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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

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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)

Submitter: 鈴木 利治

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