Sex-Dependent Effects of Chronic Circadian Disruption in APP/PS1 Mice

Background: Chronic disruption of the circadian timing system, often reflected as a loss of restful sleep, also includes myriad other pathophysiological effects. Objective: The current study examined how chronic circadian disruption (CD) could contribute to pathology and rate of progression in the A beta PP/PS1 mouse model of Alzheimer's disease (AD). Methods: A chronic CD was imposed until animals reached 6 or 12 months of age in A beta PP/PS1 and C57BL/6J control mice. Home cage activity was monitored for a period of 3-4 weeks prior to the endpoint along with a single timepoint measure of glucose sensitivity. To assess long term effects of CD on the AD phenotype, animals were re-entrained to a no disruption (ND) schedule just prior to the endpoint, after which a Morris water maze (MWM) was used to assess spatial learning and memory. Results: Dampening of nighttime activity levels occurred in disrupted animals, and female animals demonstrated a greater adaptability to CD. Diminished arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) levels in the suprachiasmatic nucleus (SCN) of 12-month male A beta PP/PS1 exposed to the CD paradigm were observed, potentially accounting for the diminished re-entrainment response. Similarly, CD worsened performance in the MWM in 12-month male A beta PP/PS1 animals, whereas no effect was seen in females. Conclusions: Collectively, these findings show that exposure to chronic CD impairs circadian behavioral patterns and cognitive phenotypes of A beta PP/PS1 mouse model in a sex-dependent manner.