Reversible Tau Phosphorylation Induced by Synthetic Torpor in the Spinal Cord of the Rat

Tau is a key protein in neurons, where it affects the dynamicsof the microtubulesystem. The hyperphosphorylation of Tau (PP-Tau) commonlyleads to the formationof neurofibrillary tangles, as it occurs in tauopathies, a group of neurodegenerativediseases, including Alzheimer’s. Hypothermia-related accumulation of PP-Tau has beendescribed in hibernators and during synthetic torpor (ST),a torpor-like condition that hasbeen induced in rats, a non-hibernating species. Remarkably, in ST PP-Tau is reversibleand Tau de-phosphorylates within a few hours following the torpor bout, apparentlynot evolving into pathology. These observations have been limited to the brain, but inanimal models of tauopathies, PP-Tau accumulation also appears to occur in the spinalcord (SpCo). The aim of the present work was to assess whetherST leads to PP-Tauaccumulation 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 onSpCo coronal sections. AT8-IF was clearly expressed in the dorsal horns (DH) duringST, while in the ventral horns (VH) no staining was observed.The AT8-IF completelydisappeared after 6h from the return to euthermia. Tau-1-IFdisappeared in both DH andVH during ST, returning to normal levels during recovery. Toshed light on the cellularprocess 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., inmotor neurons) were highly stained mainly during ST, while in DH there was no staining.Since tauopathies are also related to neuroinflammation, microglia activation was alsoassessed through morphometric analyses, but no ST-inducedmicroglia activation wasfound in the SpCo. Taken together, the present results show that, in the DH of SpCo, STinduces 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 theaccumulation of PP-Tau and apparently avoid the neurodegenerative outcome.Keywords: hypothermia, hibernation, microglia, tauopathies, GSK3β, motor neurons, adaptive response