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The Physiological Link Between Metabolic Rate Depression and Tau Phosphorylation in Mammalian Hibernation

TitleThe Physiological Link Between Metabolic Rate Depression and Tau Phosphorylation in Mammalian Hibernation
Publication TypeJournal Article
Year of Publication2011
AuthorsStieler, JT, Bullmann, T, Kohl, F, Toien, O, Bruckner, MK, Hartig, W, Barnes, BM, Arendt, T
JournalPLOS One

Abnormal phosphorylation and aggregation of tau protein are hallmarks of a variety of neurological disorders, includingAlzheimer’s disease (AD). Increased tau phosphorylation is assumed to represent an early event in pathogenesis and apivotal aspect for aggregation and formation of neurofibrillary tangles. However, the regulation of tau phosphorylation invivo and the causes for its increased stage of phosphorylation in AD are still not well understood, a fact that is primarilybased on the lack of adequate animal models. Recently we described the reversible formation of highly phosphorylated tauprotein in hibernating European ground squirrels. Hence, mammalian hibernation represents a model system very wellsuited to study molecular mechanisms of both tau phosphorylation and dephosphorylation under in vivo physiologicalconditions. Here, we analysed the extent and kinetics of hibernation-state dependent tau phosphorylation in various brainregions of three species of hibernating mammals: arctic ground squirrels, Syrian hamsters and black bears. Overall, tauprotein was highly phosphorylated in torpor states and phosphorylation levels decreased after arousal in all species.Differences between brain regions, hibernation-states and phosphosites were observed with respect to degree and kineticsof tau phosphorylation. Furthermore, we tested the phosphate net turnover of tau protein to analyse potential alterations inkinase and/or phosphatase activities during hibernation. Our results demonstrate that the hibernation-state dependentphosphorylation of tau protein is specifically regulated but involves, in addition, passive, temperature driven regulatorymechanisms. By determining the activity-state profile for key enzymes of tau phosphorylation we could identify kinasespotentially involved in the differentially regulated, reversible tau phosphorylation that occurs during hibernation. We showthat in black bears hibernation is associated with conformational changes of highly phosphorylated tau protein that aretypically related to neuropathological alterations. The particular hibernation characteristics of black bears with a continuoustorpor period and an only slightly decreased body temperature, therefore, potentially reflects the limitations of this adaptivereaction pattern and, thus, might indicate a transitional state of a physiological process.

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