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Brain on standby — how torpor made ‘tauopathy’ reversible

Nature Reviews Neuroscience volume 26, page 590 (2025)Cite this article

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The mature brain was once thought to be hardwired — its circuitry static and fragile, particularly in the face of physiological stresses such as changes in temperature. By the time I reached my doctoral studies in 2012, the view of adult neuroplasticity had shifted from sharp scepticism in the 1960s to mainstream acceptance, and the study of brain dynamics had become central to understanding neural function. While studying neurodegeneration related to tau — a microtubule-associated protein that becomes irreversibly tangled in dementia — I chanced upon a paper from Arendt et al. on the hibernating brain. Far from leaving me cold, this paper transformed my thinking and the direction of my thesis; it illustrated how some dementia-linked changes in tau were physiologically coupled to adult neuroplasticity in the context of neuroprotection, rather than neurodegeneration.

Torpor is a reversible state of reduced metabolism, body temperature and physical activity that occurs repeatedly during hibernation. Arendt et al. studied the forebrains of ground squirrels under non-hibernating conditions and at different stages of the torpor–arousal cycle. Using immunohistochemistry, electron microscopy and biochemistry, they tested whether cyclical structural changes in hippocampal synapses correlated with changes in tau. They showed that torpor-associated tau modifications were post-translational and mimicked the phosphorylation pattern seen in the insoluble, aggregated paired helical filament (PHF) tau of Alzheimer’s disease, but with a twist: the observed tau hyperphosphorylation was fully reversible upon arousal. The spatiotemporal mapping of ‘PHF-like’ tau could seduce any neuropathologist — yet no insoluble PHF tau was extracted from torpid brain tissue and thus no intra-neuronal tangles of PHF tau formed in torpid animals. Critically, the cellular and subcellular distribution of ‘PHF-like’ tau during the torpor–arousal cycle elegantly paralleled the cyclical regression and reafferentation of mossy fibre contacts.

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References

Original article

  • Arendt, T. et al. Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating mammals. J. Neurosci. 23, 6972–6981 (2003)

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Related article

  • Rzechorzek, N. M. et al. Hypothermic preconditioning reverses tau ontogenesis in human cortical neurons and is mimicked by protein phosphatase 2A inhibition. eBioMedicine 3, 141–154 (2015)

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  1. Department of Engineering, University of Cambridge, Cambridge, UK

    Nina M. Rzechorzek

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  1. Nina M. Rzechorzek
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Correspondence to Nina M. Rzechorzek.

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Rzechorzek, N.M. Brain on standby — how torpor made ‘tauopathy’ reversible. Nat. Rev. Neurosci. 26, 590 (2025). https://doi.org/10.1038/s41583-025-00964-9

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