Insoluble intracellular aggregation of tau proteins into filaments and neurodegeneration are histopathological hallmarks of Alzheimer disease (AD) and other tauopathies. Recently, prefibrillar, soluble, oligomeric tau intermediates have emerged as relevant pathological tau species; however, the molecular mechanisms of neuronal responses to tau oligomers are not fully understood. Here, we show that hippocampal neurons in six-month-old transgenic mouse model of tauopathy, THY-Tau22, are enriched with oligomeric tau, contain elongated mitochondria, and display cellular stress, but no overt cytotoxicity compared to the control mice. The levels of several key mitochondrial proteins were markedly different between the THY-Tau22 and control mice hippocampi including the mitochondrial SIRT3, PINK1, ANT1 and the fission protein DRP1. DNA base excision repair (BER) is the primary defense system against oxidative DNA damage and it was elevated in six-month-old transgenic mice. DNA polymerase β, the key BER DNA polymerase, was enriched in the cytoplasm of hippocampal neurons in six-month-old transgenic mice and localized with and within mitochondria. Polβ also co-localized with mitochondria in human AD brains in neurons containing oligomeric tau. Most of these altered mitochondrial and DNA repair events were specific to the transgenic mice at 6 months of age and were not different from control mice at 12 months of age when tau pathology reaches its maximum and oligomeric forms of tau are no longer detectable. In summary, our data suggests that we have identified key cellular stress responses at early stages of tau pathology to preserve neuronal integrity and to promote survival. To our knowledge, this work provides the first description of multiple stress responses involving mitochondrial homeostasis and BER early during the progression of tau pathology, and represents an important advance in the etiopathogenesis of tauopathies.

中文翻译：

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在tau病理模型中，tau病理早期的海马tau寡聚与线粒体稳态的短暂改变和DNA修复相吻合。

tau蛋白不可溶的细胞内聚集成细丝和神经变性是阿尔茨海默病（AD）和其他陶氏病的组织病理学标志。最近，原纤维状的，可溶的，低聚的tau中间体已经成为相关的病理tau种类。然而，对tau寡聚物的神经元反应的分子机制尚不完全清楚。在这里，我们显示在六个月大的tauopathy转基因小鼠模型THY-Tau22中，海马神经元富含tau寡聚体，包含延长的线粒体，并显示细胞应激，但与对照小鼠相比没有明显的细胞毒性。THY-Tau22和对照组小鼠海马中的几种关键线粒体蛋白水平明显不同，包括线粒体SIRT3，PINK1，ANT1和裂变蛋白DRP1。DNA碱基切除修复（BER）是抵抗氧化性DNA损伤的主要防御系统，在六个月大的转基因小鼠中其含量升高。DNA聚合酶β是关键的BER DNA聚合酶，在6个月大的转基因小鼠的海马神经元细胞质中富集，并定位于线粒体中和线粒体内。Polβ也与线粒体共定位在人AD脑中含有低聚tau蛋白的神经元中。当tau病理达到最大且tau的寡聚形式不再可检测时，大多数这些改变的线粒体和DNA修复事件对6个月大的转基因小鼠具有特异性，与12个月大的对照小鼠没有区别。总而言之，我们的数据表明我们已经在tau病理学的早期阶段确定了关键的细胞应激反应，以保持神经元完整性并促进存活。