2010 Fiscal Year Final Research Report
Analysis of the mechanism of pathological synaptic alterations in Alzheimer's disease
| Project/Area Number |
20300124
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | Kyoto University |
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Principal Investigator |
KINOSHITA Ayae Kyoto University, 大学院・医学研究科, 教授 (80321610)
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| Co-Investigator(Kenkyū-buntansha) |
KUBOTA Masakazu 京都大学, 大学院・医学研究科, 助教 (80452267)
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| Project Period (FY) |
2008 – 2010
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| Keywords | アルツハイマー病 / 老化 / 神経変性 / シナプス / 認知症 |
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| Research Abstract |
We investigated the pathological mechanisms caused by mutations of Presenilin 1, a responsible protein for familial Alzheimer's disease(AD). We focused on insulin signaling as an influential factor of PS1 and revealed its effect on the localization and conformation of PS1. Our result showed that insulin inhibited GSK3 beta activation, thus leading to inhibition of PS1 phosphorylation and that insulin signaling is involved in the translocation of PS1 to the cell surface and its cleavage functions. Furthermore, we found that insulin receptor, IR, is cleaved by PS1, then its intracellular domain translocates to the nucleus, which activates transcription of Akt. Taken together, we conclude that insulin signaling is modulated by PS1. Next, we created a novel AD model mouse with diabetic condition by giving high fat diet to APP Tg mouse. This mouse showed a marked impairment of short-term memory, suggesting that diabetes is an aggravating factor for AD.
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Research Products
(21 results)
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[Journal Article] N-cadherin regulates p38 MAPK signaling via association with JNK-associated leucine zipper protein : implications for neurodegeneration in Alzheimer disease.2011
Author(s)
Ando K, Uemura K, Kuzuya A, Maesako M, Asada-Utsugi M, Kubota M, Aoyagi N, Yoshioka K, Okawa K, Inoue H, Kawamata J, Shimohama S, Arai T, Takahashi R, Kinoshita A
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Journal Title
J Biol Chem 286
Pages: 7619-7628
Peer Reviewed
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[Journal Article] N-cadherin-based adhesion enhances Aβ release and decrerased Aβ42/40 ratio.2009
Author(s)
Uemura, K, Lill CM, Banks M, Aoyagi N, Ando, K., Kubota M, Kihara T, Nishimoto T, Sugimoto H, Takahashi R, Hyman BT, Shimohama S, Berezovska O, Kinoshita A
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Journal Title
J Neurochem 156
Pages: 350-360
Peer Reviewed
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[Journal Article] J Neurochemistry N-cadherin enhances APP dimerization at the extracellular domain and modulates Abeta production.
Author(s)
Megumi Asada-Utsugi, Kengo Uemura, Yashuha Noda, Akira Kuzuya, Masato Maesako, Koichi Ando, Masakazu Kubota, Kiwamu Watanabe, Makio Takahashi, Takeshi Kihara, Shun Shimohama, Ryosuke Takahashi, Oksana Berezovska, Ayae Kinoshita
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Journal Title
J Neurochemistry(accepted)
Peer Reviewed
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