A time-restricted feeding intervention reduces alterations in circadian behaviors and pathology in a mouse model of Alzheimer's disease.

Abstract

Circadian rhythm disruptions impact nearly all Alzheimer's disease (AD) patients, with daytime sleepiness, sundowning, sleep fragmentation, and night-time insomnia being common disturbances. These early and progressive declines support the role of circadian dysfunction as a driver of AD pathology, hence the therapeutic potential of circadian-modulating interventions needs to be investigated. One of the most powerful regulators of the circadian system is the daily feed/fast cycle. We have recently shown that early, presymptomatic time-restricted feeding (TRF) can ameliorate a range of symptoms related to neurodegenerative conditions, including improving sleep/wake timing and circadian rhythmicity. At 12 months of age, the APP23 mouse model of AD (expressing the human APP gene containing the Swedish mutation) exhibits disrupted behavior resembling sundowning. We hypothesized that imposing early-age TRF in APP23 mice would improve circadian rhythmicity and deter the disruptions observed to emerge and progress with advancing neuropathology. Adult male and female APP23 transgenic (AD) and littermate non-transgenic (control) mice were housed individually and subjected to ab libitum (ALF) feeding or a TRF protocol consisting of 6-hours feeding in the middle of the active phase followed by 18-hours fasting for 3 months. Behavioral sleep (48 hours) and ongoing cage locomotor activity were recorded from an early age. Our analysis shows that AD mice exhibit disruptions in total sleep (P < 0.001) and the emergence of excessive wakefulness (P < 0.001). AD mice also show significant active-phase agitation (P < 0.05) accompanied by excessive sleep-phase fragmentation (P < 0.05). TRF induced nutritional ketosis (β-Hydroxybutyrate > 0.5 mM) accompanied by reduced blood glucose when compared to ALF mice, although mice consumed equivalent volumes of food in both experimental groups. Importantly, TRF improved total and sleep-phase sleep in AD mice (P < 0.05) and significantly reduced agitation and fragmentation (P < 0.05). Early application of TRF can forestall circadian disruptions in AD mice. TRF has been reported to modulate expression of clock and clock-controlled genes, transcriptional regulators, metabolism related genes, BDNF, and other neurotrophic factors. Our results suggest that these changes may also impact sleep, circadian behaviors, and agitation associated with AD.