The role of M16 family metalloprotease in Alzheimer's disease

• Project/Area Number: 21700351
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Neuroscience in general
• Research Institution: Kyoto University
• Principal Investigator: HIRAOKA Yoshinori Kyoto University, 医学研究科, 助教 (60397552)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2009: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: アルツハイマー病 / M16メタロプロテアーゼ / αセクレターゼ / メタロプロテアーゼ

Research Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the formation of amyloidβpeptide (Aβ) and their deposition in the brain as senile plaques. In the nonamyloidgenic pathway, the amyloid precursor protein (APP) is cleaved by theα-secretase within the Aβsequence. Proteinases of the ADAM family are the main candidates, but the underlying mechanism is not cleared. We have demonstrated that nardilysin (N-arginine dibasic convertase; NRDc), a metalloendopeptidase of M16 family, enhacesα-secretase (ADAM9, ADAM10, TACE/ADAM17) activity and reduces Aβgeneration in vitro. We have generated NRDc transgenic (NRDc-Tg) mice that overexpress NRDc in neuron and NRDc hetero-knockout mice (NRDc+/-). A neuronal overexpression of NRDc in model mice of AD (APP-Tg) led to a decrease in the number and size of amyloid plaques. Analysis of mice which reduces NRDc expression in neuron is still going on. Our findings demonstrate that upregulation of NRDc represents an efficacious therapeutic approach to combating AD in vivo.

Research Products

• [Journal Article] Nardilysin Regulates Axonal Maturation and Myelination in the Central and Peripheral Nervous System.Nat. (2009)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Tomimoto H, Takao K, Miyakawa T, Oshima N, Kiyonari H, Kimura T, Kita T, Nishi E.
  • Journal Title: Neurosci. 12 Pages: 1506-1513
  • Peer Reviewed
• [Journal Article] Nardilysin Regulates Axonal Maturation and Myelination in the Central and Peripheral Nervous System (2009)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Tomimoto H, Takao K, Miyakawa T, Oshima N, Kiyonari H, Kimura T, Kita T, Nishi E
  • Journal Title: Nat.Neurosci. 12 Pages: 1506-1513
  • Peer Reviewed
• [Presentation] The role of a metalloendopeptidase nardilysin in adaptive thermogenesis. (2010)
  • Author(s): Hiraoka Y, Matsuoka T, Ohno M, Kita T, Kimura T, Nishi E.
  • Organizer: BMB2010
  • Place of Presentation: 神戸(ポスター発表)
• [Presentation] NRDc controls lipid and glucose metabolism through the modulation of PPARalpha activity. (2010)
  • Author(s): Matsuoka T, Hiraoka Y, Ohno M, Ohshima N, Kiyonari H, Kimura T, Kita T, Nishi E.
  • Organizer: BMB2010
  • Place of Presentation: 神戸(ポスター発表)
• [Presentation] シェディング活性化因子ナルディライジンの多発性硬化症における意義の解明 (2010)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Nishi K, Kimura T, Kita T, Nishi E.
  • Organizer: BMB2010
  • Place of Presentation: 神戸(ポスター発表)
• [Presentation] A Metalloendopeptidase Nardilysin controls Lipid and Glucose metabolism through the modulation of Peroxisome Proliferator-activated Receptor alpha activity. (2010)
  • Author(s): Matsuoka T, Hiraoka Y, Ohno M, Nishi K, Kimura T, Kita T, Nishi E.
  • Organizer: American Heart Association Sessions
  • Place of Presentation: Chicago, Illinois
• [Presentation] A metalloendopeptidase nardilysin is an essential regulator for glucose and lipid metabolism (2010)
  • Author(s): 松岡龍彦、平岡義範、大野美紀子、大島尚子、清成寛、木村剛、北徹、西英一郎.
  • Organizer: 第47回日本臨床分子生物学会
  • Place of Presentation: 東京
• [Presentation] Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system (2010)
  • Author(s): 大野美紀子、平岡義範、松岡龍彦、木村剛、北徹、西英一郎
  • Organizer: 第47回日本臨床分子生物学会
  • Place of Presentation: 東京
• [Presentation] A Metalloendopeptidase Nardilysin is a Regulator of Blood Pressure and Heart Rate (2010)
  • Author(s): Ohno M, Matsuoka T, Hiraoka Y, Niizuma S, Shioi T, Kita T, Kimura T, Nishi E.
  • Organizer: The 74^<rd> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Kyoto(Oral Presentation)
• [Presentation] Nardilysin, a Novel Transcriptional Co-regulator of PPARalpha, Controls Glucose and Lipid Metabolism (2010)
  • Author(s): Matsuoka T, Ohno M, Hiraoka Y, Kita T, Kimura T, Nishi E.
  • Organizer: The 74^<rd> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Kyoto(Poster Presentation)
• [Presentation] The role of a metalloendopeptidase nardilysin in adaptive thermogenesis (2010)
  • Author(s): Hiraoka Y, Matsuoka T, Ohno M, Kita T, Kimura T, Nishi E
  • Organizer: BMB2010
  • Place of Presentation: 神戸
• [Presentation] NRDcはPPARalphaの活性を修飾することにより糖脂質代謝を調節する (2010)
  • Author(s): 松岡龍彦、平岡義範、大野美紀子、西清人、木村剛、北徹、西英一郎
  • Organizer: BMB2010
  • Place of Presentation: 神戸
• [Presentation] シェディング活性化因子ナルディライジンの多発性硬化症における意義の解明 (2010)
  • Author(s): 大野美紀子、平岡義範、松岡龍彦、西清人、西英一郎
  • Organizer: BMB2010
  • Place of Presentation: 神戸
• [Presentation] A metalloendopeptidase nardilysin is a regulator of blood pressure and heart rate (2010)
  • Author(s): Ohno M, Matsuoka T, Hiraoka Y, Niizuma S, Shioi T, Kita T, Kimura T, Nish, E
  • Organizer: The 74th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Kyoto
• [Presentation] Nardilysin, a novel transcriptional co-regulator of PPARalpha, controls glucose and lipid metabolism. (2010)
  • Author(s): Hiraoka Y, Matsuoka T, Ohno M, Kita T, Kimura T, Nishi E
  • Organizer: The 74th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Kyoto
• [Presentation] Critical roles of nardilysin in energy balance and thermoregulation. (2009)
  • Author(s): Hiraoka Y, Matsuoka T, Ohno M, Kita T, Kimura T, Nishi E.
  • Organizer: 第32回日本分子生物学会年回
  • Place of Presentation: 横浜(ポスター発表)
• [Presentation] Nardilysin regulates axonal maturation and myelination in the CNS and PNS. (2009)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Kimura T, Kita T, Nishi E.
  • Organizer: 第32回日本分子生物学会年回
  • Place of Presentation: 横浜(ポスター発表)
• [Presentation] A metalloendopeptidase nardilysin is an essential regulator for glucose and lipid metabolism. (2009)
  • Author(s): Matsuoka T, Ohno M, Hiraoka Y, Kita T, Kimura T, Nishi E.
  • Organizer: 第32回日本分子生物学会年回
  • Place of Presentation: 横浜(ポスター発表)
• [Presentation] A metalloendopeptidase nardilysin is an essential regulator for glucose and lipid metabolism. (2009)
  • Author(s): Matsuoka T, Ohno M, Hiraoka Y, Kita T, Kimura T, Nishi E.
  • Organizer: The 82th Scientific Sessions of American Heart Association
  • Place of Presentation: Orland, Florida(Poster presentation)
• [Presentation] Nardilysin Regulates Axonal Maturation and Myelination in the Central and Peripheral Nervous System. (2009)
  • Author(s): Ohno M, Matsuoka T, Hiraoka Y, Kita T, Nishi E.
  • Organizer: Gordon Research Conference (Matrix Metalloproteinases)
  • Place of Presentation: Les Diablerets, Switzerland(Poster presentation)
• [Presentation] Nardilysin, a Metalloendopeptidase, is a Novel Regulator of Blood Pressure and Heart Rate (2009)
  • Author(s): Ohno M, Matsuoka T, Hiraoka Y, Kita T, Nishi E.
  • Organizer: The 73^<rd> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Osaka(Featured Research Session)
• [Presentation] Nardilysin Deficiency Causes Lean Phenotype with Hypotriglyceridemia and Hypoinsulinemia (2009)
  • Author(s): Matsuoka T, Ohno M, Hiraoka Y, Kita T, Nishi E.
  • Organizer: The 73^<rd> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Osaka(Oral Presentation)
• [Presentation] Critical roles of nardilysin in energy balance and thermoregulation. (2009)
  • Author(s): Hiraoka Y, Matsuoka T, Ohno M, Kita T, Kimura T, Nishi E
  • Organizer: The 32nd Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: Yokohama
• [Presentation] Nardilysin regulates axonal maturation and myelination in the CNS and PNS. (2009)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Kimura T, Kita T, Nishi E
  • Organizer: The 32nd Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: Yokohama
• [Presentation] A metalloendopeptidase nardilysin is an essential regulator for glucose and lipid metabolism. (2009)
  • Author(s): Matsuoka T, Ohno M, Hiraoka Y, Kita T, Kimura T, Nishi E
  • Organizer: The 32nd Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: Yokohama
• [Remarks] ホームページ等
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/sentan-bunshi/
• [Remarks]
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/sentan-bunshi/
• [Remarks]
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/sentan-bunshi/
• [Patent(Industrial Property Rights)] ナルディライジンの高感度免疫測定法 (2009)
  • Inventor(s): 西英一郎、平岡義範、松本恭一、國近誠
  • Industrial Property Rights Holder: 京都大学(50%)、三洋化成工業株式会社(50%)
  • Industrial Property Number: 2009-160792
  • Filing Date: 2009-07-07
• [Patent(Industrial Property Rights)] ナルディライジンの高感度免疫測定法 (2009)
  • Inventor(s): 西英一郎、平岡義範, 他
  • Industrial Property Rights Holder: 京都大学, 他
  • Industrial Property Number: 2009-160792
  • Filing Date: 2009-07-07