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Mechanism of NFT formation

NFT形成机制

基本信息

批准号：
13210147
负责人：
TAKASHIMA Akihiko
金额：
$ 38.4万
依托单位：
RIKEN
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13210147/
关键词：
Alzheimer's disease GSK-3 Neurofibrillary tangles Tau Aging JNK Aβ Presenilin 神経原線維変化細胞骨格痴呆 FTDP-17 GSK-3β FTDP17 マウスモデル行動異常

项目摘要

We generated the mouse overexpressing human 4 repeat tau driven by PDGF-β promoter, which contains V337M frontotemporal dementia-17(FTDP-17) mutation. The amount of expression was about 5-10% of endogenous mouse tau, and the accumulation of hyper-phosphorylated tau was seen in the hippocampus CA2 and 3 region and the cerebral cortex at 11 month old. At this age tau in Tg mouse became insoluble for SDS and form filamentous structure, and Tg mouse could form NFT with aging. The decrease in the neuronal activity in the hippocampus was observed in the electrophysiological experiments. In addition, Tg mice didn't show habituation, and significantly stay longer in open arm in elevated plus maze test. Thus, it was clarified that NFT formation reduced neural activity in hippocampus and caused behavioral disorder.In case of the other tau Tg mouse overexpressed human 4 repeat tau with the R406W mutation under control of CAMK II promoter, the mouse model also showed NFT like pathology accompanying with memory deficit, which pathophysiological features are very similar to the patient of AD and R406W. In addition, we could find the activation of GSK-3b and JNK in neurons, which accumulate hyperphosphorylated tau, suggesting that GSK-3 and JNK might be involved in NFT formation.To confirm the involvement of GSK-3 and JNK on NFT formation, we expressed JNK, deltaMEKK, GSK-3b, and human tau in COS7 cells. Tau showed the increased phosphorylation at 12 phosphorylation sites, including AT100 immunoreactive site, which is known as a peculiar antigen of PHF-tau seen in AD. SDS insoluble materials showed anti-phospho-tau immunoreactive aggregates. Thus, an excessive phosphorylation of Tau by GSK-3 β and JNK took part in NFT formation. In addition, when GSK-3 was activated by β amyloid, tau TG mouse resulted in the neurofibrillary tangle formation, the synapse loss, and the neuron death.

我们建立了由PDGF-β启动子驱动的过表达人4重复tau蛋白的小鼠，该小鼠含有V337 M额颞叶痴呆-17（FTDP-17）突变。表达量约为内源性小鼠tau的5-10%，并且在11月龄时在海马CA 2和3区以及大脑皮质中观察到过度磷酸化tau的积累。在此年龄段，Tg小鼠的tau蛋白不溶于SDS，形成丝状结构，并且随着年龄的增长，Tg小鼠可以形成NFT。在电生理实验中观察到海马神经元活动的减少。此外，在高架十字迷宫实验中，Tg小鼠没有表现出习惯性，在开放臂中停留时间明显延长。在另一种过表达具有CAMK II启动子控制下的R406 W突变的人4重复tau的tau Tg小鼠的情况下，小鼠模型也显示出伴随记忆缺陷的NFT样病理，其病理生理特征与AD和R406 W患者非常相似。此外，我们还发现神经元中存在GSK-3b和JNK的激活，这些激活的神经元积累了过度磷酸化的tau蛋白，这表明GSK-3和JNK可能参与了NFT的形成。Tau在12个磷酸化位点上显示出增加的磷酸化，包括AT 100免疫反应位点，其被认为是AD中所见的PHF-tau的特异性抗原。SDS不溶性材料显示抗磷酸化tau免疫反应性聚集体。因此，GSK-3 β和JNK过度磷酸化Tau参与了NFT的形成。此外，当β淀粉样蛋白激活GSK-3时，tau TG小鼠可导致神经元缠结形成、突触丢失和神经元死亡。