| Title: | Cytoplasmic Fragment of Alcadein alpha Generated by Regulated Intramembrane Proteolysis Enhances Amyloid beta-Protein Precursor (APP) Transport into the Late Secretory Pathway and Facilitates APP Cleavage |
| Authors: | Takei, Norio Browse this author |
| Sobu, Yuriko Browse this author |
| Kimura, Ayano Browse this author |
| Urano, Satomi Browse this author |
| Piao, Yi Browse this author |
| Araki, Yoichi Browse this author |
| Taru, Hidenori Browse this author →KAKEN DB |
| Yamamoto, Tohru Browse this author →KAKEN DB |
| Hata, Saori Browse this author →KAKEN DB |
| Nakaya, Tadashi Browse this author →KAKEN DB |
| Suzuki, Toshiharu Browse this author →KAKEN DB |
| Issue Date: | 9-Jan-2015 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Journal Title: | Journal of biological chemistry |
| Volume: | 290 |
| Issue: | 2 |
| Start Page: | 987 |
| End Page: | 995 |
| Publisher DOI: | 10.1074/jbc.M114.599852 |
| PMID: | 25406318 |
| Abstract: | The neural type I membrane protein Alcadein alpha (Alc alpha), is primarily cleaved by amyloid beta-protein precursor (APP) alpha-secretase to generate a membrane-associated carboxyl-terminal fragment (Alc alpha CTF), which is further cleaved by gamma-secretase to secrete p3-Alc alpha peptides and generate an intracellular cytoplasmic domain fragment (Alc alpha ICD) in the late secretory pathway. By association with the neural adaptor protein X11L (X11-like), Alc alpha and APP form a ternary complex that suppresses the cleavage of both Alc alpha and APP by regulating the transport of these membrane proteins into the late secretory pathway where secretases are active. However, it has not been revealed how Alc alpha and APP are directed from the ternary complex formed largely in the Golgi into the late secretory pathway to reach a nerve terminus. Using a novel transgenic mouse line expressing excess amounts of human Alc alpha CTF (hAlc alpha CTF) in neurons, we found that expression of hAlc alpha CTF induced excess production of hAlc alpha ICD, which facilitated APP transport into the nerve terminus and enhanced APP metabolism, including A beta generation. In vitro cell studies also demonstrated that excess expression of Alc alpha ICD released both APP and Alc alpha from the ternary complex. These results indicate that regulated intramembrane proteolysis of Alc alpha by gamma-secretase regulates APP trafficking and the production of A beta in vivo. |
| Rights: | This research was originally published in Journal of Biological Chemistry. Takei N., et al. Cytoplasmic fragment of Alcadein α generated by regulated intramembrane proteolysis enhances amyloid β-protein precursor (APP) transport into the late secretory pathway and facilitates APP cleavage. Journal of Biological Chemistry. 2015; 290(2):987-995. © the American Society for Biochemistry and Molecular Biology. |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/58151 |
| Appears in Collections: | 薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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