2006 Fiscal Year Final Research Report Summary
Development of therapy for deposits of AB and tau in Alzheimer disease.
| Project/Area Number |
16390251
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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 | Hirosaki University (2006)
Okayama University (2004-2005) |
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Principal Investigator |
SHOJI Mikio Hirosaki University, School of Medicine, Professor, 医学部, 教授 (60171021)
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| Co-Investigator(Kenkyū-buntansha) |
MATUBARA Etsuro National Institute for longevity Science, Department of Alzheimer's disease research, general manager, アルツハイマー病研究部, 室長 (70219468)
ABE Koji Okayama University, Graduate School of Medicene, Professor, 大学院・医歯学総合研究科, 教授 (20212540)
IKEDA Masaki Gunma University, Graduate School of Medicine, Assistant, 大学院・医学系研究科, 助手 (50222899)
KAWARABAYSHI Takeshi Hirosaki University, University Hospital, Assistant Professor, 医学部附属病院, 講師 (90186156)
TOMIYAMA Masahiko Hirosaki University, School of Medicine, Associate Professor, 医学部, 助教授 (40311542)
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| Project Period (FY) |
2004 – 2006
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| Keywords | Alzheimer's disease / Aβ / tau / Neuronal cell death / Transgenic mouse / Therapy |
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| Research Abstract |
We developed TgTauP301L transgenic mouse which reproduced pathological characteristic features of Alzheimer's disease, such as neurofibrillary tangles, pretangels, glial tangles, chemical abnormality, loss of synapses and neuronal cells, and memory disturbances. This mouse model is the first model animals of tauopathies in this research field. This remarkable and worldwide finding suggests the establishment of important mouse model which is useful to develop therapy to prevent neurofibrillary tangles leading to neuronal cell loss. We also found that double transgenic mouse expressing Aβ amyloidosis and tauopathy do not accelerate the presence of neurofibrillary tangles, indicating that Aβ cascade theory do not explain all events on Alzheimer pathological series and that therapy of Aβ amyloidosis is not enough to cure all pathological changes and clinical dementia. These findings suggested that therapy of tauopathy is essentially necessary to cure Alzheimer's disease.
Next, we found the earliest change is the accumulation of AB oligomer in lipid rafts in the MCI, AD and AD animal models. After our report, additional experiments were carried out in the world. All of these additional confirmed our findings. Now, the trends of Alzheimer research focus this small Aβ aggregates (Aβ oligomer or Aβ star) in order to develop essential therapy of Alzheimer's disease. Thus we found that Aβ oligomer is essential therapeutic target of Alzheimer's disease. Furthermore, we developed two novel essential therapy of Aβ amyloidosis. One is melatonin and the other is administration of Aβ42 specific immunoglobulin. Both therapies remarkably improve Aβ amyloid deposits in transgenic model mouse brains. Detailed examinations showed that both therapy are useful to reduce Aβ oligomer selectively in the barins.
In this study, we also clarify the pathological mechanisms of y secretase abnormality, apptotic neuronal cell death induced by Alzheimer pathology.
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