Abstract
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 ST 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 6 h 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 3β (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.
Highlights
In neurons, tau protein (Tau) is a key protein involved in the functional regulation of the microtubule system and belongs to the wider family of microtubule-associated proteins (Wang and Mandelkow, 2016)
The present results show that, to what has been observed in the brain (Luppi et al, 2019), synthetic torpor induces a reversible accumulation of phosphorylated form of Tau (PP-Tau) in the spinal cord (SpCo) of rats, a non-hibernating species
Different phosphorylation patterns were observed within the SpCo: surprisingly, no AT8ir was observed in the ventral horn (Table 1)
Summary
Tau is a key protein involved in the functional regulation of the microtubule system and belongs to the wider family of microtubule-associated proteins (Wang and Mandelkow, 2016). Tau has represented a focus of interest since it is primarily involved in many neurodegenerative diseases (among them, Alzheimer’s disease), commonly defined as tauopathies (Gerson et al, 2016; Kovacs, 2017) In these cases the pathologic neuronal death is triggered by the accumulation of a hyper-phosphorylated form of Tau (PP-Tau), that detaches from microtubules and tends to aggregate in oligomers firstly and into neurofibrillary tangles (Gerson et al, 2016). The accumulation of PP-Tau has been described in nonneurodegenerative conditions in either hibernating mammals (Arendt et al, 2003, 2015) or mice exposed to physiological challenges (Planel et al, 2001, 2007; Okawa et al, 2003) In all these cases, the hyper-phosphorylation was reversible and did not apparently evolve toward neurodegeneration. A reversible accumulation of PP-Tau has been shown in the rat during “synthetic torpor” (ST; Cerri et al, 2013; Cerri, 2017), a torpor-like state which is induced in a non-hibernator by means of the central nervous pharmacological blockade of thermogenesis
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