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アルツハイマー病、他の認知症、老化 2
Alzheimer's Disease, Other Dementia, Aging 2

開催日 2014/9/11
時間 15:00 - 16:00
会場 Room I(311+312)
Chairperson(s) 山田 麻紀 / Maki K. Yamada (東京大学 大学院医学系研究科 代謝生理化学分野 / Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, Japan)
西村 正樹 / Masaki Nishimura (滋賀医科大学分子神経科学研究センター / Moleculer Neuroscience Research Center, Shiga University of Medical Science, Japan)

ILEI reduces amyloid-β generation by destabilizing APP-C99

  • O1-I-4-4
  • 劉 磊 / Lei Liu:1 長谷川 浩史 / Hiroshi Hasegawa:1 遠山 育夫 / Ikuo Tooyama:1 村山 繁雄 / Shigeo Murayama:2 西村 正樹 / Masaki Nishimura:1 
  • 1:滋賀医科大学分子神経科学研究センター / Mol Neurosci Res Cent, Shiga Univ of Med Sci, Shiga, Japan 2:東京都健康長寿医療センター神経病理学 / Dept of Neuropathol, Tokyo Met Inst of Gerontol, Tokyo, Japan 

Accumulation of amyloid-β peptide (Aβ) in the brain underlies the pathogenesis of Alzheimer's disease (AD). Aβ is produced in neurons by β- and γ-secretase-mediated sequential proteolysis of amyloid-β precursor protein (APP). Although γ-secretase is a major target for therapeutic intervention, non-selective inhibition of its activity causes serious adverse effects due to blockade of Notch signaling and accumulation of neurotoxic APP-C-terminal fragments. Here we identified 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 destabilized the β-secretase-cleaved APP C-terminal fragment, APP-C99, by binding to the γ-secretase complex and interfering with its chaperone properties. Notch signaling and γ-secretase activity were not affected by ILEI. We also show neuronal expression of ILEI and its induction by transforming growth factor-β signaling. The level of secreted ILEI was markedly decreased in the brains of AD patients. Transgenic overexpression of ILEI significantly reduced the brain Aβ burden and ameliorated the memory deficit in AD model mice. ILEI may be a plausible target for the development of disease-modifying therapies.

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