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The FAM3 superfamily member ILEI ameliorates Alzheimer’s disease-like pathology by destabilizing the penultimate amyloid-β precursor

Author

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  • Hiroshi Hasegawa

    (Molecular Neuroscience Research Center, Shiga University of Medical Science
    Present address: Minami-Kyoto Hospital, Kyoto, Japan)

  • Lei Liu

    (Molecular Neuroscience Research Center, Shiga University of Medical Science)

  • Ikuo Tooyama

    (Molecular Neuroscience Research Center, Shiga University of Medical Science)

  • Shigeo Murayama

    (Tokyo Metropolitan Institute of Gerontology)

  • Masaki Nishimura

    (Molecular Neuroscience Research Center, Shiga University of Medical Science)

Abstract

Accumulation of amyloid-β peptide (Aβ) in the brain underlies the pathogenesis of Alzheimer’s disease (AD). Aβ is produced by β- and γ-secretase-mediated sequential proteolysis of amyloid-β precursor protein (APP). Here we identify a secretory protein named interleukin-like epithelial-mesenchymal transition inducer (ILEI, also known as FAM3 superfamily member C) as a negative regulator of Aβ production. ILEI destabilizes the β-secretase-cleaved APP carboxy-terminal fragment, the penultimate precursor of Aβ, by binding to the γ-secretase complex and interfering with its chaperone properties. Notch signalling and γ-secretase activity are not affected by ILEI. We also show neuronal expression of ILEI and its induction by transforming growth factor-β signalling. The level of secreted ILEI is markedly decreased in the brains of AD patients. Transgenic (Tg) overexpression of ILEI significantly reduces the brain Aβ burden and ameliorates the memory deficit in AD model mice. ILEI may be a plausible target for the development of disease-modifying therapies.

Suggested Citation

  • Hiroshi Hasegawa & Lei Liu & Ikuo Tooyama & Shigeo Murayama & Masaki Nishimura, 2014. "The FAM3 superfamily member ILEI ameliorates Alzheimer’s disease-like pathology by destabilizing the penultimate amyloid-β precursor," Nature Communications, Nature, vol. 5(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4917
    DOI: 10.1038/ncomms4917
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