Abstract
Neuronal Tau protein hyperphosphorylation (PPtau) is a hallmark of tauopathic neurodegeneration. However, a reversible brain PPtau occurs in mammals during either natural or “synthetic” torpor (ST), a transient deep hypothermic state that can be pharmacologically induced in rats. Since in both conditions a high sleep pressure builds up during the regaining of euthermia, the aim of this work was to assess the possible role of post-ST sleep in PPtau dephosphorylation. Male rats were studied at the hypothermic nadir of ST, and 3–6 h after the recovery of euthermia, after either normal sleep (NS) or total sleep deprivation (SD). The effects of SD were studied by assessing: (i) deep brain temperature (Tb); (ii) immunofluorescent staining for AT8 (phosphorylated Tau) and Tau-1 (non-phosphorylated Tau), assessed in 19 brain structures; (iii) different phosphorylated forms of Tau and the main cellular factors involved in Tau phospho-regulation, including pro- and anti-apoptotic markers, assessed through western blot in the parietal cortex and hippocampus; (iv) systemic factors which are involved in natural torpor; (v) microglia activation state, by considering morphometric variations. Unexpectedly, the reversibility of PPtau was more efficient in SD than in NS animals, and was concomitant with a higher Tb, higher melatonin plasma levels, and a higher frequency of the microglia resting phenotype. Since the reversibility of ST-induced PPtau was previously shown to be driven by a latent physiological molecular mechanism triggered by deep hypothermia, short-term SD soon after the regaining of euthermia seems to boost the possible neuroprotective effects of this mechanism.
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Data availability
All the original data are accessible upon reasonable request to the Corresponding author. All the images from western-blot analysis are available on AMS Acta, the Open Science repository of the University of Bologna (http://amsacta.unibo.it/id/eprint/6884—https://doi.org/10.6092/unibo/amsacta/6884).
Abbreviations
- aCSF:
-
Artificial cerebrospinal fluid
- AT8:
-
Tau protein phosphorylated at S202 and T205
- C:
-
Control group
- DP-Index:
-
Dephosphorylation-index
- Hip:
-
Hippocampus
- IF:
-
Immunofluorescence
- MI:
-
Morphological index
- N:
-
Nadir of hypothermia
- NND:
-
Nearest neighbor distance
- NREMS:
-
Non-rapid eye movement sleep
- NS:
-
Normal sleep
- P-Cx:
-
Parietal cortex
- PPtau:
-
Hyperphosphorylated tau protein
- R3:
-
3H after Tb reached 35.5 °C
- R3SD:
-
R3 with total sleep deprivation
- R6:
-
6H after Tb reached 35.5 °C
- R6SD:
-
R6 with total sleep deprivation
- REMS:
-
Rapid eye movement sleep
- RPa:
-
Raphe Pallidus
- SD:
-
Sleep deprivation
- ST:
-
Synthetic torpor
- t*:
-
Modified t-test
- Ta:
-
Ambient temperature
- Tau-1:
-
Tau protein with no phosphorylation within residues 189–207
- Tb:
-
Deep brain temperature
- WB:
-
Western-blot
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The authors wish to thank Ms. Melissa Stott for reviewing the English.
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This work has been supported by the Ministero dell'Università e della Ricerca Scientifica (MUR) – Italy, by the University of Bologna, and with the contribution of: Fondazione Cassa di Risparmio in Bologna and European Space Agency (Research agreement collaboration 4000123556).
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Hitrec, T., Squarcio, F., Piscitiello, E. et al. Sleep deprivation soon after recovery from synthetic torpor enhances tau protein dephosphorylation in the rat brain. J Comp Physiol B 194, 347–368 (2024). https://doi.org/10.1007/s00360-023-01516-2
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DOI: https://doi.org/10.1007/s00360-023-01516-2