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In healthy humans, the cerebrospinal fluid (CSF) is renewed approximately four times a day. In aging adults, impaired function of lymphatic vessels in the meninges can lead to accelerated accumulation of toxic amyloid beta protein in the brain. The meninges are made up of membranes that line the skull in order to protect the brain and spinal cord. The existence of these lymphatic vessels in the meninges was first mentioned toward the end of the 18th century, but it took more than 200 years for the hypothesis to be confirmed using state of the art imaging technology in the laboratory of Dr. Jonathan (Jony) Kipnis.

In the 30th Anniversary Issue of Neuron, Dr. Kipnis, along with his collaborators Drs. Sandro Da Mesquita and Zhongxiao Fu, put forth their perspective on the relevance of the meningeal lymphatic system for cerebral spinal fluid drainage, aging-associated brain dysfunction, and amyloid beta clearance in Alzheimer’s disease.

This research has challenged the conventional model for how cerebral spinal fluid remains in equilibrium. The existence of these lymphatic vessels in the meninges took a long time to confirm as this finding does not fit the previously prevailing hypothesis that the central nervous system has no direct contact with the immune system.

One of the keys to cracking the case of whether or not lymphatic vessels exist in the meninges of the central nervous system was confirming that these vessels expressed the same markers as other lymphatic cells, specifically lymphatic endothelial cells. The other requirement for confirmation was determining that these lymphatic vessels could efficiently drain both molecules and immune cells from a region of the brain called the subarachnoid space into lymph nodes.

The traditional model for how the cerebrospinal fluid drained was directly challenged when the scientists injected molecular tracers into the CSF and demonstrated that the drainage occurred through the lymphatic vessels – demonstrating a new route for clearing molecules from the brain. The presence of a “brain drain” is critical for maintaining intracranial pressure and removal of waste. The protein concentration of the CSF increases with aging and has been shown to be even higher in patients with age-associated dementia.

Meningeal lymphatic vessels are evolutionarily conserved and have been reported in fish, rats, non-human primates, and humans. A critical question that remains is whether the network of lymphatic vessels increases in complexity in humans with their more complicated cognitive behaviors and more convoluted brains.