Circadian rhythm disturbances in Alzheimer’s disease: insights from plaque-free and plaque-burdened stages in APP_SWE/PS1_dE9 mice

Background: Disruptions in circadian rhythms are commonly observed in patients with Alzheimer’s disease (AD) and could potentially accelerate the progression of the condition. However, the relationship between circadian rhythm disruptions and AD development, as well as the mechanisms involved, remain poorly understood. Methods: This study investigated the circadian behavior, rhythmic gene expression in multiple brain regions, and its correlation with sleep architecture of AD mice at two disease stages: plaque-free stage (2-month-old) and plaque-burdened stage (10-month-old) as compared to age-matched wild-type (WT) mice. Results: Two-month-old AD mice already displayed alteration in the activity patterns compared to WT mice, showing increased activity during the light phase and decreased activity during the dark phase, and the change in the activity pattern of 10-month-old AD mice was more significant. Further, electroencephalogram (EEG) examination showed increased wakefulness and reduced non-rapid eye movement (NREM) sleep in 2- and 10-month-old AD mice. In addition, we documented a significant change in circadian core clock genes in the suprachiasmatic nucleus (SCN), hippocampus, and cortex of 2- and 10-month-old AD mice. Correlation analyses demonstrated the close relationship between circadian clock gene expression level and specific sleep-wake parameters, especially within the SCN and hippocampus. Conclusions: These findings revealed that circadian rhythm disturbances in AD mice preceded Aβ deposition. The circadian rhythm disturbances observed in the early AD might be attributed to the abnormal expression of core clock genes in the brain regions involved in circadian rhythm regulation.