Nardilysin prevents amyloid plaque formation by enhancing alpha-secretase activity in an Alzheimer's disease mouse model.

2013 Fiscal Year Final Research Report

• Project/Area Number: 24700366
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Kyoto University
• Principal Investigator: OHNO Mikiko 京都大学, 医学(系)研究科(研究院), 助教 (10583198)
• Co-Investigator(Renkei-kenkyūsha): NISHI Eiichiro 京都大学, 医学研究科, 准教授 (30362528)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: アルツハイマー病 / アミロイドβ / シェディング

Research Abstract

Amyloid beta peptide, the main component of senile plaques in patients with Alzheimer's disease (AD), is derived from proteolytic cleavage of amyloid precursor protein (APP) by beta- and gamma-secretases. Alpha-cleavage of APP has a potential to preclude the generation of A-beta because it occurs within the A-beta domain. We reported that a metalloendopeptidase, nardilysin (N-arginine dibasic convertase; NRDc) enhances alpha-cleavage of APP, which results in the decreased generation of A-beta in vitro. To clarify the in vivo role of NRDc in AD, we intercrossed transgenic mice expressing NRDc in the forebrain with an AD mouse model. Here we demonstrate that the neuron-specific overexpression of NRDc prevents A-beta deposition in the AD mouse model. The activity of alpha-secretase in the mouse brain was enhanced by the overexpression of NRDc, and was reduced by the deletion of NRDc. Our results indicate that NRDc controls A-beta formation through the regulation of alpha-secretase.

Research Products

• [Journal Article] Critical roles of nardilysin in the maintenance of body temperature homoeostasis (2014)
  • Author(s): Hiraoka Y, Matsuoka T, Ohno M, Nakamura K, Saijo S, Matsumura S, Nishi K, Sakamoto J, Chen PM, Inoue K, Fushiki T, Kita T, Kimura T and Nishi E.
  • Journal Title: Nat Commun Volume: 5 Pages: 3224
• [Journal Article] Nardilysin prevents amyloid plaque formation by enhancingα-secretase activity in an Alzheimer's disease mouse model (2014)
  • Author(s): Ohno M, Hiraoka Y, Lichtenthaler S.F, Nishi K, Saijo S, Matsuoka T, Tomimoto H, Araki W, Takahashi R, Kita T, Kimura T and Nishi E.
  • Journal Title: Neurobiol Aging Volume: 35(1) Pages: 213-22
• [Journal Article] Nardilysin and ADAM proteases promote gastric cancer cell growth by activating intrinsic cytokine signaling via enhanced ectodomain shedding of TNF-α (2012)
  • Author(s): Kanda K, Komekado H, Sawabu T, Ishizu S, Nakanishi Y, Nakatsuji M, Akitake-Kawano R, Ohno M, Hiraoka Y, Kawada M, Kawada K, Sakai Y, Matsumoto K, Kunichika M, Kimura T, Seno H, Nishi E and Chiba T.
  • Journal Title: EMBO Mol Med Volume: 4(5) Pages: 396-411
• [Presentation] Nardilysin prevents amyloid plaque formation by enhancing alpha-secretase activity in an Alzheimer's disease mouse model (2013)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Nishi K, Saijo S, Sakamoto J, Chen PM, Kita T, Kimura T, Nishi E.
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2013-12-04
• [Presentation] エネルギー代謝におけるナルディライジンの役割 (2013)
  • Author(s): 大野美紀子、平岡義範、松岡龍彦、西清人、西城さやか、坂本二郎、陳博敏、北徹、木村剛、西英一郎
  • Organizer: 動脈硬化若手研究会
  • Place of Presentation: 東京
  • Year and Date: 2013-10-19
• [Presentation] ナルディライジンによる交感神経系分布及び循環動態制御機構 (2013)
  • Author(s): 大野美紀子
  • Organizer: 第一回京都循環動態研究会
  • Place of Presentation: 京都
  • Year and Date: 2013-10-18
• [Presentation] ナルディライジンによる心拍数制御機構 (2013)
  • Author(s): 大野美紀子、平岡義範、松浦博、西清人、西城さやか、坂本二郎、陳博敏、北徹、木村剛、西英一郎
  • Organizer: 第18回日本病態プロテアーゼ学会
  • Place of Presentation: 大阪
  • Year and Date: 2013-08-16
• [Presentation] Nardilysin, an Activator of Ectodomain Shedding, is a Novel and Potent Biomarker for Acute Coronary Syndrome (2013)
  • Author(s): Ohno M, Watanabe S, Hiraoka Y, Matsuoka T, Nishi K, Saijo S, Sakamoto J, Chen PM, Inoue K, Kita T, Kimura T, Nishi E.
  • Organizer: 第回日本循環器学会近畿地方会
  • Place of Presentation: 京都
  • Year and Date: 2013-06-15
• [Presentation] Nardilysin regulates cardiovascular functions through modulating cardiac sympathetic innervation
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Nishi K, Saijo S, Sakamoto J, Chen PM, Kita T, Kimura T, Nishi E.
• [Remarks]
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/sentan-bunshi/