Central nervous system lymphatic network: from the maintenance of brain homeostasis to emerging therapeutic perspectives in neurodegenerative diseases

The brain was long been regarded as an immune-privileged organ with a lack of lymphatic drainage, partly because of the absence of parenchymal lymphatic vessels. This long-held doctrine has been challenged by recent advancements in central lymphatic vascular biology. The central drainage network, which consists of the glymphatic system, meningeal lymphatic vessels, and cranial perineural drainage pathways, plays a crucial role in the clearance of metabolic brain waste and the maintenance of brain homeostasis. Furthermore, the meninges and brain perivascular spaces are rich in immune cells that regulate neuronal activities and diverse behaviors through secretion of cytokines. Dysfunction of the central lymphatic network is widely observed in natural aging and neurodegenerative disorders, which is characterized by mislocalization of aquaporin-4 on astrocytic endfeet, impairment of lymphatic valvular integrity, and alterations in the proportion and phenotype of meningeal immune cells. In this review, we provide a comprehensive overview of the anatomical foundations, molecular regulatory mechanisms, and physiological functions of this system. We summarize the pathological roles of the central lymphatic network across neurodegenerative conditions and discuss emerging clinical assessment frameworks based on multimodal imaging and liquid biomarkers. We also highlight promising therapeutic strategies, such as restoring meningeal lymphatic function, targeting glymphatic drainage, and modulating the meningeal immune microenvironment. Elucidating the dynamics of the central lymphatic network will reshape our understanding of brain homeostasis, paving the way for novel diagnostic and therapeutic strategies for neurodegenerative diseases. Future research should focus on translating fundamental findings into clinical applications, thereby accelerating the transition from basic research to clinical practice.