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

Naoya Gotoh, Yuhki Saito, Saori Hata, Haruka Saito, Daiki Ojima, Chiaki Murayama, Mayo Shigeta, Takaya Abe, Daijiro Konno, Fumio Matsuzaki, Toshiharu Suzuki, Tohru Yamamoto

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)9650-9662
Number of pages13
JournalThe Journal of biological chemistry
Volume295
Issue number28
DOIs
Publication statusPublished - Jul 10 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Gotoh, N., Saito, Y., Hata, S., Saito, H., Ojima, D., Murayama, C., Shigeta, M., Abe, T., Konno, D., Matsuzaki, F., Suzuki, T., & Yamamoto, T. (2020). Amyloidogenic processing of amyloid β protein precursor (APP) is enhanced in the brains of alcadein α-deficient mice. The Journal of biological chemistry, 295(28), 9650-9662. https://doi.org/10.1074/jbc.RA119.012386