open access

https://hdl.handle.net/2115/58151

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

英語

2015-01-09

American Society for Biochemistry and Molecular Biology

Journal of biological chemistry

290(2)

987-995

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.

学術雑誌論文

Accepted Manuscript

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.

0021-9258