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

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

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

Gotoh, Naoya; Saito, Yuhki; Hata, Saori et al.

Journal of Biological Chemistry (JBC), 2020, 295(28), 9650-9662

Permalink : https://hdl.handle.net/2115/82208

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アクセス権	open access
URI	https://hdl.handle.net/2115/82208
タイトル	Amyloidogenic processing of amyloid β protein precursor (APP) is enhanced in the brains of alcadein α–deficient mice
著者	Gotoh, Naoya ; Saito, Yuhki ; Hata, Saori ; Saito, Haruka ; Ojima, Daiki ; Murayama, Chiaki ; Shigeta, Mayo ; Abe, Takaya ; Konno, Daijiro ; Matsuzaki, Fumio ; Suzuki, Toshiharu ; Yamamoto, Tohru
著者名 Gotoh, Naoya
e-Rad_Researcher 70548180 著者名 Saito, Yuhki
e-Rad_Researcher 40581012 著者名 Hata, Saori
著者名 Saito, Haruka
著者名 Ojima, Daiki
著者名 Murayama, Chiaki
著者名 Shigeta, Mayo
e-Rad_Researcher 10720609 著者名 Abe, Takaya
e-Rad_Researcher 00362715 著者名 Konno, Daijiro
e-Rad_Researcher 10173824 著者名 Matsuzaki, Fumio
e-Rad_Researcher 80179233 著者名 Suzuki, Toshiharu
e-Rad_Researcher 10251480 著者名 Yamamoto, Tohru
言語	英語
キーワード	amyloid β (Aβ)
	alcadein
	calsyntenin
	Alzheimer's disease
	amyloid β protein precursor (APP)
	membrane protein
	metabolism
	X11-like
	Mint2
	neurodegeneration
発行日	2020-07-10
出版者	American Society for Biochemistry and Molecular Biology (ASBMB)
収録物名	Journal of Biological Chemistry (JBC)
巻(号)	295(28)
ページ	9650-9662
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Version of Record
権利情報	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).
PISSN	0021-9258
EISSN	1083-351X
関連情報	PMID 32467230
関連情報 (isIdenticalTo)	出版社版DOI https://doi.org/10.1074/jbc.RA119.012386