Tau is a key protein in neurons, where it affects the dynamics of the microtubule system. The hyperphosphorylation of Tau (PP-Tau) commonly leads to the formation of neurofibrillary tangles, as it occurs in tauopathies, a group of neurodegenerative diseases, including Alzheimer’s. Hypothermia-related accumulation of PP-Tau has been described in hibernators and during synthetic torpor (ST), a torpor-like condition that has been induced in rats, a non-hibernating species. Remarkably, in synthetic torpor PP-Tau is reversible and Tau de-phosphorylates within a few hours following the torpor bout, apparently not evolving into pathology. These observations have been limited to the brain, but in animal models of tauopathies, PP-Tau accumulation also appears to occur in the spinal cord (SpCo). The aim of the present work was to assess whether ST leads to PP-Tau accumulation in the SpCo and whether this process is reversible. Immunofluorescence (IF) for AT8 (to assess PP-Tau) and Tau 1 (non-phosphorylated Tau) was carried out on SpCo coronal sections. AT8-IF was clearly expressed in the dorsal horns (DH) during ST, while in the ventral horns (VH) no staining was observed. The AT8-IF completely disappeared after 6h from the return to euthermia. Tau-1-IF disappeared in both DH and VH during ST, returning to normal levels during recovery. To shed light on the cellular process underlying the PP-Tau pattern observed, the inhibited form of the glycogen-synthase kinase 3 (the main kinase acting on Tau) was assessed using IF: VH (i.e., in motor neurons) were highly stained mainly during ST, while in DH there was no staining. Since tauopathies are also related to neuroinflammation, microglia activation was also assessed through morphometric analyses, but no ST-induced microglia activation was found in the SpCo. Taken together, the present results show that, in the DH of SpCo, ST induces a reversible accumulation of PP-Tau. Since during ST there is no motor activity, the lack of AT8-IF in VH may result from an activity-related process at a cellular level. Thus, ST demonstrates a newly-described physiological mechanism that is able to resolve the accumulation of PP-Tau and apparently avoid the neurodegenerative outcome.

中文翻译：

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合成Torpor在大鼠脊髓中诱导的可逆Tau磷酸化。

Tau是神经元中的关键蛋白质，它会影响微管系统的动力学。Tau（PP-Tau）的过度磷酸化通常会导致神经原纤维缠结的形成，因为它发生在tauopathies中，后者是一组神经退行性疾病，包括阿尔茨海默氏病。PP-Tau的低温相关的积累已在冬眠动物中以及在合成冬眠（ST）期间进行了描述，这是一种在非冬眠物种的大鼠中诱发的类似冬眠的病状。值得注意的是，在人工合成的torpor中，PP-Tau是可逆的，并且在torpor发作后的几个小时内，Tau会去磷酸化，显然不会演变为病理。这些观察仅限于大脑，但在tauopathies的动物模型中，PP-Tau蓄积似乎也发生在脊髓（SpCo）中。本工作的目的是评估ST是否导致SpCo中的PP-Tau积累以及该过程是否可逆。在SpCo冠状切片上进行了AT8的免疫荧光（IF）（以评估PP-Tau）和Tau 1（非磷酸化Tau）。在ST期间，在背角（DH）中清楚地表达了AT8-IF，而在腹角（VH）中未观察到染色。从恢复正常温度起6小时后，AT8-IF完全消失。在ST期间，Tau-1-IF在DH和VH中均消失，在恢复期间恢复至正常水平。为了阐明观察到的PP-Tau模式的细胞过程，使用IF评估了糖原合酶激酶3（作用于Tau的主要激酶）的抑制形式：VH（即在运动神经元中）被高度染色主要在ST期间，而在DH中则没有染色。由于tauopathies也与神经炎症相关，因此还通过形态计量分析评估了小胶质细胞的活化，但在SpCo中未发现ST诱导的小胶质细胞的活化。综上所述，目前的结果表明，在SpCo的DH中，ST诱导PP-Tau的可逆积累。由于在ST期间没有运动活动，因此VH中AT8-IF的缺乏可能是由于细胞水平上与活动有关的过程所致。因此，ST展示了一种新近描述的生理机制，该机制能够解决PP-Tau的积聚并明显避免神经退行性结局。ST诱导PP-Tau的可逆积累。由于在ST期间没有运动活动，因此VH中AT8-IF的缺乏可能是由于细胞水平上与活动有关的过程所致。因此，ST展示了一种新近描述的生理机制，该机制能够解决PP-Tau的积聚并明显避免神经退行性结局。ST诱导PP-Tau的可逆积累。由于在ST期间没有运动活动，因此VH中AT8-IF的缺乏可能是由于细胞水平上与活动有关的过程所致。因此，ST展示了一种新近描述的生理机制，该机制能够解决PP-Tau的积聚并明显避免神经退行性结局。