Abstract
Tau protein is of primary importance for neuronal homeostasis and when hyperphosphorylated (PP-Tau), it tends to aggregate in neurofibrillary tangles, as is the case with tauopathies, a class of neurodegenerative disorders. Reversible PP-Tau accumulation occurs in the brain of hibernating rodents and it was recently observed in rats (a non-hibernator) during synthetic torpor (ST), a pharmacological-induced torpor-like condition. To date, the expression of PP-Tau in the rat enteric nervous system (ENS) is still unknown. The present study immunohistochemically investigates the PP-Tau expression in the myenteric plexus of the ileum and colon of normothermic rats (CTRL) and during ST, focusing on the two major subclasses of enteric neurons, i.e., cholinergic and nitrergic.Results showed that both groups of rats expressed PP-Tau, with a significantly increased percentage of PP-Tau immunoreactive (IR) neurons in ST vs. CTRL. In all rats, the majority of PP-Tau-IR neurons were cholinergic. In ST rats, the percentage of PP-Tau-IR neurons expressing a nitrergic phenotype increased, although with no significant differences between groups. In addition, the ileum of ST rats showed a significant decrease in the percentage of nitrergic neurons. In conclusion, our findings suggest an adaptive response of ENS to very low core body temperatures, with changes involving PP-tau expression in enteric neurons, especially the ileal nitrergic subpopulation. In addition, the high presence of PP-Tau in cholinergic neurons, specifically, is very interesting and deserves further investigation. Altogether, these data strengthen the hypothesis of a common cellular mechanism triggered by ST, natural hibernation and tauopathies occurring in ENS neurons.
Highlights
Tau protein (Tau) is a microtubule-associated protein that is predominantly present in neurons, where it is of primary importance for many physiological processes due to its effects on the dynamics of the microtubule system (Wang and Mandelkow 2016)
Besides the presence of AT8 in enteric nervous system (ENS) of adult rats, our findings indicated a great percentage of constitutive PP-Tau (AT8) in the myenteric plexus (MP) cholinergic neurons of the ileum; even though this result is fascinating, at present we are not able to give a trustable explanation and we can only speculate that when this modification of Tau protein occurs, it is related to cholinergic neurons function
The induction of a widespread AT8 immunolabeling has been described in the ENS of a non-hibernating mammal, which underwent an experimental reversible deep hypothermia with suspended animation (i.e., synthetic torpor” (ST); Cerri et al 2013)
Summary
Tau protein (Tau) is a microtubule-associated protein that is predominantly present in neurons, where it is of primary importance for many physiological processes due to its effects on the dynamics of the microtubule system (Wang and Mandelkow 2016). In sharp contrast to what is observed in the healthy adult brain, it has been shown that fetal brain neurons express PPTau, suggesting that degenerating neurons, during tauopathies, may lose their regulatory control of phosphorylation, resulting in the reappearance of a fetal phosphorylation pattern (Anderton et al 1995). In line with this evidence, Lionnet et al (2018) demonstrated that cultured fetal neurons of the rat “second brain,” i.e., the enteric nervous system (ENS), express constitutive PP-Tau protein and that their levels of phosphorylation can be downregulated and upregulated
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