Interactions between Circadian Organization and the Gut Microbiome in Alzheimer's Disease Pathogenesis

Alzheimer’s disease (AD) is associated with gut microbiome disruptions, that may contribute to AD pathogenesis and progression by promoting neuroinflammation and metabolic imbalance. AD is also associated with profound disturbances in sleep and circadian rhythms, many of which predate the cognitive decline in AD patients and are considered as risk and progressive factors of AD. Interestingly, recent work from us and others revealed extensive interactions between the gut microbiome and sleep/circadian rhythms as well as the impact of such interactions on inflammatory and metabolic processes. These recent advances raise an intriguing hypothesis that the interactions between the circadian organization and the gut microbiome play an important role in the pathogenesis and progression of AD. To test this hypothesis, we will investigate whether circadian phase-restricted feeding, a behavioral manipulation that potently modulates circadian organization, influences the deficits in hippocampus-dependent memory and other AD-relevant changes in a widely used mouse model of AD, the 5xFAD mice. By profiling the fecal microbiome in mice before and after circadian phase-restricted feeding, we will identify specific gut microbial taxa and functions that are relevant to AD pathogenesis: results expected to reveal key insights for developing circadian-behavioral and gut microbiome-based approaches for AD prevention and treatment.