Work

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

Year: 2023

Type: article

Abstract: Background: The glymphatic system has been considered to contribute to a larger portion of parenchyma waste clearance and related to pathogenesis of many neural degenerative diseases such as the Alzheimer’s disease (AD). However, up to date, the key route for the efflux from perivascular spaces to the blood pool remains a mystery.Methods: BBB-impermeable fluorescent lanthanide probes of different size were first applied as cerebrospinal fluid (CSF)/interstitial fluid (ISF) tracers to quantitatively clarify the relative importance of different pathways to drain CSF/ISF solutes. The in vivo dynamic flows of subarachnoid CSF labeled with fluorescein isothiocyanate-dextran (4 kDa) tracers along brain blood vessels were observed under a two-photon confocal laser scanning microscope. Results: Three phasic process for the brain drainage was observed, in which the rapid efflux of ISF solutes with a time constant close to the CSF oscillation during sleep appeals for new routes from perivenuous spaces to the blood pool. Careful observation on the dynamic efflux in vivo revealed a novel drainage pathway in which CSF molecules converge into the bloodstream directly through dynamic trumpet-like pores (basolateral f＜8 μm; apical f＜2 μm) on the wall of brain venule in mice. Zn2+, an inducer of reconstruction of the tight junctions (TJs) in vascular endothelial cells, could facilitate the brain clearance of macromolecular ISF solutes. Deficit clearance of Aβ through the asymmetric pores on venule potentially causing perivascular space dilation was observed on the AD model mice.Conclusions: The novel asymmetric pore path through reconstruction of endothelial TJs on the wall of venule shall provide a key piece for ISF solutes to drainage from brain in very rapid pathway. The update image would help to understand the structure and the regulation of glymphatic clearance of brain metabolites such as Aβ in search for the solutions of neurodegenerative diseases.

Source: Exploration

DOI: 10.1002/exp.20230029