| Project/Area Number |
17K08668
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Keio University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | アルツハイマー病 / iPS細胞 / シナプス / プレセニリン / 神経科学 |
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| Outline of Final Research Achievements |
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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| Academic Significance and Societal Importance of the Research Achievements |
アルツハイマー病（AD）の臨床・病理診断には長らく老人斑や神経原線維変化の責任分子であるAβやタウが用いられており、ADの発症や進展に関与していると広く受け入れられている。しかし、家族性ADで同定されている変異の大部分はPS遺伝子であるにもかかわらず、老人斑や神経原線維変化への寄与がマウスでは顕著ではなかった。本研究成果は、ヒト人工多能性幹細胞を用いることでヒト神経細胞でのPSの生理的機能を探求し、ヒトとマウスでのAβの産生能に対するPSの機能に差があることが分かった。AD発症におけるPS変異の機能的な影響を解明していくことは、画期的なAD治療薬の創出に繋がることが考えられる。
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