Takei Norio, Sobu Yuriko, Kimura Ayano, Urano Satomi, Piao Yi, Araki Yoichi, Taru Hidenori, Yamamoto Tohru, Hata Saori, Nakaya Tadashi, Suzuki Toshiharu
From the Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan and.
Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Miki-cho 761-0793, Japan.
J Biol Chem. 2015 Jan 9;290(2):987-95. doi: 10.1074/jbc.M114.599852. Epub 2014 Nov 18.
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.
神经I型膜蛋白阿尔卡地因α（Alcα）主要由淀粉样β蛋白前体（APP）α-分泌酶切割，产生一个膜相关的羧基末端片段（Alcα CTF），该片段在晚期分泌途径中进一步被γ-分泌酶切割，分泌p3-Alcα肽并产生细胞内胞质结构域片段（Alcα ICD）。通过与神经衔接蛋白X11L（X11样）结合，Alcα和APP形成三元复合物，通过调节这些膜蛋白向分泌酶活跃的晚期分泌途径的转运，抑制Alcα和APP的切割。然而，尚未揭示Alcα和APP如何从主要在高尔基体中形成的三元复合物被导向晚期分泌途径以到达神经末梢。使用一种在神经元中表达过量人Alcα CTF（hAlcα CTF）的新型转基因小鼠品系，我们发现hAlcα CTF的表达诱导了hAlcα ICD的过量产生，这促进了APP向神经末梢的转运并增强了APP代谢，包括Aβ的产生。体外细胞研究还表明，Alcα ICD的过量表达使APP和Alcα从三元复合物中释放出来。这些结果表明，γ-分泌酶对Alcα的调节性膜内蛋白水解在体内调节APP的运输和Aβ的产生。
