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

Abstract

Study Objectives 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. Methods 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. Results 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. Conclusion 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.

Association between Lower Body Temperature and Increased Tau Pathology in Cognitively Normal Older Adults

“…These notably included Ser 202/Thr 205 [36,37,42], used for Braak staging [5] and to characterize MK6420 uptake in post mortem audioradiography [73], as well as other phosphosites found to be hyperphosphorylated in AD, including Thr 181 [42,47], relevant to CSF and plasma P-tau. A temperature decrease of 37.4°C to 36.3°C also robustly increased human neuronal tau phosphorylation at these phosphosites in vitro [47]. Additional temperature-dependent molecular processes involved in tau proteostasis may also link lower Tb to tau aggregation.…”

“…Planel et al, Arendt et al, and others showed in an elegant series of rodent experiments made over the last 20 years that a small (< 1°C) decrease in body temperature (Tb) within the human physiological range substantially increases neuronal tau phosphorylation-notably at phosphosites that are hyperphosphorylated in AD patients [36][37][38][39][40][41]. This effect was induced by experimental Tb decrease [36,37,42], seasonal torpor [43,44], as well as sleep-associated Tb decrease, which drove a robust increase in tau phosphorylation compared to waking in wild-type mouse [45]. Regarding the underlying mechanism, Tb decrease inhibited the activity of the major tau phosphatase (PP2A) more so than tau kinase activity, resulting in a net phosphorylation increase [36,46].…”

“…Regarding the underlying mechanism, Tb decrease inhibited the activity of the major tau phosphatase (PP2A) more so than tau kinase activity, resulting in a net phosphorylation increase [36,46]. Importantly, decreasing temperature from 37.4°C to 36.3°C also robustly increased phosphorylation at AD relevant phosphosites on human neuronal tau in vitro [42,47], suggesting that in human, too, lower Tb and brain temperature could increase tau phosphorylation and potentially, tau pathology.…”

“…Further, age-related molecular pathway alterations may exacerbate hypothermia-induced tau phosphorylation or impair its reversibility [39,54,55]. Therefore, lower Tb or disturbed Tb circadian rhythm may be a mechanism by which age [39,56], diabetes [57,58], sleep disturbance [47,59], and other AD risk factors exert risk. Toward AD prevention, mitigating thermoregulatory impairment with targeted Tb interventions could prevent NFT formation [60].…”

“…Tb was continuously measured with ingestible telemetry [75][76][77] for up to 48 hours. Given recent reports of circadian variation in tau phosphorylation in wild-type mice [45], nocturnal polysomnography (NPSG) was performed on both nights of this 48-hour period to delineate whether tau pathology was differentially associated with Tb during waking vs sleep.…”