Synthetic torpor triggers a regulated mechanism in the rat brain, favoring the reversibility of Tau protein hyperphosphorylation
Introduction: Hyperphosphorylated Tau protein (PPTau) is the hallmark of tauopathic neurodegeneration. During “synthetic torpor” (ST), a transient hypothermic state which can be induced in rats by the local pharmacological inhibition of the Raphe Pallidus, a reversible brain Tau hyperphosphorylation...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2023.1129278/full |
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| author | Fabio Squarcio Timna Hitrec Emiliana Piscitiello Emiliana Piscitiello Matteo Cerri Catia Giovannini Catia Giovannini Davide Martelli Alessandra Occhinegro Alessandra Occhinegro Ludovico Taddei Domenico Tupone Domenico Tupone Roberto Amici Marco Luppi Marco Luppi |
| author_facet | Fabio Squarcio Timna Hitrec Emiliana Piscitiello Emiliana Piscitiello Matteo Cerri Catia Giovannini Catia Giovannini Davide Martelli Alessandra Occhinegro Alessandra Occhinegro Ludovico Taddei Domenico Tupone Domenico Tupone Roberto Amici Marco Luppi Marco Luppi |
| author_sort | Fabio Squarcio |
| collection | DOAJ |
| description | Introduction: Hyperphosphorylated Tau protein (PPTau) is the hallmark of tauopathic neurodegeneration. During “synthetic torpor” (ST), a transient hypothermic state which can be induced in rats by the local pharmacological inhibition of the Raphe Pallidus, a reversible brain Tau hyperphosphorylation occurs. The aim of the present study was to elucidate the – as yet unknown – molecular mechanisms underlying this process, at both a cellular and systemic level.Methods: Different phosphorylated forms of Tau and the main cellular factors involved in Tau phospho-regulation were assessed by western blot in the parietal cortex and hippocampus of rats induced in ST, at either the hypothermic nadir or after the recovery of euthermia. Pro- and anti-apoptotic markers, as well as different systemic factors which are involved in natural torpor, were also assessed. Finally, the degree of microglia activation was determined through morphometry.Results: Overall, the results show that ST triggers a regulated biochemical process which can dam PPTau formation and favor its reversibility starting, unexpectedly for a non-hibernator, from the hypothermic nadir. In particular, at the nadir, the glycogen synthase kinase‐β was largely inhibited in both regions, the melatonin plasma levels were significantly increased and the antiapoptotic factor Akt was significantly activated in the hippocampus early after, while a transient neuroinflammation was observed during the recovery period.Discussion: Together, the present data suggest that ST can trigger a previously undescribed latent and regulated physiological process, that is able to cope with brain PPTau formation. |
| first_indexed | 2024-03-12T21:53:53Z |
| format | Article |
| id | doaj.art-2add5cb63b90442fb366d59effa2e371 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-03-12T21:53:53Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-2add5cb63b90442fb366d59effa2e3712023-07-25T21:20:34ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2023-03-011410.3389/fphys.2023.11292781129278Synthetic torpor triggers a regulated mechanism in the rat brain, favoring the reversibility of Tau protein hyperphosphorylationFabio Squarcio0Timna Hitrec1Emiliana Piscitiello2Emiliana Piscitiello3Matteo Cerri4Catia Giovannini5Catia Giovannini6Davide Martelli7Alessandra Occhinegro8Alessandra Occhinegro9Ludovico Taddei10Domenico Tupone11Domenico Tupone12Roberto Amici13Marco Luppi14Marco Luppi15Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, ItalyCentre for Applied Biomedical Research—CRBA, St. Orsola Hospital, University of Bologna, Bologna, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicines, University of Bologna, Bologna, ItalyCentre for Applied Biomedical Research—CRBA, St. Orsola Hospital, University of Bologna, Bologna, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, ItalyCentre for Applied Biomedical Research—CRBA, St. Orsola Hospital, University of Bologna, Bologna, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, ItalyDepartment of Neurological Surgery, Oregon Health and Science University, Portland, OR, United StatesDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, ItalyDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, ItalyCentre for Applied Biomedical Research—CRBA, St. Orsola Hospital, University of Bologna, Bologna, ItalyIntroduction: Hyperphosphorylated Tau protein (PPTau) is the hallmark of tauopathic neurodegeneration. During “synthetic torpor” (ST), a transient hypothermic state which can be induced in rats by the local pharmacological inhibition of the Raphe Pallidus, a reversible brain Tau hyperphosphorylation occurs. The aim of the present study was to elucidate the – as yet unknown – molecular mechanisms underlying this process, at both a cellular and systemic level.Methods: Different phosphorylated forms of Tau and the main cellular factors involved in Tau phospho-regulation were assessed by western blot in the parietal cortex and hippocampus of rats induced in ST, at either the hypothermic nadir or after the recovery of euthermia. Pro- and anti-apoptotic markers, as well as different systemic factors which are involved in natural torpor, were also assessed. Finally, the degree of microglia activation was determined through morphometry.Results: Overall, the results show that ST triggers a regulated biochemical process which can dam PPTau formation and favor its reversibility starting, unexpectedly for a non-hibernator, from the hypothermic nadir. In particular, at the nadir, the glycogen synthase kinase‐β was largely inhibited in both regions, the melatonin plasma levels were significantly increased and the antiapoptotic factor Akt was significantly activated in the hippocampus early after, while a transient neuroinflammation was observed during the recovery period.Discussion: Together, the present data suggest that ST can trigger a previously undescribed latent and regulated physiological process, that is able to cope with brain PPTau formation.https://www.frontiersin.org/articles/10.3389/fphys.2023.1129278/fulldeep hypothermiamicrotubulesmelatoninglycogen synthase kinase 3βhippocampusparietal cortex |
| spellingShingle | Fabio Squarcio Timna Hitrec Emiliana Piscitiello Emiliana Piscitiello Matteo Cerri Catia Giovannini Catia Giovannini Davide Martelli Alessandra Occhinegro Alessandra Occhinegro Ludovico Taddei Domenico Tupone Domenico Tupone Roberto Amici Marco Luppi Marco Luppi Synthetic torpor triggers a regulated mechanism in the rat brain, favoring the reversibility of Tau protein hyperphosphorylation Frontiers in Physiology deep hypothermia microtubules melatonin glycogen synthase kinase 3β hippocampus parietal cortex |
| title | Synthetic torpor triggers a regulated mechanism in the rat brain, favoring the reversibility of Tau protein hyperphosphorylation |
| title_full | Synthetic torpor triggers a regulated mechanism in the rat brain, favoring the reversibility of Tau protein hyperphosphorylation |
| title_fullStr | Synthetic torpor triggers a regulated mechanism in the rat brain, favoring the reversibility of Tau protein hyperphosphorylation |
| title_full_unstemmed | Synthetic torpor triggers a regulated mechanism in the rat brain, favoring the reversibility of Tau protein hyperphosphorylation |
| title_short | Synthetic torpor triggers a regulated mechanism in the rat brain, favoring the reversibility of Tau protein hyperphosphorylation |
| title_sort | synthetic torpor triggers a regulated mechanism in the rat brain favoring the reversibility of tau protein hyperphosphorylation |
| topic | deep hypothermia microtubules melatonin glycogen synthase kinase 3β hippocampus parietal cortex |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2023.1129278/full |
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