Amyloid-β (Aβ) accumulation in the brain extracellular space is a hallmark of Alzheimer's disease (AD). The study shows that Aβ levels in the brain interstitial fluid (ISF) fluctuate with the sleep-wake cycle and are regulated by orexin. Using in vivo microdialysis, the researchers found that ISF Aβ levels correlate with wakefulness, increase during acute sleep deprivation and orexin infusion, and decrease with a dual orexin receptor antagonist. Chronic sleep restriction significantly increases Aβ plaque formation in amyloid precursor protein transgenic mice, while a dual orexin receptor antagonist decreases it. These findings suggest that the sleep-wake cycle and orexin may play a role in AD pathogenesis. The study also shows that Aβ levels in the brain fluctuate diurnally, with higher levels during the dark period compared to the light period. This diurnal variation is independent of light exposure and is linked to the sleep-wake cycle. Orexin, a molecule that regulates wakefulness, shows a diurnal fluctuation similar to that of ISF Aβ. Orexin administration increases ISF Aβ levels, while a dual orexin receptor antagonist decreases them. This indicates that endogenous orexin signaling via orexin receptors is required for the diurnal rhythm of ISF Aβ levels. Chronic sleep restriction accelerates Aβ plaque burden, while orexin receptor blockade enhances sleep and markedly inhibits Aβ plaque accumulation. The study also suggests that changes in ISF Aβ levels can contribute to Aβ plaque deposition. Behavioral and pharmacological manipulations that result in changes in ISF Aβ levels of 20-25% likely cause the observed changes in Aβ accumulation. Sleep disturbances, in addition to being prominent in neurodegenerative diseases, could exacerbate a fundamental process leading to neurodegeneration. Optimization of sleep time could potentially inhibit aggregation of toxic proteins and slow the progression of AD.Amyloid-β (Aβ) accumulation in the brain extracellular space is a hallmark of Alzheimer's disease (AD). The study shows that Aβ levels in the brain interstitial fluid (ISF) fluctuate with the sleep-wake cycle and are regulated by orexin. Using in vivo microdialysis, the researchers found that ISF Aβ levels correlate with wakefulness, increase during acute sleep deprivation and orexin infusion, and decrease with a dual orexin receptor antagonist. Chronic sleep restriction significantly increases Aβ plaque formation in amyloid precursor protein transgenic mice, while a dual orexin receptor antagonist decreases it. These findings suggest that the sleep-wake cycle and orexin may play a role in AD pathogenesis. The study also shows that Aβ levels in the brain fluctuate diurnally, with higher levels during the dark period compared to the light period. This diurnal variation is independent of light exposure and is linked to the sleep-wake cycle. Orexin, a molecule that regulates wakefulness, shows a diurnal fluctuation similar to that of ISF Aβ. Orexin administration increases ISF Aβ levels, while a dual orexin receptor antagonist decreases them. This indicates that endogenous orexin signaling via orexin receptors is required for the diurnal rhythm of ISF Aβ levels. Chronic sleep restriction accelerates Aβ plaque burden, while orexin receptor blockade enhances sleep and markedly inhibits Aβ plaque accumulation. The study also suggests that changes in ISF Aβ levels can contribute to Aβ plaque deposition. Behavioral and pharmacological manipulations that result in changes in ISF Aβ levels of 20-25% likely cause the observed changes in Aβ accumulation. Sleep disturbances, in addition to being prominent in neurodegenerative diseases, could exacerbate a fundamental process leading to neurodegeneration. Optimization of sleep time could potentially inhibit aggregation of toxic proteins and slow the progression of AD.