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

我们建立了TgTauP301L转基因小鼠，复制了阿尔茨海默病的病理特征，如神经原纤维缠结、前天使、神经胶质缠结、化学异常、突触和神经细胞丢失以及记忆障碍。该小鼠模型是该研究领域的首个动物模型。这一值得注意的世界性发现表明，建立了重要的小鼠模型，该模型有助于开发预防神经原纤维缠结导致神经细胞丢失的治疗方法。我们还发现，表达Aβ淀粉样变性和间变性的双转基因小鼠并不加速神经原纤维缠结的存在，这表明β级联理论不能解释阿尔茨海默病病理系列的所有事件，Aβ淀粉样变性的治疗不足以治愈所有的病理变化和临床痴呆。接下来，我们发现在MCI、AD和AD动物模型中，最早的变化是AB寡聚体在脂筏中的积聚。在我们的报告之后，世界上进行了更多的实验。所有这些补充都证实了我们的发现。现在，阿尔茨海默病的研究趋势集中在这种小的Aβ聚集体(Aβ寡聚体或AβSTAR)上，以开发阿尔茨海默病的基本治疗方法。因此，我们发现Aβ寡聚体是阿尔茨海默病的重要治疗靶点。此外，我们还开发了两种治疗Aβ淀粉样变性的新的基本疗法。一种是褪黑素，另一种是注射Aβ42特异性免疫球蛋白。这两种疗法都显著改善了转基因模型小鼠大脑中Aβ淀粉样蛋白的沉积。详细的检查表明，两种治疗方法都有助于选择性地减少杆状体内的Aβ寡聚体。在本研究中，我们还阐明了阿尔茨海默病引起的γ分泌酶异常、神经细胞死亡的病理机制。

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.