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KAKEN_17K08668seika.pdf
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:281.0 KB
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:Mar 5, 2021 |
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プレシナプスにおけるアルツハイマー病発症の分子機序解析
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プレシナプス ニ オケル アルツハイマービョウ ハッショウ ノ ブンシ キジョ カイセキ
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Pureshinapusu ni okeru arutsuhaimābyō hasshō no bunshi kijo kaiseki
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Study of synaptic mechanism for Alzheimer's disease pathogenesis
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渡部, 博貴
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ワタナベ, ヒロタカ
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Watanabe, Hirotaka
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慶應義塾大学・医学部 (信濃町) ・特任講師
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Research team head
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科研費研究者番号 : 30422413
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2020
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科学研究費補助金研究成果報告書
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2019
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PS遺伝子のヒト神経細胞での生理的機能を検討するため、CRISPR/Cas9系を用いて、健常人由来ヒト人工多能性幹細胞 (iPSC) からPS条件的ノックアウトiPSCを作製した。これらのiPSCを大脳皮質神経細胞へ分化誘導し、Cre発現レンチウイルスを感染させることで、神経細胞でのPS発現を消失させることに成功した。これらのPSノックアウト神経を用いてAβ産生を測定したところ、PS1/PS2の両方ともノックアウトした神経細胞のみAβの低下が認められた。マウスでのAβ産生には主にPS1が重要であることから、ヒト神経細胞ではマウスとは異なるPS/γセクレターゼの性質を持つことが示された。
In this study, to investigate whether presenilin 1 (PS1) plays essential physiological roles in human cortical mature neurons, we generated PS1 conditional knockout (cKO) induced pluripotent stem cells (iPSCs), in which PS1 can be ablated selectively under an introduction of Cre recombinase, and/or additional PS2 KO iPSC. We then differentiated the fPS1/fPS1 and fPS1/fPS1;PS2-/- iPSCs into human cortical neurons in vitro, and ablated PS1 proteins by infection of lentivirus expressing Cre. Whereas no gross morphological alteration and neuronal marker expression was observed between PS1- and/or PS2-null neurons and control neurons, Aβ production was robustly reduced only in PS1/PS2-null neurons. In contrast to previous studies using mouse genetics, in which γ-secretase activity is mainly attributable to PS1, human PS2/γ-secretase activity is unexpectedly comparable with PS1/γ-secretase in human neurons. These results suggest an importance of enzyme/substrate subcellular localization.
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研究種目 : 基盤研究 (C) (一般)
研究期間 : 2017～2019
課題番号 : 17K08668
研究分野 : 神経科学
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