Cerebral glymphatic system: Structure, regulation, ageing, and mechanisms of encephalopathy

The glymphatic system was initially considered as a perivascular channel, responsible for the clearance of substances within the brain. With the deepening comprehension of the functions of the extracellular space (ECS) and the discovery of meningeal lymphatic vessels and subarachnoid lymphatic-like membrane, it is proposed that the glymphatic system should be a complex system encompassing the perivascular space, ECS, and lymphatic-like structures, and it plays crucial roles in the delivery of substances, waste clearance, and neuroimmune functions within the brain. Recent studies have revealed that brain ECS essentially regulates these fundamental functions, including sleep, memory, and sensory processing. Here, in this review, we delineate advances in the roles of glymphatic system in structure, functions, ageing and brain diseases. The imaging technologies have facilitated a more nuanced understanding of the glymphatic system's architecture, particularly the pericellular space. The compartmentalized system, characterized by myelin sheath separation, serves as the conduit for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange and plays a predominant role in modulating the ISF within the deep brain region. Furthermore, we discuss the pathophysiological implications of excessive formaldehyde (FA) accumulation in the aging brain. Especially, ageing-associated FA can cross-link Aβ, tau, α-synuclein, hemoglobin and extracellular matrix in the ECS and/or endochylema, which leads to the disorder of ISF-CSF exchanges and encephalopathy onset, such as: Alzheimer's disease, Parkinson's disease, multiple sclerosis, gliomas and sleep disorders. Hence, glymphatic system including ECS may be a promising therapeutic target for brain diseases.