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Amyloidogenic processing of amyloid β protein precursor (APP) is enhanced in the brains of alcadein α–deficient mice

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Title: Amyloidogenic processing of amyloid β protein precursor (APP) is enhanced in the brains of alcadein α–deficient mice
Authors: Gotoh, Naoya Browse this author
Saito, Yuhki Browse this author →KAKEN DB
Hata, Saori Browse this author →KAKEN DB
Saito, Haruka Browse this author
Ojima, Daiki Browse this author
Murayama, Chiaki Browse this author
Shigeta, Mayo Browse this author
Abe, Takaya Browse this author →KAKEN DB
Konno, Daijiro Browse this author →KAKEN DB
Matsuzaki, Fumio Browse this author →KAKEN DB
Suzuki, Toshiharu Browse this author →KAKEN DB
Yamamoto, Tohru Browse this author →KAKEN DB
Keywords: amyloid β (Aβ)
Alzheimer's disease
amyloid β protein precursor (APP)
membrane protein
Issue Date: 10-Jul-2020
Publisher: American Society for Biochemistry and Molecular Biology (ASBMB)
Journal Title: Journal of Biological Chemistry (JBC)
Volume: 295
Issue: 28
Start Page: 9650
End Page: 9662
Publisher DOI: 10.1074/jbc.RA119.012386
PMID: 32467230
Abstract: Alzheimer's disease (AD) is a very common neurodegenerative disorder, chiefly caused by increased production of neurotoxic β-amyloid (Aβ) peptide generated from proteolytic cleavage of β-amyloid protein precursor (APP). Except for familial AD arising from mutations in the APP and presenilin (PSEN) genes, the molecular mechanisms regulating the amyloidogenic processing of APP are largely unclear. Alcadein α/calsyntenin1 (ALCα/CLSTN1) is a neuronal type I transmembrane protein that forms a complex with APP, mediated by the neuronal adaptor protein X11-like (X11L or MINT2). Formation of the ALCα–X11L–APP tripartite complex suppresses Aβ generation in vitro, and X11L-deficient mice exhibit enhanced amyloidogenic processing of endogenous APP. However, the role of ALCα in APP metabolism in vivo remains unclear. Here, by generating ALCα-deficient mice and using immunohistochemistry, immunoblotting, and co-immunoprecipitation analyses, we verified the role of ALCα in the suppression of amyloidogenic processing of endogenous APP in vivo. We observed that ALCα deficiency attenuates the association of X11L with APP, significantly enhances amyloidogenic β-site cleavage of APP, especially in endosomes, and increases the generation of endogenous Aβ in the brain. Furthermore, we noted amyloid plaque formation in the brains of human APP-transgenic mice in an ALCα-deficient background. These results unveil a potential role of ALCα in protecting cerebral neurons from Aβ-dependent pathogenicity in AD.
Rights: This research was originally published in the Journal of Biological Chemistry. Gotoh, Naoya, et al. "Amyloidogenic processing of amyloid β protein precursor (APP) is enhanced in the brains of Alcadein α-deficient mice." J Biol Chem. 2020; Vol295:9650-9662. © the American Society for Biochemistry and Molecular Biology or © the Author(s).
Type: article
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 鈴木 利治

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