Neuronal activity promotes tau phosphorylation via enhancement of APP processing

• Project/Area Number: 26870209
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Nerve anatomy/Neuropathology; Neurology
• Research Institution: Niigata University
• Principal Investigator: Kasuga Kensaku 新潟大学, 研究推進機構, 助教 (70547546)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: アルツハイマー病 / 神経活動 / アミロイド前駆体蛋白 / Aβ / タウ蛋白 / アミロイドβ / タウ蛋白リン酸化 / Alzheimer's disease / Neuronal activity / Amyloid beta / Phosphorylated tau

Outline of Final Research Achievements

Alzheimer’s disease (AD) is the most common cause of dementia, which is pathologically characterized by extracellular deposits of β-amyloid (Aβ) and intracellular accumulation of hyperphosphorylated tau. Hippocampal neurons showing hyperactivity early in the disease course send those axons to the default-mode network where Aβ accumulates remarkably in the brain. Aβ is derived from amyloid precursor protein (APP) by sequential cleavages.
Here we performed in vitro assay with murine neuroblastoma cells and rat cortical neuron primary cultures. After glutamatergic stimulation, we found that full length APP was reduced in a neuronal activity dependent manner. In addition, C-terminal fragments of APP increased after the stimulation, suggesting that the stimulation enhanced β-cleavage. We previously showed Aβ-dependent tau phosphorylation by using the coculture system. Taken together, neuronal activity may affect APP processing and tau phosphorylation in neuronal network.

Research Products

• [Journal Article] Systematic review and meta-analysis of Japanese familial Alzheimer's disease and FTDP-17. (2015)
  • Author(s): Ｋａｓｕｇａ，ｅｔ ａｌ
  • Journal Title: Ｊｏｕｒｎａｌ ｏｆ Ｈｕｍａｎ Ｇｅｎｅｔｉｃｓ Volume: in press Issue: 5 Pages: 1-3
  • DOI: 10.1038/jhg.2015.15
  • Peer Reviewed / Open Access
• [Presentation] Neuronal activity enhances APP processing in cultured neurons (2015)
  • Author(s): Saito K, Kasuga K and Ikeuchi T
  • Organizer: Neuroscience annual meeting 2015
  • Place of Presentation: McCormick Place, IL, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Systematic review of Japanese familial Alzheimer’s disease and FTDP-17 (2015)
  • Author(s): Kasuga K, Kikuchi M, Tokutake T, Nakaya A, Tezuka T, Tsukie T, Hara N, Miyashita A, Kuwano R and Ikeuchi T
  • Organizer: Alzheimer’s Association International Conference 2015
  • Place of Presentation: Convention Center, Washington DC, USA
  • Year and Date: 2015-07-18
  • Int'l Joint Research
• [Presentation] 本邦における家族アルツハイマー病データベース(Japanese Familial Alzheimer's Disease database, JFADdb)の構築 (2015)
  • Author(s): 春日健作、菊地正隆、徳武孝允、手塚敏之、月江珠緒、原範和、宮下哲典、中谷明弘、桑野良三、池内健
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 朱鷺メッセ、新潟
  • Year and Date: 2015-05-20
• [Presentation] ニワトリと卵, 神経活動とAβ放出 (2014)
  • Author(s): 春日健作
  • Organizer: 第33回日本認知症学会学術集会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2014-10-29 – 2014-11-01
  • Invited
• [Remarks] http://alzdb.bri.niigata-u.ac.jp/