The influence of sleep‐wake rhythms on AD‐related pathology in 3xTgAD mice

Background Age‐associated fragmentation of the daily sleep‐wake rhythm is believed to be significant in the development of AD. While it is known that sleep deprivation can worsen AD‐related pathology, such as amyloid (Aβ) deposition and neuroinflammation, the effects of fragmentation of the daily sleep‐wake rhythm are unknown. It is possible that sleep fragmentation (SF), as a less stressful approach to the manipulation of the sleep‐wake cycle, could better model AD‐related sleep disturbances. Methods We tested this hypothesis by subjecting female 3x‐TgAD mice to a chronic SF protocol for a period of 4 weeks. SF consisted of 4 daily x 1 hour sleep disruptions, evenly interspersed throughout the light phase. During SF, mice were kept awake with novel objects and gently stimulated with a paintbrush; control mice were left undisturbed (US) during these periods. Mice were individually housed in PiezoSleep cages (Signal Solutions LLC) for sleep recordings during the first and fourth weeks of the study and group‐housed in regular cages during the second and third weeks. Results Per 24 hours, SF mice exhibited significantly lower levels of sleep in the light phase (∼18% reduction) and higher levels of sleep in the dark phase (∼15% increase), with only a modest decrease (∼4%) in the total amount of daily sleep. After SF, Aβ40 and Aβ42 levels were significantly higher in the RIPA soluble fraction, as assayed by ELISA. An examination of mRNA using TaqMan low‐density gene expression arrays indicated that markers of both microglial activation (ctsd, cst7, and clec7a) and proinflammatory cytokines (TNFα, IL6, and IL‐1β) were elevated in mice subjected to SF as compared to the US group. Interestingly, the increase in Aβ and markers of neuroinflammation found in the hippocampus was not observed in the cortex, indicating at least some degree of neuroanatomical specificity in the effects of SF. Conclusion These findings demonstrate that a protocol for fragmenting the daily sleep‐wake rhythm in 3x‐TgAD mice can impact the development of AD‐related pathology. These studies also support the concept that improving sleep consolidation in individuals at risk for AD may be beneficial for slowing the onset or progression of AD.