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

Norio Takei, Yuriko Sobu, Ayano Kimura, Satomi Urano, Yi Piao, Yoichi Araki, Hidenori Taru, Tohru Yamamoto, Saori Hata, Tadashi Nakaya, Toshiharu Suzuki

Research output: Contribution to journalArticle

Abstract

The neural type I membrane protein Alcadein α (Alcα), is primarily cleaved by amyloid β-protein precursor (APP) α-secretase to generate a membrane-associated carboxyl-terminal fragment (Alcα CTF), which is further cleaved by γ-secretase to secrete p3-Alcα peptides and generate an intracellular cytoplasmic domain fragment (Alcα ICD) in the late secretory pathway. By association with the neural adaptor protein X11L (X11-like), Alcα and APP form a ternary complex that suppresses the cleavage of both Alcα andAPPby regulating the transport of these membrane proteins into the late secretorypathwaywheresecretases are active. However, it has not been revealed how Alcα 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 Alcα CTF (hAlcα CTF) in neurons, we found that expression of hAlcα CTF induced excess production of hAlcα ICD, which facilitated APP transport into the nerve terminus and enhanced APP metabolism, including Aβ generation. In vitro cell studies also demonstrated that excess expression of Alcα ICD released both APP and Alcα from the ternary complex. These results indicate that regulated intramembrane proteolysis of Alcα by γ-secretase regulates APP trafficking and the production of Aβ in vivo.

Original languageEnglish (US)
Pages (from-to)987-995
Number of pages9
JournalJournal of Biological Chemistry
Volume290
Issue number2
DOIs
StatePublished - Jan 9 2015
Externally publishedYes

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Proteolysis
Amyloid beta-Protein Precursor
Secretory Pathway
Protein Transport
Amyloid Precursor Protein Secretases
Amyloidogenic Proteins
Membrane Transport Proteins
Transgenic Mice
Membrane Proteins
Metabolism
Neurons
Association reactions
Membranes
Peptides
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

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. / Takei, Norio; Sobu, Yuriko; Kimura, Ayano; Urano, Satomi; Piao, Yi; Araki, Yoichi; Taru, Hidenori; Yamamoto, Tohru; Hata, Saori; Nakaya, Tadashi; Suzuki, Toshiharu.

In: Journal of Biological Chemistry, Vol. 290, No. 2, 09.01.2015, p. 987-995.

Research output: Contribution to journalArticle

Takei, Norio ; Sobu, Yuriko ; Kimura, Ayano ; Urano, Satomi ; Piao, Yi ; Araki, Yoichi ; Taru, Hidenori ; Yamamoto, Tohru ; Hata, Saori ; Nakaya, Tadashi ; Suzuki, Toshiharu. / 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. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 2. pp. 987-995.
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