Due to binding to tubulin, tau promotes assembly and stability of microtubules. The tau-microtubule interaction is a dynamic process that plays a pivotal role in structural remodelling of the cytoskeleton during neuronal and synaptic plasticity. The binding capacity of tau to microtubules is regulated at different levels. The expression of four instead of three microtubule binding repeats results in tau-isoforms that differ in affinity to microtubules. In addition, protein modification by phosphorylation represents a very rapid mechanism to regulate the binding capacity of tau. Phosphorylation of tau is a physiological process and elevated phospho-degrees give rise to a decreased microtubule binding. In early ontogenesis tau protein is highly phosphorylated which promotes a flexible microtubule network for neuronal plasticity and synaptogenesis during development. A variety of neurodegenerative disorders is characterised by the formation of intracellular deposits of phosphorylated tau 
protein aggregated into paired helical filaments. For example, neurofibrillary tangles consisting of PHF-tau represent a major hallmark of Alzheimer’s disease, the most prominent type of so-called ”tauopathies”. Aggregated tau protein differs from normal tau by its high degree of phosphorylation, its conformation as well as its solubility. Still, little is known about functional links between degree of phosphorylation and aggregation of tau protein. Tau phosphorylation can induce conformational changes that subsequently modulate its propensity for self-aggregation. Moreover, phosphorylation of tau can promote self-assembly and filament formation, at least under in vitro conditions. On the other hand, phosphorylation may also lessen PHF-tau assembly. Thus, depending on the particular phospho-site, tau protein aggregation can either be promoted or impaired. In the human tau protein more than 30 phosphorylation sites have been identified as being involved in both physiological and pathological processes. It had been hypothesised that tau phosphorylation in AD may initially represent a physiological reaction with a protective function that in the course of pathogenesis eventually turns into a pathological result. However, the lack of appropriate in vivo models of PHF-like tau phosphorylation so far impedes a proof of this concept. We have demonstrated a PHF-like phosphorylation of tau in hibernating mammals, a finding that recently has been replicated by other groups. In the state of torpor with decreased metabolism and body temperature, brains of hibernating animals show an intensely elevated PHF-like pattern of tau phosphorylation which is fully reversed when animals return to the normal state after arousal. Furthermore, torpor in hibernating animals shows significant analogies to the pathophysiological condition of AD with respect to an altered synaptic connectivity, the types of neurons affected, and the impairment of cognitive function. Therefore, mammalian 4-(Benzyloxy)phenol hibernation represents a model system very well suited to analyse conditions and mechanisms physiologically associated with increased tau phosphorylation and altered synaptic connectivity. In addition, the hibernation model helps to identify potential differences between tau hyperphosphorylation in torpor and AD, thereby contributing to our understanding of the significance of tau phosphorylation for neurodegeneration. In the present study we analysed the reversible tau phosphorylation in arctic ground squirrels, Syrian hamsters and black bears. These species were selected since they differ with respect to their hibernation characteristics as well as their degree of body Gentamycin Sulfate temperature change during torpor. With a body temperature of about 0uC arctic ground squirrels show the most extreme reduction followed by the Syrian hamsters where body temperature is lowered to about 5uC during hibernation. Black bears, however, show only a slight temperature change during hibernation with a body temperature of no lower than 30uC. In arctic ground squirrels and Syrian hamsters hibernation is characterised by regular torpor intervals interrupted.