Circadian disruption (CD) has emerged as a critical factor compromising human health in contemporary society. Increasing evidence suggests that disturbances in circadian rhythms are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). The hyperphosphorylation of tau and the deposition of amyloid-β (Aβ) are recognized as major pathological hallmarks of AD. In this study, we aimed to explore the impact of long-term CD on AD-like pathological changes and to explore the underlying molecular mechanisms using a mouse model. To mimic the CD experienced by shift workers, mice were subjected to lighting conditions involving repeated reversals of the light-dark cycle. In this study, qPCR was to employed detect the expression profile of clock genes in the hippocampus. Subsequently, Western blotting and immunohistochemical analyses were used to evaluate AD-like pathological changes in the hippocampus following CD. For elucidating the underlying mechanisms, we assessed circadian expression patterns of major neurotransmitters, activation of microglia and astrocytes, and alterations of tight junction proteins within the hippocampus. Our findings demonstrated that light-dark cycle disruption triggered CD in mice, and then CD led to increased expression of Aβ protein and tau hyperphosphorylation. CD significantly disrupted the circadian expression profiles of hippocampal clock genes and major neurotransmitters, induced microglial and astrocytic activation, and decreased the expression of the tight junction proteins zonula occludens-1 and occludin in the hippocampus. These results suggest that changes in the light-dark cycles induced abnormal expression of hippocampal clock genes involved in circadian rhythm regulation, suggesting that the body is in a state of endogenous CD. CD induces AD-like pathological changes in mice, potentially mediated by dysregulated circadian oscillations of clock genes, neuroinflammation, loss of key blood-brain barrier proteins, and disturbed neurotransmitter expression in the hippocampus. Collectively, this study underscores the importance of circadian stability for brain health, and highlights the necessity for deeper exploration into the connection between AD and CD.
