Sleep-wake body temperature regulates tau secretion in mice and correlates with CSF and plasma tau in humans

TL;DR

This study shows that body temperature changes during sleep and wakefulness affect tau protein levels in mice and humans, linking sleep patterns to neurodegenerative diseases.

Contribution

The study identifies a novel temperature-dependent pathway through which wakefulness increases extracellular tau levels.

Findings

Higher body temperature during wakefulness and sleep deprivation increases CSF tau in mice.

Wakefulness temperatures upregulate tau secretion via caspase-3, PIP2, and syndecan-3 in vitro.

Human CSF and plasma tau levels correlate with body temperature increases post-wakefulness.

Abstract

The sleep-wake cycle regulates interstitial fluid and cerebrospinal fluid (CSF) tau levels in both mouse and human by mechanisms that remain unestablished. Here, we reveal a novel pathway by which wakefulness increases extracellular tau levels in mouse and humans. In mice, higher body temperature (BT) associated with wakefulness and sleep deprivation increased CSF tau. In vitro, wakefulness temperatures upregulated tau secretion via a temperature-dependent increase in activity and expression of unconventional protein secretion pathway-1 components, namely caspase-3-mediated C-terminal cleavage of tau (TauC3), and membrane expression of PIP2 and syndecan-3. In humans, the increase in both CSF and plasma tau levels observed post-wakefulness correlated with BT increase during wakefulness. Our findings suggest sleep-wake variation in BT may contribute to regulating extracellular tau levels, highlighting the importance of thermoregulation in pathways linking sleep disturbance to neurodegeneration, and the potential for thermal intervention to prevent or delay tau-mediated neurodegeneration.

Figures