| Project/Area Number |
14370208
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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 |
Neurology
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| Research Institution | OKAYAMA UNIVERSITY |
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Principal Investigator |
SHOJI Mikio Okayama University, Graduate School of Medicine and Dentistry, Associate Professor, 大学院・医歯学総合研究科, 助教授 (60171021)
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| Co-Investigator(Kenkyū-buntansha) |
ABE Koji Okayama University, Graduate School of Medicine and Dentistry, Professor, 大学院・医歯学総合研究科, 教授 (20212540)
NAGANO Isao Okayama University, Hospital, lecturer, 医学部・歯学部附属病院, 講師 (80335603)
MATSUBARA Etsuro Okayama University, Hospital, Assistant, 医学部・歯学部附属病院, 助手 (70219468)
IKEDA Masaki Gunma University, Graduate School of Medicine, Assistant, 大学院・医学系研究科, 助手 (50222899)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥12,000,000 (Direct Cost: ¥12,000,000)
Fiscal Year 2003: ¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 2002: ¥6,100,000 (Direct Cost: ¥6,100,000)
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| Keywords | Alzheimer's disease / amyloid / Neurofibrillary tangles / Treatment / transgenic mice / Vaccine / passive immunization / Melatonin |
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| Research Abstract |
1) Memory disturbance of Tg2576 initiated before amyloid plaque appearance and correlated with selective decrease of acetylcholine in the brain. Since Tg2576 reproduced almost all pathological alterations of Alzheimer's brains except neurofibrillary tangles, Tg2576 is an excellent animal model for evaluation of the effects of acetylcholine esterase inhibitors. 2) Double transgenic mouse (Tg2576xPS-1 L286V) showed extensive acceleration of Aβ amyloid deposits and induced secondary tauopathy. In elder double transgenic mice, straight tubules were observed. 3) Injections of antibodies to Aβ40 and Aβ42 increased 〜5 times of plasma Aβ concentrations respectively, suggesting that passive immunization using these specific antibodies can clear brain Aβ burden. These antibodies may decrease Aβ protofibril and Aβ oligomers and improve memory disturbance before histological amyloid plaque appearance. 4) We found accumulation of Aβ dimer as an initiating factor of amyloid starts in lipid rafts in Tg brains and AD brains, These findings indicate that Aβ accumulation in lipid rafts is an important target for treatment. In lipid rafts, secondary accumulation of AopE and phosphorylated tau were revealed in Tg and AD brains. 5) Administration of melatonin decreases Aβ burden in the Tg brain and improve memory disturbance in Tg. Improve survival rate and oxidative also observed. Clinical application is now planed. 6) Administration of simvastain did not improve Aβ burden in the Tg brain. However, regulation of Aβ generation by cholesterol dependant γ-secretase was possible in lipid raft level. In AopE adjusted 1800 autopsied cohort, high choresterolemia in early adulthood is a risk factor for AD. These findings suggest that treatment of high choresterolemia is protective for onset of AD. Prospective multicenter study, clarification of effects of stains for AD should be studied in cellular and animal model levels.
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