Involvement of sigma 1 receptor in Alzheimer's disease and treatment development based on it

• Project/Area Number: 16K10213
• 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: Kudo Takashi 大阪大学, キャンパスライフ健康支援センター, 教授 (10273632)
• Project Period (FY): 2016-10-21 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 小胞体ストレス / シグマ1受容体 / フルボキサミン / アルツハイマー病 / シグマ１受容体 / 神経細胞死 / ERストレス / 細胞死 / アミロイドペプチド

Outline of Final Research Achievements

We have shown that Sig-1R is transcriptionally upregulated via the PERK / eIF2a / ATF4 pathway of endoplasmic reticulum (ER) stress and improves cell death signaling.
Fluvoxamine (Flv) is a selective serotonin reuptake inhibitor (SSRI) with high affinity for Sig-1R. In the present study, it was shown that Flv induces Sig-1R expression by directly increasing ATF4 translation through its own activation, without involvement of the PERK pathway. This Flv-mediated induction of Sig-1R has been shown to prevent neuronal cell death resulting from ER stress, and is expected to be applied to a new treatment for Alzheimer's disease.

Academic Significance and Societal Importance of the Research Achievements

アルツハイマー病をはじめとする認知症の治療法確立は、高齢化社会を迎え、喫緊の課題である。しかしながら、現在までのところ根本治療法は確立されていない。一方、多くの認知症発症の機序として小胞体ストレスの関与が示唆されている。本研究はシグマ1受容体が小胞体ストレス反応による細胞死を抑止する効果を持つことを示し、これに基づいた治療法開発の可能性を示した。

Research Products

• [Journal Article] Semagacestat Is a Pseudo-Inhibitor of γ-Secretase (2017)
  • Author(s): Tagami S, Yanagida K, Kodama TS, Takami M, Mizuta N, Oyama H, Nishitomi K, Chiu YW, Okamoto T, Ikeuchi T, Sakaguchi G, Kudo T, Matsuura Y, Fukumori A, Takeda M, Ihara Y, Okochi M.
  • Journal Title: Cell Rep Volume: 21 Issue: 1 Pages: 259-273
  • DOI: 10.1016/j.celrep.2017.09.032
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Small Peptides in Human Cerebrospinal Fluid upon Amyloid-β Degradation (2017)
  • Author(s): Mizuta N, Yanagida K, Kodama T, Tomonaga T, Takami M, Oyama H, Kudo T, Ikeda M, Takeda M, Tagami S, Okochi M
  • Journal Title: Neurodegener Dis Volume: 17 Pages: 103-109
  • Peer Reviewed / Open Access
• [Journal Article] Changing Moods: How Manual Tracking by Family Caregivers Improves Caring and Family Communication. (2017)
  • Author(s): Yamashita N, Kuzuoka H, Hirata K, Kudo T, Aramaki E, Hattori K
  • Journal Title: CHI Volume: May Pages: 06-11
  • Peer Reviewed
• [Journal Article] Sleep disturbances are key symptoms of very early stage Alzheimer disease with behavioral and psychological symptoms: a Japan multi-center cross-sectional study (J-BIRD). (2016)
  • Author(s): Kabeshita Y, Adachi H, Matsushita M, Kanemoto H, Sato S, Suzuki Y, Yoshiyama K, Shimomura T, Yoshida T, Shimizu H, Matsumoto T, Mori T, Kashibayashi T, Tanaka H, Hatada Y, Hashimoto M, Nishio Y, Komori K, Tanaka T, Yokoyama K, Tanimukai S, Ikeda M, Takeda M, Mori E, Kudo T, Kazui H.
  • Journal Title: Int J Geriatr Psychiatry. Volume: - Issue: 2 Pages: 222-230
  • DOI: 10.1002/gps.4470
  • Peer Reviewed