Torpor induces reversible tau hyperphosphorylation and accumulation in mice expressing human tau.

Tau protein hyperphosphorylation and aggregation are key pathological events in neurodegenerative tauopathies such as Alzheimer's disease. Interestingly, seasonal hibernators show extensive tau hyperphosphorylation during torpor, i.e., the hypothermic and hypometabolic state of hibernation, which is completely reversed during arousal. Torpor-associated mechanisms that reverse tau hyperphosphorylation may be of therapeutic relevance, however, it is currently not known to what extent they apply to human tau. Here we addressed this issue using daily torpor in wildtype mice that express mouse tau (mtau) and in mice that lack mtau expression and instead express human tau (htau). AT8, AT100 and Ser396 immunoblotting and immunohistochemistry were used to assess tau (hyper)phosphorylation at clinically relevant phosphorylation sites. We found that torpor robustly and reversibly increases the levels of phosphorylated tau in both mtau and htau mice. Immunohistochemistry revealed four brain areas that show prominent tau phosphorylation: the hippocampus, posterior parietal cortex, piriform cortex and cortical amygdala. Whereas wildtype mice primarily showed increased levels of diffusely organized hyperphosphorylated tau during torpor, htau mice contained clear somato-dendritic accumulations of AT8 reactivity resembling tau pre-tangles as observed in the Alzheimer brain. Interestingly, AT8-positive accumulations disappeared upon arousal, and tau phosphorylation levels at 24 h after arousal were lower than observed at baseline, suggesting a beneficial effect of torpor-arousal cycles on preexisting hyperphosphorylated tau. In conclusion, daily torpor in mice offers a quick and standardized method to study tau phosphorylation, accumulation and clearance in mouse models relevant for neurodegeneration, as well as opportunities to discover new targets for the treatment of human tauopathies.

Neuroprotective hypothermia - Why keep your head cool during ischemia and reperfusion.

BACKGROUND: Targeted temperature management (TTM) is the induced cooling of the entire body or specific organs to help prevent ischemia and reperfusion (I/R) injury, as may occur during major surgery, cardiac resuscitation, traumatic brain injury and stroke. Ischemia and reperfusion induce neuronal damage by mitochondrial dysfunction and oxidative injury, ER stress, neuronal excitotoxicity, and a neuroinflammatory response, which may lead to activation of apoptosis pathways. SCOPE OF REVIEW: The aim of the current review is to discuss TTM targets that convey neuroprotection and to identify potential novel pharmacological intervention strategies for the prevention of cerebral ischemia and reperfusion injury. MAJOR CONCLUSIONS: TTM precludes I/R injury by reducing glutamate release and oxidative stress and inhibiting release of pro-inflammatory factors and thereby counteracts mitochondrial induced apoptosis, neuronal excitotoxicity, and neuroinflammation. Moreover, TTM promotes regulation of the unfolded protein response and induces SUMOylation and the production of cold shock proteins. These advantageous effects of TTM seem to depend on the clinical setting, as well as type and extent of the injury. Therefore, future aims should be to refine hypothermia management in order to optimize TTM utilization and to search for pharmacological agents mimicking the cellular effects of TTM. GENERAL SIGNIFICANCE: Bundling knowledge about TTM in the experimental, translational and clinical setting may result in better approaches for diminishing I/R damage. While application of TTM in the clinical setting has some disadvantages, targeting its putative protective pathways may be useful to prevent I/R injury and reduce neurological complications.