Accumulation of abnormal tau aggregates in the brain is a pathological hallmark of multiple neurodegenerative disorders including Alzheimer's disease. Increasing evidence suggests that soluble tau aggregates play a key role in tau pathology as neurotoxic species causing neuronal cell death and act as prion-like seeds mediating tau propagation. Despite the pathological relevance, there is a paucity of methods to monitor tau oligomerization in the brain. As a tool to monitor tau self-assembly in the brain, we generated a novel tau transgenic mouse, named TauP301L-BiFC. By inroducing bimolecular fluorescence complementation technique to human tau containing a P301L mutation, we were able to monitor and quantify tau self-assembly, represented by BiFC fluorescence in the brains of transgenic TauP301L-BiFC mice. TauP301L-BiFC mice showed soluble tau oligomerization from 3 months, showing significantly enriched BiFC fluorescence in the brain. Then, massive tau fragmentation occured at 6 months showing dramatically decreased TauP301L-BiFC fluorescence. The fragmented tau species served as a seed for insoluble tau aggregation. In a result, insoluble TauP301L-BiFC aggregates coaggregated with endogenous mouse tau accumulated in the brain, showing subsequently increased BiFC fluorescence from 9 months. Neuronal degeneration and cognitive deficits were observed from 12 months of age. TauP301L-BiFC mouse model demonstrated that methylene blue reduced the amount of soluble tau oligomers in the brain, resulting in the prevention of cognitive impairments. We assure that TauP301L-BiFC mice are a bona-fide animal tool to monitor pathological tau oligomerization in AD and other tauopathies.

中文翻译：

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TauP301L-BiFC转基因小鼠中可溶性tau低聚物的可视化表明tauopathy的进展。

大脑中异常tau聚集物的积累是包括阿尔茨海默氏病在内的多种神经退行性疾病的病理标志。越来越多的证据表明，可溶性tau聚集体在tau病理中起关键作用，因为它会引起神经元细胞死亡，并成为neuro蛋白样的种子，介导tau的繁殖，是神经毒性物种。尽管有病理相关性，但仍缺乏监测脑中tau寡聚化的方法。作为监测tau在大脑中自我组装的工具，我们产生了一种新型的tau转基因小鼠，名为TauP301L-BiFC。通过向包含P301L突变的人tau引入双分子荧光互补技术，我们能够监测和量化tau自组装，由转基因TauP301L-BiFC小鼠脑中的BiFC荧光表示。TauP301L-BiFC小鼠从3个月开始显示可溶性tau寡聚，显示大脑中BiFC荧光明显丰富。然后，在6个月时出现大量的tau片段，表明TauP301L-BiFC荧光显着降低。破碎的tau物种充当不溶性tau聚集的种子。结果，不溶性TauP301L-BiFC聚集体与大脑中积累的内源性小鼠tau聚集在一起，显示从9个月起BiFC荧光随之增加。从12个月大开始观察到神经元变性和认知缺陷。TauP301L-BiFC小鼠模型证明，亚甲基蓝减少了大脑中可溶性tau低聚物的量，从而预防了认知障碍。