The glymphatic system in sleep: a nexus of waste clearance, brain homeostasis, and disease intervention

The homeostasis of the brain's extracellular microenvironment exhibits circadian oscillations between sleep and wakefulness. Metabolites such as adenosine, lactate, and amyloid-beta (Aβ) accumulate during wakefulness while being actively cleared during sleep. However, the regulatory mechanisms governing extracellular solute homeostasis and their sleep-dependent clearance have long remained enigmatic. The glymphatic system, a macroscopic waste clearance pathway discovered in recent years, leverages perivascular channels formed by astrocytes to facilitate the removal of soluble proteins and metabolites from the central nervous system. Notably, glymphatic system activity is predominantly active during sleep and largely quiescent during wakefulness, suggesting that the universal biological demand for sleep may reflect the brain's need to engage this specialized state for detoxification of endogenous neurotoxic waste. This review delineates the structural architecture, functional principles and therapeutic applications of the glymphatic system, with a focus on its role in sleep-mediated cerebral homeostasis. Future research should aim to unravel the molecular mechanisms underlying glymphatic system physiology and identify regulatory targets for therapeutic intervention. Such advances hold transformative potential for treating neurodegenerative and neuropsychiatric disorders, positioning the glymphatic system as a cornerstone of clinical innovation in neurology. The schematic diagram of glymphatic system (Left); Physiological and pathological linkages of the glymphatic system (Right).