Circadian and sleep/wake-dependent variations in tau phosphorylation are driven by temperature.

Abstract

Aggregates of hyperphosphorylated tau protein are a hallmark of Alzheimer's disease (AD) and other tauopathies. Sleep disturbances are common in AD patients, and insufficient sleep may be a risk factor for AD. Recent evidence suggests that tau phosphorylation is dysregulated by sleep disturbances in mice. However, the physiological regulation of tau phosphorylation during the sleep-wake cycle is currently unknown. We thus aimed to determine whether tau phosphorylation is regulated by circadian rhythms, inherently linked to the sleep-wake cycle. To answer these questions, we analyzed by Western blotting tau protein and associated kinases and phosphatases in the brains of awake, sleeping, and sleep-deprived B6 mice. We also recorded their temperature. We found that tau phosphorylation undergoes sleep-driven circadian variations as it is hyperphosphorylated during sleep but not during acute sleep deprivation. Moreover, we demonstrate that the mechanism behind these changes involves temperature, as tau phosphorylation was inversely correlated with circadian- and sleep deprivation-induced variations in body temperature, and prevented by housing the animals at a warmer temperature. Notably, similar changes in tau phosphorylation were reproduced in neuronal cells exposed to temperatures recorded during the sleep-wake cycle. Our results also suggest that inhibition of protein phosphatase 2A (PP2A) may explain the hyperphosphorylation of tau during sleep-induced hypothermia. Taken together, our results demonstrate that tau phosphorylation follows a circadian rhythm driven mostly by body temperature and sleep, and provide the physiological basis for further understanding how sleep deregulation can affect tau and ultimately AD pathology.