To elucidate the involvement of individual kinases in the differentially regulated tau phosphorylation, we studied the activity state profile of the tau kinases glycogen synthase kinase 3 beta cyclin dependent kinase 5, stress-activated protein kinase/Jun-amino-terminal kinase and mitogen activated protein kinases/extracellular regulated protein kinase in arctic ground squirrels and Syrian hamsters. Interestingly, the Albaspidin-AA results revealed a differentially regulated enzyme activity pattern. Generally, GSK3-beta is supposed to be the primary candidate kinase responsible for tau hyperphosphorylation whereas the other kinases are assumed to modulate tau phosphorylation. In contrast, our results demonstrate an increased phosphorylation of the S9 residue of GSK3-beta indicating an inhibited or at least reduced GSK3-beta activity in torpid animals. In addition, the results are consistent with findings showing inhibition of GSK3-beta in starved mice. GSK3-beta is involved in a variety of physiological Ginsenoside-F4 processes including the regulation of metabolism. Therefore a differential, hibernation-state dependent GSK3-beta activity is a very likely phenomenon. However, a decreased activity does not correlate with the abnormally high degree of tau phosphorylation. The phosphorylation of cdk5 at S159, in contrast, indicates an increased activity in the state of torpor. The enzymatic activity of cdk5 is mainly regulated by its binding to a regulatory subunit. However, since there is no hibernationstate dependent alteration in expression of the regulatory subunit p35 and no formation of p25 we suggest that cdk5 activity underlies a moderate regulation that may directly or indirectly contribute to tau phosphorylation. The decreased phosphorylation of SAPK/JNK indicates an inhibited activity during torpor. This finding is consistent with results showing decreased SAPK/JNK activity in torpid arctic ground squirrels. The MAP-kinases ERK1 and ERK2 showed a differentially regulated activity pattern. ERK1 phosphorylation was increased while ERK2 was less phosphorylated in torpid animals. These results are contrary to findings reporting on a decrease of both ERK1 and ERK2 activity during torpor in arctic ground squirrels. To summarise, we found cdk5 and ERK1 positively yet GSK3beta, SAPK/JNK and ERK2 negatively regulated in torpid animals. The determined kinase activity-state pattern was analogous in both analysed species indicating equivalent regulatory mechanisms. Based on our findings cdk5 and ERK1 may act as kinases that actively phosphorylate tau under physiological conditions. Unravelling the regulation of hypometabolic states such as hibernation are of great significance for the understanding of cellular and molecular aspects of neurodegenerative disorders where hypometabolic states of a ”vita minima” precede cell death. As shown by functional brain imaging, these hypometabolic states occur very early during the course of AD, even in presymptomatic stages; they are a predictor of cognitive decline and might, thus, be attractive therapeutic targets. A potential role of hypometabolic stages in the pathomechanism of AD is supported by recent data on thyroid disease as a potential risk factor for AD. Hypometabolic states and deficiencies in brain energy metabolism have been proposed as primary events in a pathogenetic chain eventually leading to a hyperphosphorylation of tau and the whole spectrum of AD pathology. For that reason, physiological adaptations that are observed at the hypometabolic state in hibernation are potentially analogous to neuronal reactions to a hypometabolism in very early stages of AD. Both, the increased tau phosphorylation and the reduced expression of the four-repeat isoforms result in a decreased microtubule binding capacity of tau protein. This coincidence strongly suggests that this particular condition is one prerequisite for neurons to endure the state of torpor. In this regard the biological relevance of an increased phosphorylation of tau protein in preclinical stages of AD might be reconsidered.