The examination of AD pathology from the perspective of the astrocyte-neuron interaction: the participation of IGFBP-3 released by astrocytes.

• Project/Area Number: 26461270
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Kyoto University
• Principal Investigator: Uemura Kengo 京都大学, 医学研究科, 非常勤講師 (00378663)
• Co-Investigator(Renkei-kenkyūsha): KINOSHITA Ayae 京都大学, 医学研究科, 教授 (80321610)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 神経分子病態学 / 認知症 / 脳、神経

Outline of Final Research Achievements

We presumed that astrocytes might trigger neuronal reactions, leading to tau phosphorylation. In this study, we examined AD pathology from the perspective of the astrocyte-neuron interaction. A cytokine-array analysis revealed that Abeta stimulates astrocytes to release several chemical mediators that are primarily related to inflammation and cell adhesion. Among those mediators, insulin-like growth factor (IGF)-binding protein 3 (IGFBP-3) was highly upregulated. In this study, we found that IGF-Ι suppressed tau phosphorylation induced by Abeta, although IGFBP-3 inhibited this property of IGF-Ι. As a result, IGFBP-3 contributed to tau phosphorylation and cell death induced by Abeeta. Our study suggested that calcineurin in astrocytes was activated by Abeta, leading to IGFBP-3 release. We further demonstrated that IGFBP-3 produced by astrocytes induced tau phosphorylation in neurons. Our study provides novel insights into the role of astrocytes in the induction of tau phosphorylation.

Research Products

• [Journal Article] The participation of insulin-like growth factor-binding protein 3 released by astrocytes in the pathology of Alzheimer's disease. (2015)
  • Author(s): Watanabe K, Uemura K, Asada M, Maesako M, Akiyama H, Shimohama S, Takahashi R, Kinoshita A.
  • Journal Title: Mol Brain Volume: 4;8(1) Issue: 1 Pages: 82-82
  • DOI: 10.1186/s13041-015-0174-2
  • NAID: 120005708017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High Fat Diet Enhances β-Site Cleavage of Amyloid Precursor Protein (APP) via Promoting β-Site APP Cleaving Enzyme 1/Adaptor Protein 2/Clathrin Complex Formation. (2015)
  • Author(s): Maesako M, Uemura M, Tashiro Y, Sasaki K, Watanabe K, Noda Y, Ueda K, Asada-Utsugi M, Kubota M, Okawa K, Ihara M, Shimohama S, Uemura K, Kinoshita A.
  • Journal Title: PLoS One. Volume: 10(9) Issue: 9 Pages: e0131199-e0131199
  • DOI: 10.1371/journal.pone.0131199
  • NAID: 120005947169
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Idiopathic Normal Pressure Hydrocephalus has a Different Cerebrospinal Fluid Biomarker Profile from Alzheimer's Disease (2014)
  • Author(s): Naoto Jingami, Megumi Asada-Utsugi, Kengo Uemura, Rio Noto, Makio Takahashi, Akihiko Ozaki, Takeshi Kihara, Takashi Kageyama, Ryosuke Takahashi, Shun Shimohama, Ayae Kinoshita.
  • Journal Title: Jounral of Alzheimer's Disease Volume: 126（４） Issue: 1 Pages: 675-81
  • DOI: 10.3233/jad-142622
  • NAID: 120005593597
  • Peer Reviewed / Open Access