Altered sleep and EEG power in the P301S Tau transgenic mouse model

Abstract

ObjectiveSleep disturbances are prevalent in human tauopathies yet despite the importance of sleep, little is known about its relationship with tau pathology. Here, we investigate this interaction by analyzing sleep and tau pathology throughout tauopathy disease progression in P301S human tau transgenic mice.MethodsP301S and wild‐type mice were analyzed by electroencephalography (EEG)/electromyography at 3, 6, 9, and 11 months of age for sleep/wake time, EEG power, and homeostatic response. Cortical volume and tau pathology was also assessed by anti‐phospho‐tau AT8 staining.ResultsP301S tau mice had significantly decreased rapid eye movement (REM) sleep at 9 months of age and decreased REM and non‐REM (NREM) sleep as well as increased wakefulness at 11 months. Sleep loss was characterized by fewer wake, REM, and NREM bouts, increased wake bout duration, and decreased sleep bout duration. Decreased REM and NREM sleep was associated with increased brainstem tau pathology in the sublaterodorsal area and parafacial zone, respectively. P301S mice also showed increased EEG power at 6 and 9 months of age and decreased power at 11 months. Decreased EEG power was associated with decreased cortical volume. Despite sleep disturbances, P301S mice maintained homeostatic response to sleep deprivation.InterpretationOur results indicate that tau pathology is associated with sleep disturbances that worsen with age and these changes may be related to tau pathology in brainstem sleep regulating regions as well as neurodegeneration. Tau‐induced sleep changes could affect disease progression and be a marker for therapeutic efficacy in this and other tauopathy models.

Disease-Associated Mutant Tau Prevents Circadian Changes in the Cytoskeleton of Central Pacemaker Neurons

“…A more active role is further supported by findings that sleep disruptions can precede the development of other symptoms of AD, including cognitive decline (Guarnieri and Sorbi, 2015). However, while several studies have suggested a link between the accumulation of plaque-associated β-amyloid and sleep (Brown et al, 2016;Cedernaes et al, 2017;Macedo et al, 2017;Yulug et al, 2017), a role of neuropathic forms of Tau in disrupting sleep has only recently been addressed (Holth et al, 2017). Furthermore, in contrast to amyloid plaques which are characteristic for AD, Tau pathology is found in all Tauopathies and therefore effects of Tau on sleep could account for the sleep disruptions in many Tauopathies, including AD.…”

“…Tauopathy is a dominant inherited disease and the most prominent symptoms are behavioral and personality changes, cognitive impairment, and motor symptoms (Wszolek et al, 2006). In addition, FTDP-17 patients and other Tauopathy patients show changes in their sleep patterns (McCarter et al, 2016;Holth et al, 2017;Liu et al, 2018). Disturbances in sleepwake cycles and other circadian rhythms are also very common in Alzheimer patients (van Someren et al, 2007;Reddy and O'Neill, 2010;Kondratova and Kondratov, 2012;Hastings and Goedert, 2013;Musiek et al, 2018;Leng et al, 2019) and recent evidence in AD suggests that sleep abnormalities are not simply a consequence but an intimate and bi-directional component of the pathophysiology.…”

“…While it has been shown in a variety of models that APP or Aβ expression disrupts sleep, it has only recently been described that a FTPD-17 mouse model shows changes in its sleep patterns. Knock-in mice expressing human Tau (hTau) with the disease-associated P301L or R406W mutation in the forebrain reveal decreased non-REM sleep and increased wakefulness (Koss et al, 2016;Holth et al, 2017). To study the emerging connection between mutant Tau and sleep, we used the Drosophila model to create knock-in flies that either express wild type human Tau (hTau WT ) or FTDP-17-causing mutant hTau V337M instead of Drosophila Tau (dTau).…”

Miniature Untethered EEG Recorder Improves Advanced Neuroscience Methodologies

“…Lowering the sample rate is desirable when long-duration recordings are required, EEG with 1/f PSD, 2 EEG with 1/f2 PSD, 3 Limited by ADC, 4 Continuous operating power. 5 Based on 4Gbit, and 8Gbit flash-memory capacities. At lower sample rates, recording time becomes battery limited.…”

Longitudinal changes in EEG power, sleep cycles and behaviour in a tau model of neurodegeneration.

“…Both AD and FTD often present with desynchronization of circadian rhythms, lower sleep e ciency, lower percentage of non-rapid-eyemovement (NREM) sleep and a greater frequency of arousals and awakenings (9)(10)(11)(12)(13). These changes have recently been shown to correlate with pathological de cits produced my misfolded proteins such as Ab and tau (14,15). A reduced percentage of REM or the deeper stages of NREM sleep are the most consistently reported in patients with mild to moderate AD.…”