TY - JOUR
T1 - 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
AU - Takei, Norio
AU - Sobu, Yuriko
AU - Kimura, Ayano
AU - Urano, Satomi
AU - Piao, Yi
AU - Araki, Yoichi
AU - Taru, Hidenori
AU - Yamamoto, Tohru
AU - Hata, Saori
AU - Nakaya, Tadashi
AU - Suzuki, Toshiharu
N1 - Publisher Copyright:
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.
PY - 2015/1/9
Y1 - 2015/1/9
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M114.599852
DO - 10.1074/jbc.M114.599852
M3 - Article
C2 - 25406318
AN - SCOPUS:84920911961
SN - 0021-9258
VL - 290
SP - 987
EP - 995
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 2
ER -