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

doi:10.1074/jbc.m114.599852

Norio Takei, Yuriko Sobu + Show 9 more

Open Access

https://doi.org/10.1074/jbc.m114.599852

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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 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 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.

Highlights

Alcadein ␣ (Alc␣) forms a ternary complex with amyloid ␤-protein precursor (APP) and X11L
Using a novel transgenic mouse line expressing excess amounts of human Alc␣ CTF in neurons, we found that expression of hAlc␣ CTF induced excess production of hAlc␣ ICD, which facilitated APP transport into the nerve terminus and enhanced APP metabolism, including A␤ generation
Because it was documented that the generation of A␤ from APP and the formation of neurotoxic A␤ oligomers in neurons are closely linked to the etiology of Alzheimer disease, many efforts have been made to identify the modulator of APP metabolism, including A␤ generation and clearance [14]

Summary

Background

Alcadein ␣ (Alc␣) forms a ternary complex with APP and X11L. Results: Transport into the nerve terminus and metabolism of APP were facilitated in Alc␣ CTF transgenic mice, along with an increase in A␤. Conclusion: Alc␣ ICD, a product of ␥-secretase cleavage of Alc␣ CTF, enhanced APP trafficking from the ternary complex into a late secretory pathway. By association with the neural adaptor protein X11L (X11-like), Alc␣ and APP form a ternary complex that suppresses the cleavage of both Alc␣ and APP by regulating the transport of these membrane proteins into the late secretory pathway where secretases are active. In vitro, binding of APP to X11L is stabilized when Alc␣ is coexpressed, and this enhanced interaction of APP with X11L mediated by Alc␣ is thought to further stabilize APP metabolism as well as regulate intracellular APP trafficking because the cleavage of APP by secretases occurs in the late secretory pathway. To determine the function of Alc␣ CTF and its intracellular metabolic fragment Alc␣ ICD, we generated a transgenic mouse line expressing human Alc␣-CTF under the control of the PDGF-␤ promoter and examined its effect on the metabolism of APP in vivo

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION