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Development of therapy for deposits of AB and tau in Alzheimer disease.

开发治疗阿尔茨海默病中 AB 和 tau 蛋白沉积的疗法。

基本信息

批准号：
16390251
负责人：
SHOJI Mikio
金额：
$ 8.7万
依托单位：
Hirosaki University (2006)Okayama University (2004-2005)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390251/
关键词：
Alzheimer's disease Aβ tau Neuronal cell death Transgenic mouse Therapy As

项目摘要

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.

我们培育了TgTauP301L转基因小鼠，再现了阿尔茨海默病的病理特征，如神经原纤维缠结、前缠结、胶质缠结、化学异常、突触和神经元细胞丢失、记忆障碍等。该小鼠模型是该研究领域首次建立的牛头病模型动物。这一重大的世界性发现为开发预防神经原纤维缠结导致神经元细胞损失的治疗方法提供了重要的小鼠模型。我们还发现，表达Aβ淀粉样变和牛头病的双转基因小鼠不会加速神经原纤维缠结的出现，这表明Aβ级联理论并不能解释阿尔茨海默病系列的所有事件，而且治疗Aβ淀粉样变并不足以治愈所有病理改变和临床痴呆。这些发现表明，治疗牛头病对治疗阿尔茨海默病是必不可少的。接下来，我们发现MCI、AD和AD动物模型中最早的变化是脂筏中AB低聚物的积累。在我们的报告之后，世界各地又进行了更多的实验。所有这些都进一步证实了我们的发现。目前，阿尔茨海默病的研究趋势集中在这种小的Aβ聚集体（Aβ寡聚物或Aβ星），以开发阿尔茨海默病的必要治疗方法。因此，我们发现Aβ低聚物是阿尔茨海默病的重要治疗靶点。此外，我们还开发了两种新的治疗β淀粉样变性的基本方法。一种是褪黑素，另一种是Aβ42特异性免疫球蛋白。这两种疗法都能显著改善转基因模型小鼠大脑中的Aβ淀粉样蛋白沉积。详细检查表明，这两种治疗方法都有助于选择性地减少barin中的Aβ低聚物。在本研究中，我们还阐明了由阿尔茨海默病引起的y分泌酶异常、凋亡神经元细胞死亡的病理机制。

项目成果

期刊论文数量（30）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Passive Immunization of the Aβ42(43) C-Terminal-Specific Antibody BC05 in a Mouse Model of Alzheimer's Disease

DOI：
10.1159/000086429
发表时间：
2005-01-01
期刊：
NEURODEGENERATIVE DISEASES
影响因子：
3
作者：
Asami-Odaka, Asano;Obayashi-Adachi, Yuka;Shoji, Mikio
通讯作者：
Shoji, Mikio

Type-specific evolution of amyloid plaque and angiopathy in APPsw mice

DOI：
10.1016/j.neulet.2005.10.087
发表时间：
2006-02
期刊：
Neuroscience Letters
影响因子：
2.5
作者：
Y. Harigaya;Y. Tomidokoro;M. Ikeda;A. Sasaki;T. Kawarabayashi;E. Matsubara;M. Kanai;T. Saido;S. Younkin;M. Shoji
通讯作者：
Y. Harigaya;Y. Tomidokoro;M. Ikeda;A. Sasaki;T. Kawarabayashi;E. Matsubara;M. Kanai;T. Saido;S. Younkin;M. Shoji

図アミロイドアンギオパチー. インターベンション時代の脳卒中学(改訂第2版,上)

图淀粉样血管病。干预时代的中风学（修订版第二版，第一版）