Disturbed sleep is associated with cognitive decline in Alzheimer’s disease (AD) patients. The progressive sequence of how neurodegeneration affects aspects of sleep architecture in conjunction with behavioural changes is not well understood. We investigated changes in sleep architecture, spectral power and circadian rhythmicity in the tet-off rTg4510 mouse overexpressing human P301L tau within the same subject over time. Doxycycline-induced transgene-suppressed rTg4510 mice, tTa carriers and wild-type mice were used as comparators. Using EEG electrodes, spectral power and sleep stages were measured from within the home cage environment. In addition, locomotor activity and performance during a T-maze task were measured. Spectral power, primarily in the NREM delta band, showed a time-dependent decrease in rTg4510 mice compared to all other groups. After the initial changes in spectral power, wake during the dark period increased whereas NREM and number of REM sleep bouts decreased in rTg4510 compared to wild-type mice. Home cage locomotor activity significantly increased in rTg4510 compared to wild-type mice by 40 weeks of age. Peak-to-peak circadian rhythm amplitude and performance in the T-maze was impaired throughout the experiment independent of time. At 46 weeks brain histopathological changes were measured in all animals demonstrating significant degeneration in hippocampus and cortex, and protection with doxycycline. Pathology significantly correlated with sleep outcomes, in addition to locomotor and cognitive measures. In conclusion, we show that reduced EEG slow wave activity precedes reductions in sleep and home-cage locomotor activity in a mouse model of tauopathy. The data shows increasing mutant tau changes sleep architecture, EEG properties, behavior and cognition; which suggest tau related effects on sleep architecture in AD patients.
BACKGROUND: Disturbed sleep is associated with cognitive decline in neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The progressive sequence of how neurodegeneration affects aspects of sleep architecture in conjunction with behavioural changes is not well understood. METHODS: We investigated changes in sleep architecture, spectral power and circadian rhythmicity in the tet-off rTg4510 mouse overexpressing human P301L tau within the same subjects over time. Doxycycline-induced transgene-suppressed rTg4510 mice, tTa carriers and wild-type mice were used as comparators. Spectral power and sleep stages were measured from within the home cage environment using EEG electrodes. In addition, locomotor activity and performance during a T-maze task were measured. RESULTS: Spectral power in the delta and theta band showed a time-dependent decrease in rTg4510 mice compared to all other groups. After the initial changes in spectral power, wake during the dark period increased whereas NREM and number of REM sleep bouts decreased in rTg4510 compared to wild-type mice. Home cage locomotor activity in the dark phase significantly increased in rTg4510 compared to wild-type mice by 40 weeks of age. Peak-to-peak circadian rhythm amplitude and performance in the T-maze was impaired throughout the experiment independent of time. At 46 weeks rTG4510 mice had significant degeneration in the hippocampus and cortex whereas doxycycline treated rTG4510 mice were protected. Pathology significantly correlated with sleep and EEG outcomes, in addition to locomotor and cognitive measures. CONCLUSIONS: We show that reduced EEG spectral power precedes reductions in sleep and home-cage locomotor activity in a mouse model of tauopathy. The data shows increasing mutant tau changes sleep architecture, EEG properties, behaviour and cognition; which suggest tau related effects on sleep architecture in patients with neurodegenerative diseases.
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