Analysis of underlying mechanism to develop Alzheimer's disease

• Project/Area Number: 23617007
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Integrated Nutrition Science
• Research Institution: Gifu University
• Principal Investigator: NAKAGAWA Toshiyuki 岐阜大学, 医学(系)研究科(研究院), 教授 (00271502)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 小胞体ストレス / ATF4 / GADD34 / eIF2alpha / アミロイドーベータ / eIF2α / アミロイド-β / PERK / GCN2 / アミロイドｰβ / メタボリック症候群 / 肥満 / 糖尿病

Research Abstract

Gamma-secretase produces amyloid-beta (Ab) in the brain from Ab precursor protein, which is critical for tha pathogenesis of Alzheimer's disease (AD). The endoplasmic reticulum (ER) stress causes unfolded proteins, which are processed by unfolded protein response (UPR). Pathogenesis of obesity and diabetes, which are risk factors for AD, is related to ER stress. However, whether ER stress is engaged in the development of AD remains obscure. In this research, I showed that ER stress activated gamma-secretase, leading to augmentation of Ab through induction of activating transcription factor 4 (ATF4). Ab secretion was repressed in vitro by quercetin, which induced the growth arrest and DNA damaged-inducible gene (GADD)34. In addition, we found that phosphorylated eIF2alpha and ATF4 were increased in the brain of AD model mice APP23. These results suggest that ER stress signaling may be disturbed in the brain of AD.

Research Products

• [Journal Article] Polyglutamine expansion disturbs the endoplasmic reticulum formation, leading to caspase-7 activation through Bax (2014)
  • Author(s): M asashi Ueda, Shimo Li, Masanori Itoh, Yoshika Hayakawa-Yano, Miao-xing Wang, Miki Hayakawa, Ryoko Hasebe-Matsubara, Kazunori Ohta, Eri Ohta, Akihito Mizuno, Yoko Hida, Munekazu Matsumoto, Huayue Chen, Toshiyuki Nakagawa
  • Journal Title: Biochem Biophys Res Commun Volume: 443 Pages: 1232-1238
  • Peer Reviewed
• [Journal Article] Polyglutamine expansion disturbs the endoplasmic reticulum formation, leading to caspase-7 activation through Bax. (2014)
  • Author(s): Masashi Ueda, Shimo Li, Masanori Itoh, Yoshika Hayakawa-Yano, Miao-xing Wang, Miki Hayakawa, Ryoko Hasebe-Matsubara, Kazunori Ohta, Eri Ohta, Akihito Mizuno, Yoko Hida, Munekazu Matsumoto, Huayue Chen, Toshiyuki Nakagawa.
  • Journal Title: Biochem Biophys Res Commun. Volume: 443 Pages: 1232-1238
  • Peer Reviewed
• [Journal Article] Molecular cloning and sequence analysis of an extracellular protease from four bacillus strains (2013)
  • Author(s): Xujun Han, Yuh Shiwa, Masanori Itoh, Tohru Suzuki, Hirofumi Yoshikawa, Toshiyuki Nakagawa, Hiroko Nagano
  • Journal Title: Biosci. Biotechnol. Biochem Volume: 77 Pages: 870-873
  • Peer Reviewed
• [Journal Article] Molecular cloning and sequence analysis of an extracellular protease from four bacillus strains. (2013)
  • Author(s): Xujun Han, Yuh Shiwa, Masanori Itoh, Tohru Suzuki, Hirofumi Yoshikawa, Toshiyuki Nakagawa, Hiroko Nagano.
  • Journal Title: Biosci. Biotechnol. Biochem. Volume: 77 Pages: 870-873
  • Peer Reviewed
• [Journal Article] Miao-xing Wang, ToshiyukiNakagawa. Olfaxin as a novel Prune2 isoform predominantly expressed in olfactory system (2012)
  • Author(s): Shimo Li, YoshikaHayakawa-Yano, MasanoriItoh, MasashiUeda, Kazunori Ohta, YoshihiroSuzuki, AkihitoMizuno, EriOhta, YokoHida
  • Journal Title: Brain research Volume: 1488 Pages: 1-13
  • Peer Reviewed
• [Journal Article] Olfaxin as a novel Prune2 isoform predominantly expressed in olfactory system. (2012)
  • Author(s): Shimo Li,YoshikaHayakawa-Yano,MasanoriItoh,MasashiUeda, Kazunori Ohta,YoshihiroSuzuki,AkihitoMizuno,EriOhta,YokoHida, Miao-xing Wang,ToshiyukiNakagawa
  • Journal Title: brain research Volume: 1488 Pages: 1-13
  • DOI: 10.1016/j.brainres.2012.10.001
  • Peer Reviewed
• [Journal Article] Endoplasmic reticulum stress enhancesγ-secretase activity (2011)
  • Author(s): Ohta K, Mizuno A, Li S, Itoh M, Ueda M, Ohta E, Hida Y, Wang MX, Furoi M, Tsuzuki Y, Sobajima M, Bohmoto Y, Fukushima T, Kobori M, Inuzuka T, Nakagawa T
  • Journal Title: Biochem Biophys Res Commun Volume: 416 Pages: 362-366
  • Peer Reviewed
• [Journal Article] 認知症 (2011)
  • Author(s): 太田和徳,中川敏幸
  • Journal Title: Functional Food Volume: 5 Pages: 47-51
• [Journal Article] ケルセチンとアルツハイマー病 (2011)
  • Author(s): 太田和徳,中川敏幸
  • Journal Title: Functional Food Volume: 5 Pages: 135-138
• [Journal Article] Endoplasmic reticulum stress enhances γ-secretase activity. (2011)
  • Author(s): Ohta K, Mizuno A, Li S, Itoh M, Ueda M, Ohta E, Hida Y, Wang MX, Furoi M, Tsuzuki Y, Sobajima M, Bohmoto Y, Fukushima T, Kobori M, Inuzuka T, Nakagawa T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 416 Issue: 3-4 Pages: 362-366
  • DOI: 10.1016/j.bbrc.2011.11.042
  • Peer Reviewed
• [Presentation] CUL4B PROMOTES APAF-1 POLYYUBIQUITINATION FOR CASPASE-9 ACTIVATION (2013)
  • Author(s): Masanori Itoh, Eri Ohta, Yoko Hida, Miao-xing Wang, Masashi Ueda, Kazunori Ohta, Shimo Li, Akihito Mizuno, Tomomi Sunayama, Toshiyuki Nakagawa
  • Organizer: Cold Spring Harbor Asia
  • Place of Presentation: Suzhou(宿州)China
  • Year and Date: 2013-04-16
• [Presentation] Activation of gamma-secretase by endoplasmic reticurum stress (2012)
  • Author(s): Kazunori Ohta, Akihito Mizuno, Shimo Li, Masanori Itoh, Masashi Ueda, Yoko Hida, Miao-xing Wang, Wan-yu Lo, Toshiyuki Nakagawa
  • Organizer: 42nd ANNUAL MEETING Neuroscience
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2012-10-15
• [Presentation] Endoplasmic reticulum stress leads to increase gamma-secretase activity and beta-amyloid production (2011)
  • Author(s): Kazunori Ohta, Akihito Mizuno, Shimo Li, Masashi Ueda, Masanori Itoh, Eri Ohta, Yoko Hida, Miao-xing Wang , Manabu Furoi, Yukihiro Tuzuki, Mituaki Sobajima, Yoshimasa Bohmoto, Tatsuya Fukushima, Toshituki Nakagawa
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜(3P-701)
  • Year and Date: 2011-12-15
• [Presentation] A novel regulation mechanism of synaptic transmission by preseynapse-localizing Caymanataxia-related protein,Caytaxin (2011)
  • Author(s): Masanori itoh, Shimo Li, Kazunori Ohta, Masashi Ueda, Yoko Hida, Yoshihiro Suzuki, Eri Ohta, Akihito Mizuno, Miao-xing Wang, Toshiyuki Nakagawa
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜(1P-0921)
  • Year and Date: 2011-12-13
• [Presentation] The expression and localization of Prune2 and its novel isoform in the central neuvous system (2011)
  • Author(s): S.LI, M.ITOH, K.OHTA, M.UEDA, A.MIZUNO, E.OHTA, Y.HIDA, M.WANG, K.YAKEUCHI, T.NAKAGAWA
  • Organizer: 41th ANNUAL MEETING Neuroscience2011
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2011-11-12
• [Presentation] Endoplasmic reticulum stress leads to increase gamma-secretase activity and beta-amyloid production (2011)
  • Author(s): K. Ohta, A. Mizuno, S. Li, M. Ueda, M. Itoh, E. Ohta, Y. Hida, M. Wang , M. Furoi, Y. Tuzuki, M. Sobajima, Y. Bohmoto, T. Fukushima, T. Nakagawa
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
• [Presentation] A novel regulation mechanism of synaptic transmission by preseynapse-localizing Caymanataxia-related protein,Caytaxin (2011)
  • Author(s): M. itoh, S. Li, K. Ohta, M. Ueda, Y. Hida, Y. Suzuki, E. Ohta, A. Mizuno, M. Wang, T. Nakagawa
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
• [Presentation] The expression and localization of Prune2 and its novel isoform in the central neuvous system (2011)
  • Author(s): S.LI, M.ITOH, K.OHTA, M.UEDA, A.MIZUNO, E.OHTA, Y.HIDA, M.WANG, K.YAKEUCHI, T.NAKAGAWA
  • Organizer: 41thANNUAL MEETING Neuroscience
  • Place of Presentation: Washington DC, USA
• [Presentation] CUL4B PROMOTES APAF-1 POLYYUBIQUITINATION FOR CASPASE-9 ACTIVATION.
  • Author(s): Masanori Itoh, Eri Ohta, Yoko Hida, Miao-xing Wang, Masashi Ueda, Kazunori Ohta, Shimo Li, Akihito Mizuno, Tomomi Sunayama, Toshiyuki Nakagawa.
  • Organizer: Cold Spring Harbor Asia.
  • Place of Presentation: Suzhou（宿州） China
• [Presentation] Polyglutamine expansion affects morphology of the endoplasmic reticulum-mitochondria contact site, initiating cell death.
  • Author(s): Masashi Ueda, Shimo Li, Masanori Itoh, Kazunori Ohta, Miao-xing Wang, Huayue Chen, K.Yamaguchi, K. Kuwata, Miki Hayakawa, Yoko Hida, Toshiyuki Nakagawa.
  • Organizer: 43rd ANNUAL MEETING Neuroscience.
  • Place of Presentation: San Diego, USA
• [Presentation] Activation of gamma-secretase by endoplasmic reticurum stress.
  • Author(s): Kazunori Ohta, Akihito Mizuno, Shimo Li, Masanori Itoh, Masashi Ueda, Yoko Hida, Miao-xing Wang, Wan-yu Lo, Toshiyuki Nakagawa.
  • Organizer: 42nd ANNUAL MEETING Neuroscience
  • Place of Presentation: New Orleans, USA
• [Remarks]
  • URL: http://www1.gifu-u.ac.jp/~neurobio/
• [Remarks] http://www1.gifu-u.ac.jp/~neurobio/