Long-term exercise enhances meningeal lymphatic vessel plasticity and drainage in a mouse model of Alzheimer's disease

Abstract Background Meningeal lymphatic drainage is crucial for the clearance of amyloid β (Aβ), supporting the maintenance of brain homeostasis. This makes it a promising therapeutic target for Alzheimer's disease (AD). Long-term exercise can reduce the risk of AD; however, the underlying mechanism is not fully understood. In this study, we investigated whether exercise alleviates AD-related pathological changes by improving meningeal lymphatic drainage and its potential mechanisms. Methods The morphological and functional features of meningeal lymphatic vessels, as well as Aβ and reactive gliosis in the brain, were compared between 6.5-month-old 5 × FAD mice with or without 1 month of treadmill exercise. RNA sequencing, protein interactions analysis, gene knockdown mediated by adeno-associated virus, and lymphatic endothelial cell culture were conducted to investigate the mechanism underlying exercise-induced meningeal lymphatic vessel plasticity in 5 × FAD mice. Results The structural integrity of meningeal lymphatic vessels was compromised in 5 × FAD mice, compared with the wild-type mice. Treadmill exercise increased the diameter and the drainage capacity of the meningeal lymphatic vessels, reduced Aβ deposition, reactive gliosis and astrocyte senescence in the hippocampus and frontal cortex, and improved cognitive function of 5 × FAD mice. Mechanistically, thrombospondin-1 (TSP-1) exacerbated the inhibitory effect of Aβ on lymphatic vessel formation and plasticity through interactions with CD36 and CD47, respectively. Exercise decreased the expression of TSP-1 in reactive astrocytes of AD mice by downregulating eleven-nineteen lysine-rich leukemia-associated factor 2 (EAF2), a protein that facilitates the transcription of the TSP-1-encoding gene Thbs-1 by binding p53. Ultimately, we found that hippocampal astrocyte-specific knockdown of Thbs-1 or Eaf2 enhanced meningeal lymphatic drainage and alleviated AD-like pathology in the hippocampus of 5 × FAD mice. Conclusions Long-term exercise protects against AD by enhancing the plasticity and drainage of meningeal lymphatic vessels through downregulation of the EAF2–p53–TSP-1 pathway associated with reactive astrocytes.