Abstract
Abnormal phosphorylation and aggregation of tau protein are hallmarks of a variety of neurological disorders, including Alzheimer's disease (AD). Increased tau phosphorylation is assumed to represent an early event in pathogenesis and a pivotal aspect for aggregation and formation of neurofibrillary tangles. However, the regulation of tau phosphorylation in vivo and the causes for its increased stage of phosphorylation in AD are still not well understood, a fact that is primarily based on the lack of adequate animal models. Recently we described the reversible formation of highly phosphorylated tau protein in hibernating European ground squirrels. Hence, mammalian hibernation represents a model system very well suited to study molecular mechanisms of both tau phosphorylation and dephosphorylation under in vivo physiological conditions. Here, we analysed the extent and kinetics of hibernation-state dependent tau phosphorylation in various brain regions of three species of hibernating mammals: arctic ground squirrels, Syrian hamsters and black bears. Overall, tau protein 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 kinetics of tau phosphorylation. Furthermore, we tested the phosphate net turnover of tau protein to analyse potential alterations in kinase and/or phosphatase activities during hibernation. Our results demonstrate that the hibernation-state dependent phosphorylation of tau protein is specifically regulated but involves, in addition, passive, temperature driven regulatory mechanisms. By determining the activity-state profile for key enzymes of tau phosphorylation we could identify kinases potentially involved in the differentially regulated, reversible tau phosphorylation that occurs during hibernation. We show that in black bears hibernation is associated with conformational changes of highly phosphorylated tau protein that are typically related to neuropathological alterations. The particular hibernation characteristics of black bears with a continuous torpor period and an only slightly decreased body temperature, therefore, potentially reflects the limitations of this adaptive reaction pattern and, thus, might indicate a transitional state of a physiological process.
Highlights
Tau is an axonally located, microtubule-associated protein that is encoded by a single gene and predominantly expressed in neurons [1]
Tau protein is highly phosphorylated during torpor states and phosphorylation levels decrease after arousal as demonstrated in Figure 2 where the monoclonal antibody AT8 recognizing tau protein phosphorylated at S202/T205 was applied to analyse generation and distribution of phospho-tau during hibernation in the neocortex of Syrian hamsters
Euthermic animals are characterised by a complete absence of AT8 immunoreactivity (Figure 2A) whereas already four hours after entry into torpor a marked increase of tau phosphorylation (Figure 2B) was observed
Summary
Tau is an axonally located, microtubule-associated protein that is encoded by a single gene and predominantly expressed in neurons [1]. In the adult human brain tau is expressed in six isoforms that differ with respect to the number of N-terminal inserts and microtubule binding repeats [2]. 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 [8]. 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 [9,10,11]. In early ontogenesis tau protein is highly phosphorylated which promotes a flexible microtubule network for neuronal plasticity and synaptogenesis during development [10,12]
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