Development of therapeutic agents for Alzheimer's disease focused by a new modulator of gamma-secretase complex

• Project/Area Number: 23591705
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Osaka University
• Principal Investigator: KATAYAMA Taiichi 大阪大学, 連合小児発達学研究科, 教授 (80333459)
• Co-Investigator(Kenkyū-buntansha): YAMADA Kohei 浜松医科大学, 子どものこころの発達研究センター, 講師 (50588879)
• Project Period (FY): 2011-04-28 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: アルツハイマー病 / プレセニリン / ガンマセクレターゼ / アミロイド / 脳・神経 / 認知症 / ミトコンドリア / γセクレターゼ

Outline of Final Research Achievements

A-beta is known as a most important molecule of Alzheimer's disease (AD) pathogenesis. We tried to identify a new modulator of gamma-secretase which is the final cutting enzyme of the A-beta production using in vivo crosslink method. As a result, unknown molecule GL was identified as a immunoprecipitant with both presnilin-1 and aph-1 antibodies. It is indicated that GL binds to other gamma-secretase components, and attenuation of GL expression by siRNA decrease A-beta production. These results suggest that regulation of GL expression might be a new therapeutic target for AD prevention or inhibition of its development.

Research Products

• [Journal Article] N-ethylmaleimide-sensitive factor interacts with the serotonin transporter and modulates its trafficking: implications for pathophysiology in autism. (2014)
  • Author(s): 1.Iwata K, Matsuzaki H, Tachibana T, Ohno K, Yoshimura S, Takamura H, Yamada K, Matsuzaki S, Nakamura K, Tsuchiya KJ, Matsumoto K, Tsujii M, Sugiyama T, Katayama T, Mori N
  • Journal Title: Molecular Autism Volume: 5(33) Issue: 1 Pages: 2040-2392
  • DOI: 10.1186/2040-2392-5-33
  • Peer Reviewed / Open Access
• [Journal Article] Lack of dopaminergic inputs elongates the primary cilia of striatal neurons. (2014)
  • Author(s): 2.Miyoshi K, Kasahara K, Murakami S, Takeshima M, Kumamoto N, Sato A, Miyazaki I, Matsuzaki S, Sasaoka T, Katayama T, Asanuma M.
  • Journal Title: PLoS One Volume: 9(5) Issue: 5 Pages: e97918-e97918
  • DOI: 10.1371/journal.pone.0097918
  • Peer Reviewed / Open Access
• [Journal Article] XLMR protein related to neurite extension (Xpn/KIAA2022) regulates cell-cell and cell-matrix adhesion and migration (2013)
  • Author(s): Magome T, Hattori T, Taniguchi M, Ishikawa T, Miyata S, Yamada K, Takamura H, Matsuzaki S, Ito A, Tohyama M, Katayama T
  • Journal Title: Neurochemistry International Volume: 63 Issue: 6 Pages: 561-569
  • DOI: 10.1016/j.neuint.2013.09.011
  • Peer Reviewed
• [Journal Article] The endoplasmic reticulum-resident chaperone heat shock protein 47 protects the Golgi apparatus from the effects of o-glycosylation inhibition (2013)
  • Author(s): Miyata S, Mizuno T, Koyama Y, Katayama T, Tohyama M
  • Journal Title: PLoS ONE Volume: 8 Issue: 7 Pages: e69732-e69732
  • DOI: 10.1371/journal.pone.0069732
  • Peer Reviewed
• [Journal Article] DBZ (DISC1-binding zinc finger protein)-deficient mice display abnormalities in basket cells in the somatosensory cortices. (2013)
  • Author(s): Koyama Y, Hattori T, Shimizu S, Taniguchi M, Yamada K, Takamura H, Kumamoto N, Matsuzaki S, Ito A, Katayama T, Tohyama M.
  • Journal Title: J Chem Neuroanat. Volume: 53 Pages: 1-10
  • DOI: 10.1016/j.jchemneu.2013.07.002
  • Peer Reviewed
• [Journal Article] TRAP1 controls mitochondrial fusion/fission balance through Drp1 and Mff expression (2012)
  • Author(s): 1. Takamura H, Koyama Y, Matsuzaki S, Yamada K, Hattori T, Miyata S, Takemoto ., Tohyama M, Katayama T
  • Journal Title: PLoS ONE Volume: 7(12)
  • Peer Reviewed