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

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

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.

Abstract Image

脑脊液通过静脉上的动态旁孔流出,是大脑排水系统中缺失的一环
淋巴系统在清除实质组织中的废物方面发挥着关键作用,其功能障碍与阿尔茨海默病(AD)的发病机制有关。然而,有关其完整机制的问题依然存在。在这里,我们报告了脑脊液(CSF)/间质液(ISF)溶质的外流是通过一个三相过程发生的,而这个过程无法用现有模型来解释,而是暗示了其他以前未被发现的从蛛网膜旁空间到血液的途径的可能性。通过对外流的实时活体观察,我们发现了一种新的排泄途径,即 CSF 分子直接通过脑静脉壁上动态组装的喇叭形孔(基底侧的ϕ<8 μm;顶端的ϕ<2 μm)进入血液。由于 Zn2+ 可促进大脑清除大分子 ISF 溶质,Zn2+ 诱导的血管内皮细胞紧密连接(TJ)的重建可能参与了孔隙的形成。因此,推测出了大脑代谢物的甘油清除和潜在调节的最新模型。此外,在注意力缺失症模型小鼠中观察到,通过这些不对称静脉孔清除 Aβ 的能力不足,这支持了大脑排水功能受损导致 Aβ 积聚和注意力缺失症血管周围空间致病性扩张的观点。
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CiteScore
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