Development of therapeutic strategy for Alzheimer's disease by targeting amyloid precursor protein C99

• Project/Area Number: 23500445
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Shiga University of Medical Science
• Principal Investigator: NISHIMURA Masaki 滋賀医科大学, 分子神経科学研究センター, 准教授 (40322739)
• Co-Investigator(Kenkyū-buntansha): MATSUO Akinori 滋賀医科大学, 分子神経科学研究センター, 助教 (20324585)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: アルツハイマー病 / アミロイドβ / ILEI / FAM3C / γセクレターゼ / 神経疾患 / βアミロイド / トランスジェニック・マウス / 認知症

Research Abstract

Accumulation of amyloid-b (Ab) in the brain underlies the pathogenesis of Alzheimer's disease (AD). Ab is produced by b- and g-secretase-mediated sequential proteolysis of Ab precursor protein (APP). Although g-secretase is a major target of therapeutic intervention, non-selective inhibition of its activity causes serious adverse effects due to blockade of Notch signaling. We have identified a secretory protein named ILEI as a negative regulator of Ab production. ILEI destabilized the b-secretase-cleaved APP C-terminal fragment, APP-C99, by binding to the g-secretase complex and interfering with its chaperone properties. Notch signaling and g-secretase activity were not affected by ILEI. We also show neuronal expression of ILEI and its reduction in the brains of AD patients. transgenic over expression of ILEI significantly reduced the brain Ab burden and ameliorates the memory deficit in AD model mice. ILEI may be a plausible target for the development of disease-modifying therapies.

Research Products

• [Journal Article] The FAM3 superfamily member ILEI ameliorates Alzheimer's disease-like pathology by destabilizing the penultimate amyloid-beta precursor. (2014)
  • Author(s): Hasegawa, H., L. Liu, I. Tooyama, S. Murayama and M. Nishimura
  • Journal Title: Nat Commun Volume: 5 Issue: 1 Pages: 3917-3917
  • DOI: 10.1038/ncomms4917
  • Peer Reviewed
• [Journal Article] OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin. (2014)
  • Author(s): Han J, Jung S, Jang J, Kam TI, Choi H, Kim BJ, Nah J, Jo DG, Nakagawa T, Nishimura M, Jung YK.
  • Journal Title: Cellular and Molecular Life Sciences Volume: 未定 Issue: 13 Pages: 2561-2576
  • DOI: 10.1007/s00018-013-1515-x
  • Peer Reviewed
• [Journal Article] Hyperpolarization-activated cyclic nucleotide gated channels : a potential molecular link between epileptic seizures and Aβ generation in Alzheimer's disease (2012)
  • Author(s): Saito Y, Inoue T, Zhu G, Kimura N, Okada M, Nishimura M, Kimura N, Murayama S, Kaneko S, Shigemoto R, Imoto1 K, Suzuki T
  • Journal Title: Mol Neurodegener Volume: 7 Pages: 50-50
  • NAID: 120005133364
  • Peer Reviewed
• [Journal Article] Age-related modulation of γ-secretase activity in non-human primate brains (2012)
  • Author(s): Nishimura M, Nakamura S, Kimura N, Liu L, Suzuki T, Tooyama I
  • Journal Title: J Neurochem Volume: 123(1) Pages: 21-28
  • NAID: 120005713696
  • Peer Reviewed
• [Journal Article] Membrane-microdomain localization of amyloid β-precursor protein (APP) C-terminal fragments is regulated by phosphorylation of the cytoplasmic Thr^<668> residue (2012)
  • Author(s): Matsushima T, Saito Y, Elliott JI, Iijima-Ando K, Nishimura M, Kimura N, Hata S, Yamamoto T, Nakaya T, Suzuki T
  • Journal Title: J Biol Chem Volume: 287(23) Pages: 19715-19724
  • Peer Reviewed
• [Journal Article] γセクレターゼ複合体に作用しAβ産生を制御する内在性タンパク質 (2012)
  • Author(s): 西村正樹
  • Journal Title: Dementia Japan Volume: 26(1) Pages: 44-50
• [Journal Article] Age-related modulation of γ-secretase activity in non-human primate brains (2012)
  • Author(s): Nishimura M
  • Journal Title: J Neurochem Volume: 123 Issue: 1 Pages: 21-28
  • DOI: 10.1111/j.1471-4159.2012.07884.x
  • Peer Reviewed
• [Journal Article] Hyperpolarization-activated cyclic nucleotide gated channels: a potential molecular link between epileptic seizures and Abeta generation in Alzheimer's disease (2012)
  • Author(s): Saito Y
  • Journal Title: Mol Neurodegener Volume: 7 Issue: 1 Pages: 50-50
  • DOI: 10.1186/1750-1326-7-50
  • Peer Reviewed
• [Journal Article] Membrane-microdomain localization of amyloid β-precursor protein (APP) C-terminal fragments is regulated by phosphorylation of the cytoplasmic Thr668 residue (2012)
  • Author(s): Matsushima T
  • Journal Title: J Biol Chem Volume: 287 Issue: 23 Pages: 19715-19724
  • DOI: 10.1074/jbc.m111.334847
  • Peer Reviewed
• [Journal Article] Membrane-microdomain localization of amyloid β-precursor protein (APP) C-terminal fragments is regulated by phosphorylation of the cytoplasmic Thr668 residue. (2012)
  • Author(s): Matsushima T, et al.
  • Journal Title: Journal of Biological Chemistry Volume: 287
  • Peer Reviewed
• [Journal Article] Human neural stem cells overexpressing choline acetyltransferase restore cognitive function of kainic acid-Induced learning and memory deficit animals. (2012)
  • Author(s): Park D, et al.
  • Journal Title: Cell Transplantaion Volume: 21 Pages: 365-371
  • Peer Reviewed
• [Journal Article] Human neural stem cells overexpressing choline acetyltransferase restore cognition in rat model of cognitive dysfunction. (2012)
  • Author(s): Park D, et al.
  • Journal Title: Experimental Neurology Volume: 234 Pages: 521-526
  • Peer Reviewed
• [Journal Article] Potent amyloidogenicity and pathogenicity of Aβ43 (2011)
  • Author(s): 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 TC
  • Journal Title: Nat Neurosci Volume: 14(8) Pages: 1023-1032
  • NAID: 120006985066
  • Peer Reviewed
• [Journal Article] Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease : Evidence for γ-secretase dysfunction (2011)
  • Author(s): Hata S, Fujishige S, Araki Y, Taniguchi M, Urakami K, Peskind E, Akatsu H, Araseki M, Yamamoto K, Martins RN, Maeda M, Nishimura M, Levey A, Chung KA, Montine T, Leverenz J, Fagan A, Goate A, Bateman R, Holtzman DM, Yamamoto T, Nakaya N, Gandy S, Suzuki T
  • Journal Title: Ann Neurol Volume: 69(6) Pages: 1026-1031
  • Peer Reviewed
• [Journal Article] Nuclear choline acetyltransferase activates transcription of a high-affinity choline transporter (2011)
  • Author(s): Matsuo A, Bellier JP, Nishimura M, Yasuhara O, Saito N, Kimura H
  • Journal Title: J Biol Chem Volume: 286(7) Pages: 5836-5845
  • Peer Reviewed
• [Journal Article] アルツハイマー病に対するメマンチン治療 (2011)
  • Author(s): 西村正樹
  • Journal Title: 医事新報 Volume: 4537 Pages: 62-63
• [Journal Article] Potent amyloidogenicity and pathogenicity of Aβ43 (2011)
  • Author(s): Takashi Saito, Takahiro Suemoto, Nathalie Brouwers, Kristel Sleegers, Satoru Funamoto, Naomi Mihira, Yukio Matsuba, Kazuyuki Yamada, Per Nilsson, Jiro Takano, Masaki Nishimura, Nobuhisa Iwata, Christine Van Broeckhoven, Yasuo Ihara, Takaomi C Saido
  • Journal Title: Nature Neuroscience Volume: 14 Issue: 8 Pages: 1023-1032
  • DOI: 10.1038/nn.2858
  • NAID: 120006985066
  • Peer Reviewed
• [Journal Article] Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease : evidence for γ-secretase dysfunction (2011)
  • Author(s): Hata S
  • Journal Title: Ann.Neurol. Volume: 69 Issue: 6 Pages: 1026-1031
  • DOI: 10.1002/ana.22343
  • Peer Reviewed
• [Presentation] p24α2 interacts with γ-secretase complex at presynaptic terminals (2014)
  • Author(s): Nishimura M, Liu L, Fujino K
  • Organizer: Alzheimer's Association International Conference 2014
  • Place of Presentation: Copenhagen
• [Presentation] Expression of p24α2 in mammalian brain (2014)
  • Author(s): Nishimura M, Liu L
  • Organizer: Experimental Biology 2014
  • Place of Presentation: San Diego
• [Presentation] ILEI はアルツハイマー病モデルマウスのアミロイド沈着と記憶障害を軽減させる (2014)
  • Author(s): 劉磊, 長谷川浩史, 遠山育夫, 村山繁雄, 西村正樹
  • Organizer: 第33回日本認知症学会
  • Place of Presentation: 横浜
• [Presentation] ILEI はAPP-C99 を不安定化することによりアミロイドβ産生を減少させる (2014)
  • Author(s): 劉磊, 長谷川浩史, 遠山育夫, 村山繁雄, 西村正樹
  • Organizer: 第37回日本神経科学会
  • Place of Presentation: 横浜
• [Presentation] p24α2 interacts with γ-secretase complex at presynaptic terminals. (2014)
  • Author(s): Nishimura M, Liu L, Fujino K.
  • Organizer: Alzheimer’s Association International Conference 2014
  • Place of Presentation: Copenhagen、デンマーク王国
• [Presentation] Expression of p24α2 in mammalian brain. (2014)
  • Author(s): Nishimura M, Lei Liu.
  • Organizer: Experimental Biology 2014
  • Place of Presentation: San Diego、アメリカ合衆国
• [Presentation] Modulation of Aβ42 production (2013)
  • Author(s): Nishimura M
  • Organizer: 11th World Congress of Biological Psychiatry
  • Place of Presentation: Kyoto
• [Presentation] Modulation of Aβ42 production. (2013)
  • Author(s): Nishimura M.
  • Organizer: 11th World Congress of Biological Psychiatry
  • Place of Presentation: Kyoto
  • Invited
• [Presentation] γセクレターゼ活性阻害タンパク質p24α2のシナプス局在 (2013)
  • Author(s): 劉 磊、西村正樹
  • Organizer: 日本認知症学会
  • Place of Presentation: 長野県松本市
• [Presentation] Age-related modulation of γ-secretase activity in monkey brains (2012)
  • Author(s): Nishimura M, Nakamura S, Kimura N, Liu L, Suzuki T, Tooyama I
  • Organizer: Alzheimer's Association International Conference 2012
  • Place of Presentation: Vancouver
• [Presentation] Membrane microdomain localization of APP C-terminal fragments regulated by phosphorylation at cytoplasmic Thr668 residue (2012)
  • Author(s): Matsushima T, Saito Y, Nishimura M, Kimura N, Hata S, Suzuki T
  • Organizer: Alzheimer's Association International Conference 2012
  • Place of Presentation: Vancouver
• [Presentation] 加齢に伴うカニクイザル脳γセクレターゼ活性の修飾 : Aβ42 産生比の増加 (2012)
  • Author(s): 西村正樹, 劉磊, 中村紳一朗, 木村展之, 鈴木利治, 遠山育夫
  • Organizer: 第31回日本認知症学会
  • Place of Presentation: つくば
• [Presentation] Age-related modulation of γ-secretase activity in monkey brains. (2012)
  • Author(s): Nishimura M, Nakamura S, Kimura N, Liu L, Suzuki T, Tooyama I.
  • Organizer: Alzheimer’s Association International Conference 2012
  • Place of Presentation: Vancouver, Canada
• [Presentation] Interaction of p24α2 with γ-secretase complex attenuates γ-cleavage of APP (2011)
  • Author(s): Nishimura M, Liu L, Hasegawa H
  • Organizer: Alzheimer's Association International Conference 2011
  • Place of Presentation: Paris
• [Presentation] Nuclear choline acetyltransferase activates transcription of a high-affinity choline transporter (2011)
  • Author(s): Matsuo A, Bellier JP, Nishimura M, Yasuhara O, Saito N, Kimura H
  • Organizer: The 8th IBRO World Congress of Neuroscience
  • Place of Presentation: Florence
• [Presentation] Interaction of p24α2 with γ-secretase complex attenuates γ-cleavage of APP. (2011)
  • Author(s): Nishimura M, et al.
  • Organizer: Alzheimer’s Association International Conference 2011
  • Place of Presentation: Paris
• [Presentation] Nuclear choline acetyltransferase activates transcription of a high-affinity choline transporter. (2011)
  • Author(s): Matsuo A, et al.
  • Organizer: The 8th IBRO World Congress of Neuroscience
  • Place of Presentation: Florence
• [Book] タンパク質発現解析-免疫組織化学法に法補的な手法-. 「組織細胞化学2014」 (2014)
  • Author(s): 西村正樹
  • Publisher: 日本組織細胞化学会(印刷中)
• [Book] 日本臨床増刊号認知症学(上)-その解明と治療の最新知見- (2011)
  • Author(s): 西村正樹. Nicastrin
  • Publisher: 日本臨床社
• [Remarks] ホームページ
  • URL: http://ben.shiga-med.ac.jp/~hqmnran/index_1.html
• [Remarks] 滋賀医科大学神経難病研究推進機構分子神経科学研究センター神経難病病因学分野
  • URL: http://ben.shiga-med.ac.jp/~hqmnran/index_1.html
• [Remarks] 滋賀医科大学神経難病研究推進機構分子神経科学研究センター神経難病病因学分野
  • URL: http://ben.shiga-med.ac.jp/~hqmnran/index_1.html
• [Remarks]
  • URL: http://ben.shiga-med.ac.jp/~hqmnran/index_1.html
• [Patent(Industrial Property Rights)] アミロイドβタンパク質が異常に蓄積する疾患の治療及び/又は予防用の医薬組成物 (2013)
  • Inventor(s): 西村正樹
  • Industrial Property Rights Holder: 滋賀医科大学
  • Filing Date: 2013-12-13
  • Overseas
• [Patent(Industrial Property Rights)] アミロイドβタンパク質が異常に蓄積する疾患の治療及び／又は予防用の医薬組成物 (2013)
  • Inventor(s): 西村正樹
  • Industrial Property Rights Holder: 滋賀医科大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-12-13
  • Overseas
• [Patent(Industrial Property Rights)] アミロイドβタンパク質が異常に蓄積する疾患の治療及び/又は予防用の医薬組成物 (2012)
  • Inventor(s): 西村正樹
  • Industrial Property Rights Holder: 滋賀医科大学
  • Industrial Property Number: 2012-277068
  • Filing Date: 2012-12-19
• [Patent(Industrial Property Rights)] アミロイドβタンパク質が異常に蓄積する疾患の治療及び／又は予防用の医薬組成物 (2012)
  • Inventor(s): 西村正樹
  • Industrial Property Rights Holder: 滋賀医科大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-277068
  • Filing Date: 2012-12-19