Analysis of multiple mechanisms of APP axonal transport

• Project/Area Number: 22K15270
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Doshisha University (2023); Hokkaido University (2022)
• Principal Investigator: Sobu Yuriko 同志社大学, 脳科学研究科, 助教 (80825068)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2023: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2022: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 軸索輸送 / APP / アミロイド前駆体タンパク質 / 細胞内輸送 / キネシン1 / キネシン / 小胞輸送

Outline of Research at the Start

アルツハイマー病(AD)はアミロイドβ (Aβ)による神経毒性が主要な発症原因の一つであると考えられている。Aβの前駆体であるアミロイド前駆体タンパク質(APP)は輸送小胞上に挿入され、神経軸索中をKinesin-1により輸送されることが明らかである。しかし、APP輸送小胞とKinesin-1の接続機構については複数のメカニズムが報告されており、議論が続いている。本研究はキネシンアイソフォームの違いによってAPPが複数のメカニズムで輸送されている可能性を検討し、Aβの産生への関連およびその生理的意義の解析を行う。

Outline of Final Research Achievements

Several mechanism of axonal transport of amyloid precursor protein (APP) have reported. In this study, se showed that there is a different molecular mechanism for axonal transport of APP. We also found that this difference is due to multiple kinesin Isoforms. APP interacts with new identified kinesin by a mechanism quite different from known molecular mechanisms. In most cases, APP is transported toward axon terminals in a more rapid manner, but knockdown of the molecules responsible for this transport did not inhibit APP axonal transport. Simultaneous knockdown of the newly identified molecules in this study inhibited most APP transport, indicating that a novel transport mechanism is indeed functioning in neurons.

Translated with www.DeepL.com/Translator (free version)

Academic Significance and Societal Importance of the Research Achievements

これまで、APPの軸索輸送機構について複数の分子メカニズムが提唱されてきたが、関連分子のノックダウンがAPP輸送を完全に停止させないなど、輸送機構の複雑さが提唱されてきた。本研究は1つの軸索の中で、APPが複数のメカニズムにより輸送されていることを明らかにしたものであり、今後の軸索輸送機構の議論をより正確にするための土台になりうる。APPはアルツハイマー関連分子としてだけではなく、発生期やシナプス形成の機能も報告されており、同定した輸送機構は軸索外の機能に関与する可能性も考えられる。

Research Products

• [Journal Article] Axonal transport of Frizzled5 by Alcadein α-containing vesicles is associated with kinesin-1 (2023)
  • Author(s): Shiraki Yuzuha、Mitsuma Monet、Takada Ritsuko、Hata Saori、Kitamura Akira、Takada Shinji、Kinjo Masataka、Taru Hidenori、M?ller Ulrike C.、Yamamoto Tohru、Sobu Yuriko、Suzuki Toshiharu
  • Journal Title: Molecular Biology of the Cell Volume: 34 Issue: 11
  • DOI: 10.1091/mbc.e22-10-0495
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Brain <scp>p3‐Alcβ</scp> peptide restores neuronal viability impaired by Alzheimer's amyloid β‐peptide (2023)
  • Author(s): Hata S, Saito H, Kakiuchi T, Fukumoto D, Yamamoto S, Kasuga K, Kimura A, Moteki K, Abe R, Adachi S, Kinoshita S, Yoshizawa-Kumagaye K, Nishio H, Saito T, Saido TC, Yamamoto T, Nishimura M, Taru H, Sobu Y, Ohba H, Nishiyama S, Harada N, Ikeuchi T, Tsukada H, Ouchi Y, Suzuki T
  • Journal Title: EMBO Molecular Medicine Volume: - Issue: 5 Pages: 1-15
  • DOI: 10.15252/emmm.202217052
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Measuring Axonal Cargo Transport in Mouse Primary Cortical Cultured Neurons (2023)
  • Author(s): Sobu Yuriko、Suzuki Toshiharu
  • Journal Title: Journal of Visualized Experiments Volume: 192 Issue: 192
  • DOI: 10.3791/64999
  • Peer Reviewed
• [Presentation] Axonal transport of Amyloid precursor protein is mediated by several mechanisms (2023)
  • Author(s): Y. Sobu , S. Abe , T. Suzuki
  • Organizer: An ASCB/EMBO meeting CELL BIO 23
  • Int'l Joint Research