Aggregation of tau proteins is a distinct hallmark of tauopathies and has been a focus of research and clinical trials for Alzheimer’s Disease. Recent reports have pointed towards a toxic effect of soluble or oligomeric tau in the spreading of tau pathology in Alzheimer’s disease. Here we investigated the effects of expressing human tau repeat domain (tauRD) with pro- or anti-aggregant mutations in regulatable transgenic mouse models of Alzheimer’s Disease on the functional neuronal networks and the structural connectivity strength. Pro-aggregant and anti-aggregant mice were studied when their mutant tauRD was switched on for 12 months to reach the stage where pro-aggregant mice show cognitive impairment, whereas anti-aggregant mice remained cognitively normal. Then, mutant tauRD was switched off by doxycycline treatment for 8 weeks so that soluble transgenic tau disappeared and cognition recovered in the pro-aggregant mice, although some aggregates remained. At these two time points, at baseline after 12 months of mutant tau expression and after 8 weeks of doxycycline treatment, resting state fMRI and diffusion MRI were used to determine functional neuronal networks and fiber connectivities. Results of the transgenic mice were compared with wildtype littermates. Functional connectivity was strongly reduced in transgenic animals during mutant tauRD expression, in relation to WT mice. Interestingly, transgenic mice with the non-aggregant tau mutant showed identical functional deficits as the pro-aggregant mice, even though in this case there was no cognitive decline by behavioral testing. Upon 8 weeks doxycycline treatment and transgene switch-off, functional connectivity in both transgenic groups presented complete normalization of functional connectivity strength, equivalent to the situation in WT littermates. Structural connectivity was found only marginally sensitive to mutant tau expression (both pro- and anti-aggregant tauRD) and by doxycycline treatment. Our in vivo investigations unravel for the first time a strong reduction of functional neuronal networks by the presence of increased soluble rather than fibrillary tau, independent of its intrinsic propensity of aggregation, which is reversible by switching tau off. Our functional MRI study thus is an unexpected in vivo validation of a novel property of tau, while previous results pointed to a role of aggregation propensity for a pathological state by histopathology and cognitive decline. Our results present further evidence for early tauopathy biomarkers or a potential early stage drug target by functional networks analysis.

中文翻译：

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tau蛋白升高会损害功能网络，但在可调节的阿尔茨海默氏病小鼠模型中可逆

tau蛋白的聚集是Tauopathies的明显标志，并且一直是阿尔茨海默氏病研究和临床试验的重点。最近的报道指出可溶或低聚的tau在阿尔茨海默氏病的tau病理学传播中具有毒性作用。在这里，我们研究了在可调节的阿尔茨海默氏病转基因小鼠模型中表达具有前或抗聚集突变的人tau重复域（tauRD）对功能神经元网络和结构连接强度的影响。当将其突变体tauRD开启12个月以达到前聚集小鼠表现出认知障碍而抗聚集小鼠保持认知正常的阶段时，对前聚集小鼠和抗聚集小鼠进行了研究。然后，通过强力霉素处理8周关闭了突变体tauRD，尽管在前聚集小鼠中仍保留了一些聚集体，但可溶性转基因tau消失了，认知得以恢复。在这两个时间点，在突变tau表达12个月后和多西环素治疗8周后的基线，静息状态fMRI和扩散MRI用于确定功能性神经元网络和纤维连接性。将转基因小鼠的结果与野生型同窝仔进行比较。相对于WT小鼠，在突变tauRD表达过程中，转基因动物的功能连接性大大降低。有趣的是，具有非聚集性tau突变体的转基因小鼠表现出与聚集性前体小鼠相同的功能缺陷，即使在这种情况下，行为测试并没有导致认知能力下降。在强力霉素治疗8周和转基因关闭后，两个转基因组中的功能连接性均表现出功能连接强度的完全正常化，这与野生型同窝仔的情况相同。发现结构连通性仅对突变体tau表达（前和抗聚集性tauRD）和强力霉素处理敏感。我们的体内研究首次通过增加可溶性而不是原纤维tau的存在，首次揭示了功能神经元网络的强烈减少，而与tau的关闭具有可逆性无关，而固有的聚集倾向是可逆的。因此，我们的功能性MRI研究是tau的新特性在体内的出乎意料的验证，而先前的结果则指出，通过组织病理学和认知能力下降，聚集倾向在病理状态中的作用。我们的结果通过功能网络分析为早期tauopathy生物标志物或潜在的早期药物靶标提供了进一步的证据。