The curious case of intracranial lymphatics

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Science Translational Medicine  12 Aug 2015:
Vol. 7, Issue 300, pp. 300ec137
DOI: 10.1126/scitranslmed.aad0225

No longer an obscure research backwater, the physiology of cerebral spinal fluid (CSF) and solute drainage at the brain barriers is important for Alzheimer's disease, stroke, multiple sclerosis, and other prevalent brain diseases. In the latest advance, Aspelund et al. confirm the existence of a lymphatic system in the mouse dura mater (the tough membrane that surrounds the brain inside the skull) and investigate its function in transgenic mice.

Known since the late 1870s from experiments with vital dyes, CSF drainage outside the skull occurs along cranial nerves, with outflow to the nasal and cervical lymphatics. The evidence for intracranial dural-based lymphatics was more elusive but was reported in dogs in 1966 and in rodents in 1987. Within the brain itself, perivascular conduits act as a substitute for intraparenchymal lymphatic ducts. These passages for recycling brain CSF were recently renamed "glymphatics" in view of the fact that they are bordered by glia, but a true lymphatic system is lacking in the brain parenchyma.

The new work by Aspelund et al. is significant because the authors have used newly available molecular tools from lymphatic biology to map the dural lymphatic anatomy in unprecedented detail. They harnessed a number of highly specific promoters and antigens for lymphatic capillaries to create transgenic mice in which the dural lymphatics were specifically targeted. For example, in VEGFR3-Ig mice, in which the dural lymphatics were missing, a fluorescently labeled protein showed impaired efflux from the CSF to extracranial deep cervical lymphatics, supporting a role for lymphatics in waste clearance. Despite a total absence of dural lymphatics in this mouse model, brain interstitial pressure and whole-brain water content surprisingly were unchanged, suggesting the presence of compensatory mechanisms.

The physiological relevance of these findings for humans remains to be seen, especially because in animals with well-developed olfactory systems such as mice, CSF is shunted to nasal mucosa, whereas efflux through arachnoid granulations likely dominates in adult humans. There are still many open questions, such as how the intracranial and extracranial lymphatics are connected; their precise spatial relationship with arachnoid, veins, arteries, and perineurium; and the role of the lymphatic system in diseases with abnormal brain solute clearance and neuroinflammation.

A. Aspelund et al., A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999 (2015). [Abstract]

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