Molecular mechanism of apomorphine therapy for Alzheimer disease

• Project/Area Number: 23890150
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Neurology
• Research Institution: Kyushu University
• Principal Investigator: HIMENO Eri 九州大学, 医学研究院, 共同研究員 (10608508)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 神経分子病態学 / アルツハイマー病 / 3xTg-ADマウス / アポモルフィン / 細胞内アミロイドβ / インスリンシグナリング / インスリン分解酵素 / 毒性ターンアミロイドβ / 小胞体ストレス / モデルマウス / アミロイドβ / リン酸化タウ蛋白 / DNAマイクロアレイ / 酸化ストレス

Research Abstract

Alzheimer’s disease (AD) is the major cause of senile dementia, and development of curative drugs is an important issue. We have found apomorphine (APO) to be a novel drug that targets amyloid-β42 (Aβ42) accumulating early in the neurons. In the present research, we revealed 1) that the anti-AD effects of APO is not simply due to stimulation of dopamine receptors; 2) that APO elevates the activity of Insulin-degrading enzyme (IDE) in the cultured cells; 3) that one of the molecular mechanisms of APO effects may be inhibition of the insulin resistance and elevation of the IDE activity; 4) that APO treatment is more effective for the AD mouse model (3xTg-AD) than lithium treatment which inhibits hyper-phosphrylation of tau protein; and 5) that Apokyn(R), a drug of APO for Parkinson’s disease patients, is effective enough at low dose for memory function of the AD mouse model. While, we studied the nature of intracellular Aβ, and have demonstrated that toxic turn Aβ42 accumulates in neurons before onset of memory dysfunction inducing endoplasmic reticulum stress in 3xTg-AD mice.

Research Products

• [Journal Article] Intracellular accumulation of toxic turn amyloid-β is associated with endoplasmic reticulum stress in Alzheimer's disease. (2013)
  • Author(s): Soejima N, Ohyagi Y, Nakamura N, Himeno E, Iinuma KM, Sakae N, Yamasaki R, Tabira T, Murakami K, Irie K, Kinoshita N, LaFerla FM, Kiyohara Y, Iwaki T, Kira J
  • Journal Title: CurrAlzheimer Res Volume: 10 Issue: 1 Pages: 11-20
  • DOI: 10.2174/1567205011310010003
  • Peer Reviewed
• [Journal Article] Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation. (2011)
  • Author(s): Himeno E, Ohyagi Y, Ma L, Nakamura N, Miyoshi K, Sakae N, Motomura K, Soejima N, Yamasaki R, Hashimoto T, Tabira T, LaFerla FM, Kira J
  • Journal Title: Ann Neurol Volume: 69 Issue: 2 Pages: 248-256
  • DOI: 10.1002/ana.22319
  • Peer Reviewed
• [Journal Article] Activation of glutathione peroxidase and inhibition of p53-related apoptosis by apomorphine. (2011)
  • Author(s): Ma L, Ohyagi Y, Nakamura N, Iinuma KM, Miyoshi K, Himeno E, Soejima N, Yanagihara YT, Sakae N, Yamasaki R, Kira J
  • Journal Title: J Alzheimers Dis Volume: 27 Issue: 1 Pages: 225-237
  • DOI: 10.3233/jad-2011-110140
  • Peer Reviewed
• [Presentation] Intracellular accumulation of toxic turn amyloid-β associated with endoplasmic reticulum stress in Alzheimer’s disease (2012)
  • Author(s): Yasumasa Ohyagi
  • Organizer: 42nd Annual Meeting of Society for Neuroscience
  • Place of Presentation: アメリカ合衆国ニューオリンズ
• [Presentation] Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation (2011)
  • Author(s): Ohyagi Y, Himeno E, Motomura K, Soejima N, Nakamura N, Kira J
  • Organizer: Alzheimer's Association International Conference on Alzheimer's Disease
  • Place of Presentation: Paris, France
  • Year and Date: 2011-07-18
• [Presentation] Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation (2011)
  • Author(s): Ohyagi Y, Himeno E, et al
  • Organizer: Alzheimer's Association Interniational Conference on Alzheimer's Disease 2011
  • Place of Presentation: フランス・パリ
  • Year and Date: 2011-07-18
• [Presentation] 認知症の耐糖能と認知機能低下に関する検討 (2011)
  • Author(s): 姫野恵理、大八木保政、山下謙一郎、中村憲道、副島直子、吉良潤一
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
• [Presentation] 3xTg-AD マウスにおけるアポモルフィンの抗酸化ストレス作用とAβ分解促進 (2011)
  • Author(s): 中村憲道、大八木保政、姫野恵理、副島直子、本村今日子、栄信孝、吉良潤一
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
• [Presentation] 3xTg-AD マウス及び変異PS1 細胞の細胞内Aβオリゴマーと細胞内輸送系障害 (2011)
  • Author(s): 副島直子、大八木保政、中村憲道、姫野恵理、本村今日子、栄信孝、吉良潤一
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
• [Presentation] 3xTg-AD マウスにおけるアポモルフィンとリチウム併用治療の検討 (2011)
  • Author(s): 大八木保政、本村今日子、中村憲道、姫野恵理、副島直子、栄信孝、吉良潤一
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
• [Presentation] 細胞内アミロイドβの分子病態とアポモルフィン治療 (2011)
  • Author(s): 大八木保政、中村憲道、副島直子、姫野恵理、吉良潤一
  • Organizer: 第30回日本認知症学会学術集会
  • Place of Presentation: 東京
• [Remarks] 九州大学大学院医学研究院神経内科学
  • URL: http://www.med.kyushu-u.ac.jp/neuro/