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. 2024 Jun;194(3):347-368.
doi: 10.1007/s00360-023-01516-2. Epub 2023 Oct 9.

Sleep deprivation soon after recovery from synthetic torpor enhances tau protein dephosphorylation in the rat brain

Timna Hitrec #  1 , Fabio Squarcio #  1   2 , Emiliana Piscitiello  1   3 , Matteo Cerri  1 , Davide Martelli  1   3 , Alessandra Occhinegro  1   3 , Ludovico Taddei  1   3 , Domenico Tupone  1   4 , Roberto Amici  1 , Marco Luppi  5   6
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Sleep deprivation soon after recovery from synthetic torpor enhances tau protein dephosphorylation in the rat brain

Timna Hitrec et al. J Comp Physiol B. 2024 Jun.

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.

Keywords: Brain temperature; Deep hypothermia; Gentle handling; Melatonin; Microglia; Sleep pressure.

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