The study investigates the dynamics of amyloid-β (Aβ) in the brain and its regulation by the sleep-wake cycle and orexin. Using in vivo microdialysis, the researchers found that interstitial fluid (ISF) Aβ levels correlated with wakefulness, increasing during the dark period and decreasing during the light period. Sleep deprivation and orexin infusion increased ISF Aβ levels, while a dual orexin receptor antagonist decreased them. Chronic sleep restriction in APP transgenic mice significantly increased Aβ plaque formation, while orexin receptor blockade reduced it. These findings suggest that the sleep-wake cycle and orexin may play a role in the pathogenesis of Alzheimer's disease (AD) by regulating Aβ levels and aggregation.The study investigates the dynamics of amyloid-β (Aβ) in the brain and its regulation by the sleep-wake cycle and orexin. Using in vivo microdialysis, the researchers found that interstitial fluid (ISF) Aβ levels correlated with wakefulness, increasing during the dark period and decreasing during the light period. Sleep deprivation and orexin infusion increased ISF Aβ levels, while a dual orexin receptor antagonist decreased them. Chronic sleep restriction in APP transgenic mice significantly increased Aβ plaque formation, while orexin receptor blockade reduced it. These findings suggest that the sleep-wake cycle and orexin may play a role in the pathogenesis of Alzheimer's disease (AD) by regulating Aβ levels and aggregation.