Alzheimer disease. (2011)
  • Author(s): Ando K, Uemura K, Kuzuya A, Maesako M, Asada-Utsugi M, Kubota M, Aoyagi N, Yoshioka K, Okawa K, Inoue H, Kawamata J, Shimohama S, Arai T, Takahashi R, Kinoshita A
  • Journal Title: J Biol Chem 286 Pages: 7619-7628
  • Peer Reviewed
• [Journal Article] Effect of glycogen synthase kinase 3 β-mediated presenilin 1 phosphorylation on amyloid β production is negatively regulated by insulin receptor cleavage. (2011)
  • Author(s): Maesako M, Uemura K, Kubota M, Hiyoshi K, Ando K, Kuzuya A, Kihara T, Asada M, Akiyama H, Kinoshita A
  • Journal Title: Neuroscience 177 Pages: 298-307
  • NAID: 120002970866
  • Peer Reviewed
• [Journal Article] N-cadherin regulates p38 MAPK signaling via association with JNK-associated leucine zipper protein : implications for neurodegeneration in Alzheimer disease (2011)
  • Author(s): Ando K, Uemura K, Kuzuya A, Maesako M, Asada-Utsugi M, Kubota M, Aoyagi N, Yoshioka K, Okawa K, Inoue H, Kawamata J, Shimohama S, Arai T, Takahashi R, Kinoshita A
  • Journal Title: Journal of Biological Chemistry Volume: 286 Pages: 7619-7628
  • Peer Reviewed
• [Journal Article] Effect of glycogen synthase kinase 3 β-mediated presenilin 1 phosphorylation on amyloid β production is negatively regulated by insulin receptor cleavage (2011)
  • Author(s): Maesako M, Uemura K, Kubota M, Hiyoshi K, Ando K, Kuzuya A, Kihara T, Asada M, Akiyama H, Kinoshita A
  • Journal Title: Neuroscience Volume: 177 Pages: 298-307
  • NAID: 120002970866
  • Peer Reviewed
• [Journal Article] Insight into "synaptopathy" in Alzheimer's disease (2011)
  • Author(s): Kuzuya A, Uemura K, Kinoshita A
  • Journal Title: Journal of Alzheimer's Disease Research Volume: In press
• [Journal Article] Insulin regulates Presenilin 1 localization via PI3K/Akt signaling. (2010)
  • Author(s): Maesako M, Uemura K, Kubota M, Ando K, Kuzuya A, Kihara T, Kinoshita A
  • Journal Title: Nerosci Lett 483 Pages: 157-161
  • NAID: 120002484938
  • Peer Reviewed
• [Journal Article] The cleavage of N-cadherin is essential for chondrocyte differenciaten. (2010)
  • Author(s): Nakazora N, Matsumine A, Iino T, Hasegawa M, Kinoshita A, Uemura K, Niimi R, Uchida A, Sudo A.
  • Journal Title: Biochem Biophys Res Commun 400 Pages: 493-499
  • Peer Reviewed
• [Journal Article] PI3K inhibition causes the accumulation of ubiquitinated presenilin 1 without affecting the proteasome activity. (2010)
  • Author(s): Aoyagi N, Uemura K, Kuzuya A, Kihara T, Kawamata J, Shimohama S, Kinoshita A, Takahashi R.
  • Journal Title: Biochem Biophys Res Commun 391 Pages: 1240-5
  • Peer Reviewed
• [Journal Article] Insulin regulates Presenilin 1 localization via PI3K/Akt signaling (2010)
  • Author(s): Maesako M, Uemura K, Kubota M, Ando K, Kuzuya A, Asada M, Kihara T, Kinoshita A
  • Journal Title: Neuroscience Letters Volume: 483 Pages: 157-161
  • NAID: 120002484938
  • Peer Reviewed
• [Journal Article] Blogging is an effective way to reduce a stress for caregivers who are involvred in caring dementia patients at home-the result from the questionnaire survey (2010)
  • Author(s): Hori M, Kubota M, Kinoshita A
  • Journal Title: Gan to Kagaku Ryoho Volume: Supple 2 Pages: 192-194
• [Journal Article] The cleavage of N-cadherin is essential for chondrocyte differentiation (2010)
  • Author(s): Nakazora S, Matsumine A, Iino T, Hasegawa M, Kinoshita A, Uemura K, Niimi R, Uchida A, Sudo A
  • Journal Title: Biochem Biophys Res Commun Volume: 400 Pages: 493-499
  • Peer Reviewed
• [Journal Article] N-cadherin-based adhesion enhances Aβ release and decrerased Aβ42/40 ratio. (2009)
  • Author(s): Uemura, K, Lill CM, Banks M, Aoyagi N, Ando, K., Kubota M, Kihara T, Nishimoto T, Sugimoto H, Takahashi R, Hyman BT, Shimohama S, Berezovska O, Kinoshita A
  • Journal Title: J Neurochem 156 Pages: 350-360
  • Peer Reviewed
• [Journal Article] Cronic cerebral hypoperfusion accelerates amyloid β deposition in APPSweInd transgenic mouse. (2009)
  • Author(s): Kitaguchi H, Tomimoto H, Ihara M, Shibata M, Uemura K, Kalaria RN, Kihara T, Asada-Utsugi M, Kinoshita A, Takahashi R.
  • Journal Title: Brain Research 1294 Pages: 202-10
  • Peer Reviewed
• [Journal Article] N-cadherin-based adhesion enhances Abeta release and decreased Abeta42/40 ratio (2009)
  • Author(s): Uemura K, Lill CM, Banks M, Aoyagi N, Ando K, 久保田正和, 木原武士, Nishimoto T, Sugimoto H, 高橋良輔, Hyman BT, Shimohama S, 木下彩栄
  • Journal Title: Journal of Neurochemistry 156 Pages: 350-360
  • Peer Reviewed
• [Journal Article] Chronic cerebral hypoperfusion accelerates amyloid beta deposition in APPSwedish transgenic mouse (2009)
  • Author(s): Kitaguchi H, Tomimoto H, Ihara M, Shibata M, Uemura K, Kalaria RN, 木原武士, Asada-Utsugi M, 木下彩栄, 高橋良輔
  • Journal Title: Brain Research 1294 Pages: 202-210
  • Peer Reviewed
• [Journal Article] 在宅認知症高齢者とその家族介護者に対するテレビ電話システムを用いたコミュニケーションの有効性 (2009)
  • Author(s): 保利美也子, 久保田正和, 安藤功一, 木原武士, 高橋良輔, 木下彩栄
  • Journal Title: 癌と化学療法 36(Suppl) Pages: 36-38
• [Journal Article] (2009)
  • Author(s): 木下彩栄, 他
  • Journal Title: ガイドライン 外来診療 2009(日経メディカル開発) Pages: 395-402
• [Journal Article] (2009)
  • Author(s): 木下彩栄, 他
  • Journal Title: 外来診療ハンディガイド(日経メディカル開発) Pages: 200-203
• [Journal Article] N-cadherin-based adhesion enhances Abeta release and decreases Abeta42/40 ratio. (2009)
  • Author(s): Uemura K, et al.
  • Journal Title: Journal of Neurochemistry 108 Pages: 350-360
  • Peer Reviewed
• [Journal Article] Skypeとwebcameraを利用した在宅認知症患者とその家族への支援 (2008)
  • Author(s): 保利美也子、久保田正和、木下彩栄
  • Journal Title: 癌と化学療法 35 Pages: 46-47
• [Journal Article] γセクレターゼとシナプス機能 (2008)
  • Author(s): 植村健吾、安藤功一、久保田正和、木下彩栄
  • Journal Title: Cognition and Dementia 7 Pages: 46-54
• [Journal Article] γセクレターゼとシナプス機能 (2008)
  • Author(s): 植村健吾, 他3名
  • Journal Title: Cognition and Dementia 7 Pages: 46-54
• [Journal Article] J Neurochemistry N-cadherin enhances APP dimerization at the extracellular domain and modulates Abeta production.
  • Author(s): Megumi Asada-Utsugi, Kengo Uemura, Yashuha Noda, Akira Kuzuya, Masato Maesako, Koichi Ando, Masakazu Kubota, Kiwamu Watanabe, Makio Takahashi, Takeshi Kihara, Shun Shimohama, Ryosuke Takahashi, Oksana Berezovska, Ayae Kinoshita
  • Journal Title: J Neurochemistry(accepted)
  • Peer Reviewed
• [Journal Article] Presenilin regulates insulin signaling via gamma-secretase independent mechanism.
  • Author(s): Masato Maesako, Kengo Uemura, Akira Kuzuya, Megumi Asada, Kazuki Sasaki, Kiwamu Watanabe, Koichi Ando, Masakazu Kubota, Takeshi Kihara, Ayae Kinoshita
  • Journal Title: J Biological Chemistry (in press)
  • Peer Reviewed
• [Journal Article] Insight into 'synaptopathy' in Alzheimer's disease : From lifestyle to PS1/N-cadherin interaction.
  • Author(s): Kuzuya A, Kinoshita A, Uemura K.
  • Journal Title: Alzheimer's Disease Research Journal 2011 (in press)
  • Peer Reviewed
• [Presentation] インスリンシグナルがPS1に与える影響の解明 (2010)
  • Author(s): 前迫真人、植村健吾、佐々木和樹、安藤功一、葛谷聡、浅田めぐみ、久保田正和、秋山治彦、木下彩栄
  • Organizer: 日本認知症学会
  • Place of Presentation: 名古屋
  • Year and Date: 2010-11-06
• [Presentation] Presenilin 1, a causative gene for Alzheimer's disease, is regulated by insulin. (2010)
  • Author(s): 木下彩栄
  • Organizer: International Conference for Alzheimer's disease (Peking University).
  • Place of Presentation: 中国北京
  • Year and Date: 2010-10-23
• [Presentation] APPシスダイマー化におけるN-cadherin (2010)
  • Author(s): 浅田めぐみ、植村健吾、葛谷聡、山田奈央、前迫真人、安藤功一、渡辺究、久保田正和、Oksana Berezovska, Brad Hyman, 下浜俊、高橋良輔、木下彩栄
  • Organizer: ネクチン1の影響神経科学会
  • Place of Presentation: 神戸
  • Year and Date: 2010-09-02
• [Presentation] Effects of Presenilin 1 phosphorylation on Insulin Receptor. (2010)
  • Author(s): 前迫真人、植村健吾、久保田正和、安藤功一、葛谷聡、山田奈央、浅田めぐみ、秋山治彦、木下彩栄
  • Organizer: 神経科学会
  • Place of Presentation: 神戸
  • Year and Date: 2010-09-02
• [Presentation] Analysis of N-cadherin interacting proteins in Alzheimer's disease. (2010)
  • Author(s): Koichi A, Maesako M, Asada M, Aoyagi N, Kubota M, Kuzuya A, Uemura K, Kawamata J, Takahashi R, Kinoshita A
  • Organizer: International Conference of Alzheimer's disease.
  • Place of Presentation: 米国ハワイ州
  • Year and Date: 2010-07-12
• [Presentation] インスリンシグナルがプレセニリンの局在・機能に与える影響の解明 (2010)
  • Author(s): 木下彩栄、前迫真人、浅田めぐみ、葛谷聡、安藤功一、久保田正和、植村健吾、秋山治彦
  • Organizer: 日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-20
• [Presentation] APPシスダイマー化におけるN-cadherin、ネクチン1の影響 (2010)
  • Author(s): 浅田めぐみ、植村健吾、葛谷聡、山田奈央、前迫真人、安藤功一、渡辺究、久保田正和、Oksana Berezovska, Brad Hyman, 下浜俊、高橋良輔、木下彩栄
  • Organizer: 神経科学会
  • Place of Presentation: 神戸
• [Presentation] Effects of Presenilin 1 phosphorylation on Insulin Receptor (2010)
  • Author(s): 前迫真人、植村健吾、久保田正和、安藤功一、葛谷聡、山田奈央、浅田めぐみ、秋山治彦、木下彩栄
  • Organizer: 神経科学会
  • Place of Presentation: 神戸
• [Presentation] Analysis of N-cadherin interacting proteins in Alzheimer's disease (2010)
  • Author(s): Koichi A, Maesako M, Asada M, Aoyagi N, Kubota M, Kuzuya A, Uemura K, Kawamata J, Takahashi R, Kinoshita A
  • Organizer: International Conference of Alzheimer's disease
  • Place of Presentation: 米国ハワイ州ホノルル
• [Presentation] Presenilinl, a causahve gene for Alzheimer's disease, is regulated by insulin signaling (2010)
  • Author(s): Kinoshita A
  • Organizer: International Conference for Alzheimer's disease (Peking University)
  • Place of Presentation: 中国北京市
• [Presentation] 認知症の病態とケア (2009)
  • Author(s): 木下彩栄
  • Organizer: 聖母女学院短期大学特別講演
  • Place of Presentation: 聖母女学院短期大学
• [Presentation] 認知症の病態と治療の現状 (2009)
  • Author(s): 木下彩栄
  • Organizer: 日本作業療法士協会専門作業療法士取得研修
  • Place of Presentation: 京都大学
• [Presentation] 認知症高齢者の身体合併症に対する一般病院の対応 (2009)
  • Author(s): 江口恭子, 木下彩栄
  • Organizer: 認知症ケア学会
  • Place of Presentation: 東京
• [Presentation] 認知症患者の尊厳死に対する意識調査 (2009)
  • Author(s): 古家彩名, 久保田正和, 木下彩栄
  • Organizer: 認知症ケア学会
  • Place of Presentation: 東京
• [Presentation] 在宅要介護高齢者を介護する家族主介護者の結婚満足度と介護要因の検討 (2009)
  • Author(s): 日吉和子, カール・ベッカー, 木下彩栄
  • Organizer: 日本在宅医療学会
  • Place of Presentation: 東京
• [Presentation] 在宅認知症高齢者とその家族介護者に対するテレビ電話システムを用いたコミュニケーションの有効性 (2009)
  • Author(s): 保利美也子, 久保田正和, 安藤功一, 木原武士, 高橋良輔, 木下彩栄
  • Organizer: 日本在宅医療学会
  • Place of Presentation: 東京
• [Presentation] IT利用が在宅介護者の介護ストレスに与える影響 (2009)
  • Author(s): 久保田正和, 保利美也子, 宋慶華, 日吉和子, 木下彩栄
  • Organizer: 日本老年看護学会
  • Place of Presentation: 横浜
• [Presentation] APPダイマー化に対するN-カドヘリンの影響 (2009)
  • Author(s): 浅田めぐみ, 植村健吾, 葛谷聡, 久保田正和, 下浜俊, 高橋良輔, 木下彩栄
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] アルツハイマー病におけるN-カドヘリン関連たんぱく質の解析 (2009)
  • Author(s): 安藤功一, 前迫真人, 浅田めぐみ, 久保田正和, 青柳信寿, 植村健吾, 葛谷聡, 川又純, 高橋良輔, 木下彩栄
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] インスリンシグナルを介したプレセニリン1の機能制御 (2009)
  • Author(s): 前迫真人, 植村健吾, 久保田正和, 青柳信寿, 葛谷聡, 安藤功一, 池内健, 浅田めぐみ, 木下彩栄
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] APPダイマー化におけるN-カドヘリンの影響 (2009)
  • Author(s): 浅田めぐみ, 植村健吾, 葛谷聡, 渡辺拡人, 久保田正和, 下濱俊, 高橋良輔, 木下彩栄
  • Organizer: 日本分子生物学会
  • Place of Presentation: 横浜
• [Presentation] 細胞内たんぱく質分解系がPS1によるAPPの切断に及ぼす影響の検討 (2009)
  • Author(s): 渡辺拡人, 葛谷聡, 浅田めぐみ, 植村健吾, 渡辺拡人, 前迫真人, 久保田正和, 高橋良輔, 木下彩栄
  • Organizer: 日本分子生物学会
  • Place of Presentation: 横浜
• [Presentation] プレセニリンのリン酸化がインスリン受容体の切断に与える影響 (2009)
  • Author(s): 前迫真人, 植村健吾, 久保田正和, 安藤功一, 葛谷聡, 浅田めぐみ, 渡辺拡人, 山田奈央, 秋山治彦, 木下彩栄
  • Organizer: 日本分子生物学会
  • Place of Presentation: 横浜
• [Presentation] アルツハイマー病におけるN-カドヘリン関連蛋白質の解析 (2008)
  • Author(s): 安藤功一, 他
  • Organizer: 日本分子生物学会BMB2008
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-10
• [Presentation] APPタイマー化に対するN-カドヘリンの影響 (2008)
  • Author(s): 浅田めぐみ, 他
  • Organizer: 日本分子生物学会BMB2008
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-10
• [Presentation] アルツハイマー病におけるインスリン受容体関連蛋白質の解析 (2008)
  • Author(s): 前迫正人, 他
  • Organizer: 日本分子生物学会BMB2008
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-10
• [Presentation] N-cadherin-based adhesion enhances Abeta release and decreases Abeta42/40 ratio (2008)
  • Author(s): Uemura K, et al.
  • Organizer: 11th International Congress of Alzheimer's desease
  • Place of Presentation: Chicago, USA
  • Year and Date: 2008-07-28
• [Presentation] アルツハイマー病におけるN-ガドヘリン関連蛋白質の解析 (2008)
  • Author(s): 安藤功一, 他
  • Organizer: 第31回日本神経科学大会
  • Place of Presentation: 東京
  • Year and Date: 2008-07-10
• [Presentation] N-カドヘリンのプレセニリン・γセクレターセクレターゼ機能に与える影響 (2008)
  • Author(s): 植村健吾, 青柳信寿, 安藤功一, 浅田めぐみ, 下浜俊, 高橋良輔, 木下
  • Organizer: 第49回日本神経学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2008-05-15
• [Book] 老年性認知症「外来診療ハンディガイド」 (2010)
  • Author(s): 木下彩栄
  • Publisher: 日経メディカル
• [Book] 老年性認知症「ガイドライン外来診療2009」 (2009)
  • Author(s): 木下彩栄
  • Publisher: 日経メディカル
• [Remarks] ホームページ等
  • URL: http://www.med.kyoto-u.ac.jp/J/grad_school/introduction/5132/