Cerebrospinal fluid efflux through dynamic paracellular pores on venules as a missing piece of the brain drainage system

A novel drainage pathway through which cerebrospinal fluid (CSF)/interstitial fluid (ISF) molecules enter the bloodstream directly via dynamically assembled trumpet-shaped pores on the walls of brain venules was discovered. An updated model for glymphatic clearance of brain metabolites and potential roles in the Alzheimer disease and some neurological disorders are discussed.


The glymphatic system plays a key role in the clearance of waste from the parenchyma, and its dysfunction has been associated with the pathogenesis of Alzheimer’s disease (AD). However, questions remain regarding its complete mechanisms. Here, we report that efflux of cerebrospinal fluid (CSF)/interstitial fluid (ISF) solutes occurs through a triphasic process that cannot be explained by the current model, but rather hints at the possibility of other, previously undiscovered routes from paravenous spaces to the blood. Using real-time, in vivo observation of efflux, a novel drainage pathway was discovered, in which CSF molecules enter the bloodstream directly through dynamically assembled, trumpet-shaped pores (basolateral ϕ<8 μm; apical ϕ < 2 μm) on the walls of brain venules. As Zn2+ could facilitate the brain clearance of macromolecular ISF solutes, Zn2+-induced reconstruction of the tight junctions (TJs) in vascular endothelial cells may participate in pore formation. Thus, an updated model for glymphatic clearance of brain metabolites and potential regulation is postulated. In addition, deficient clearance of Aβ through these asymmetric venule pores was observed in AD model mice, supporting the notion that impaired brain drainage function contributes to Aβ accumulation and pathogenic dilation of the perivascular space in AD.

Author list:

Yaqiong Dong, Ting Xu, Lan Yuan, Yahan Wang, Siwang Yu, Zhi Wang, Shizhu Chen, Chunhua Chen, Weijiang He, Tessandra Stewart*, Weiguang Zhang*, Xiaoda Yang*

How to cite:

Y. Dong, T. Xu, L. Yuan, Y. Wang, S. Yu, Z. Wang, S. Chen, C. Chen, W. He, T. Stewart, W. Zhang, X. Yang, Exploration 2023, 4, 20230029.