title: 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.
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.
authors.affiliation: From the Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan and.
authors.forename: Norio
authors.initials: N
authors.lastname: Takei
authors.affiliation: From the Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan and.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Sobu
authors.affiliation: From the Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan and.
authors.forename: Ayano
authors.initials: A
authors.lastname: Kimura
authors.affiliation: From the Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan and.
authors.forename: Satomi
authors.initials: S
authors.lastname: Urano
authors.affiliation: From the Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Piao
authors.affiliation: From the Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan and.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Araki
authors.affiliation: From the Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan and.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Taru
authors.affiliation: Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Miki-cho 761-0793, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: From the Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan and.
authors.forename: Saori
authors.initials: S
authors.lastname: Hata
authors.affiliation: From the Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan and.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakaya
authors.affiliation: From the Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan and tsuzuki@pharm.hokudai.ac.jp.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015820:Cadherins; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins; D003593:Cytoplasm / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D055571:Secretory Pathway / Q000235:genetics
chemical_list: C491636:APBA2 protein, human; D016564:Amyloid beta-Protein Precursor; D015820:Cadherins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; C503227:Clstn1 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer Disease; Amyloid Precursor Protein (APP); Amyloid-beta (AB); Gamma-secretase; Proteolysis