2005 Fiscal Year Final Research Report Summary
Investigation on candidate genes involved in pathophysiology of schizophrenia
| Project/Area Number |
16390329
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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 |
Psychiatric science
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| Research Institution | Tokyo Institute of Psychiatry |
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Principal Investigator |
TATEBAYASHI Yositaka Tokyo Institute of Psychiatry, Depression Research Project, Project Leader, 東京都精神医学総合研究所, 副参事研究員 (80342814)
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| Co-Investigator(Kenkyū-buntansha) |
ITOKAWA Masanari Tokyo Institute of Psychiatry, Schizophrenia Research Project, Project Leader, 東京都精神医学総合研究所, 副参事研究員 (40332324)
TAKASHIMA Akihiko RIKEN, BSI, Lab., Alzheimer's disease, Team Leader, 脳科学総合研究センター, チームリーダー (00154774)
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| Project Period (FY) |
2004 – 2005
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| Keywords | depression / dentate gyrus / neurogenesis / senile change / neurofibrillary tangle / tau / Alzheimer's disease / frontotemporal dementia |
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| Research Abstract |
To study the effects of brain senile changes, especially those of neurofibrillary tangles (NFTs), on the depressive symptoms in the elderly, we investigated the transgenic (TG) mice expressing the moderate levels of mutant human tau with R406W mutation in the axons of forebrain neurons postnatally. This mutation causes a type of familial frontotemporal dementia in humans that resembles Alzheimer's disease and is often associated with preclinical depressive symptoms. TG mice exhibited NFTs-like changes in some hippocampal neurons only after they became 19 months old (Tatebayashi et al., 2002, PNAS USA, 99:13896). We analyzed behaviorally 3-21 month-old TG mice and found that these mice showed age-dependent prolongation of the immobile time in the forced swim test when compared to their littermate (Tatebayashi et al., 2004, Neurobil Ag, 25:S249 ; Egashira et al., 2005 Brain Res, 1059:7). This prolongation was associated with the associative memory deficits that appeared at least 7 month-
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old or older male and 15 month-old or older female TG mice. We also found the gene dosage effects in the mood-related behavioral abnormalities. Electrophysiological study further revealed that in TG mice long term potentiation was introduced normally but was associated with the significantly shorter peak decay time than that in their littermates, implying the reduced amounts of neurotransmitters in the presynaptic vesicles, thus possible impairment in the axonal transport in the TG mice. We previously found that physiological tau phosphorylation by GSK-3β may be required for the normal axonal transport (Tatebayashi et al., 2004, J Cell Sci, 117:1653). We therefore examined the effects of R406W mutation on the physiological tau phosphorylation and found that this mutation reduces physiological tau phosphorylation at the PHF-1 site by GSK-3β by affecting the phosphorylation at Ser404 (Tatebayashi et al., 2006, FASEB J, 20:762). Taken together, these data suggest a possibility that R406W tau mutation impairs axonal transport by disrupting the physiological tau phosphorylation, resulting in the age-dependent mood-related behavioral changes in TG mice. Less
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[Journal Article] c-jun N-terminal kinase yperphosphorylates R406W tau at the PHF-1 site during mitosis.2006
Author(s)
Tatebayashi Y, Planel E, Chui DH, Sato S, Miyasaka T, Sahara N, Murayama M, Kikuchi N, Yoshioka K, Rivka R, Takashima A.
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Journal Title
FASEB J. 20(6)
Pages: 762-764
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Formation of tau inclusions in knock-in mice with familial Alzheimer disease (FAD) mutation of presenilin 1 (PS1).2006
Author(s)
Tanemura K, Chui DH, Fukuda T, Murayama M, Park JM, Akagi T, Tatebayashi Y, Miyasaka T, Kimura T, Hashikawa T, Nakano Y, Kudo T, Takeda M, Takashima A.
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Journal Title
J Biol Chem. 281(8)
Pages: 5037-5041
Description
「研究成果報告書概要(欧文)」より
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