In recent years, scientists have characterized a hidden set of lymphatic vessels in the meninges, the membranes that line the skull and envelope the brain (Oct 2017 news). These meningeal lymphatic vessels carry waste from the cerebrospinal and interstitial fluids to the deep cervical lymph nodes for disposal. Might these vessels weaken with age and play a role in disease? Yes, suggest scientists led by Jonathan Kipnis, University of Virginia, Charlottesville, in the July 25 Nature. They manipulated drainage through these vessels in young, aging, and transgenic mouse models and found cerebrospinal fluid flow slowed, animals had poorer memories, and they accumulated more Aβ. The results suggest the lymph is an important route of waste clearance from the brain, and contributes to both aging and disease if damaged.
- Lymphatic vessels in the meninges clear waste from the brain.
- These vessels drain less effectively in aged mice.
- Interfering with their function exacerbates Aβ deposition.
“Collectively, these experiments suggest that drainage of brain ISF [interstitial fluid] and CSF [cerebrospinal fluid] by the meningeal lymphatics is necessary for proper cognitive function,” wrote Berislav Zlokovic and Melanie Sweeney, University of Southern California, Los Angeles, in an accompanying News and Views (see also comment below). “The finding has implications for normal aging and disorders such as Alzheimer’s disease.”
First author Sandro Da Mesquita and colleagues used several techniques to hinder drainage through the meningeal lymphatic vessels. They genetically inhibited lymphatic development in wild-type mice, gave three-month-old WT animals a drug that damaged the lymphatic vessels around the brain, or surgically tied vessels off so they couldn’t drain to the deep cervical lymph nodes. In all cases, the scientists found that perfusion of CSF through the brain slowed, as did drainage of macromolecules from ISF. CSF normally flows through the brain via the glymphatic system that runs alongside blood vessels in the brain, and scientists think the fluid eventually reaches the lymph system (Aug 2012 news). “These lymphatic vessels in the meninges are not physically connected to the brain perivascular routes, yet are able to regulate a process that takes place alongside the brain vasculature,” wrote Da Mesquita to Alzforum. “We show that there is a meningeal lymphatic-glymphatic connection, which seems to play important roles in rodent models of aging and Alzheimer’s disease.”
After a few weeks of impaired drainage, young mice had trouble remembering a sound associated with a slight foot shock. They took longer than intact animals to find the submerged platform in the Morris water maze, either when it was in a familiar location or had been moved, and they spent much less time searching the correct location when the platform was removed altogether.
Would aging similarly impair drainage? In 20-month-old animals, vessel diameter and vessel coverage in the meninges paled compared with that in young mice, and the CSF filtered more slowly through the brain tissue and into the lymph nodes. The authors were able to correct some of this by giving vascular endothelial growth factor C (VEGF-C) to the older mice. This increased vessel diameter, restored CSF flow, and improved their ability to find the platform in the water maze.
Would VEGF-C help remove Aβ from the brain? Da Mesquita and colleagues treated six- to seven-month-old J20 mice with the growth factor to no avail. VEGF-C had no effect on Aβ levels in the CSF or the amyloid burden in the hippocampus, and was not able to calm hyperactivity in these animals. In fact, by following a CSF tracer in the J20s and in three- to four-month-old 5xFAD mice, the researchers concluded that the morphology and expanse of the lymphatic vessels in these animals was no different from that in controls.
What about in older animals? To mimic aging of the vasculature, Da Mesquita and colleagues wiped out meningeal vessels in two-month-old 5xFAD mice and in six- to seven-month-old J20s. During the next six to 12 weeks, both strains accumulated more plaques in the hippocampus than did controls with intact lymph vessels (see image above). In addition, lymph ablation caused Aβ to build up in the meninges of the mice. When the authors examined postmortem brain tissue from nine AD patients, they found Aβ deposited in their cortical meninges, as well.
“As the authors speculate, it will be extremely interesting to see whether aged animals of less aggressive AD models show deposition of Aβ in the lymphatic vessels or meninges, as postmortem human AD brains in this study,” wrote Tarja Malm and Heikki Tanila from the A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (see full comment below).
Together, the results hint at another way for waste to find its way out of the brain. “In sporadic AD, researchers think that the main problem is getting rid of amyloid,” explained Costantino Iadecola, Weill Cornell Medical College, New York, who was not involved in the study. “Inasmuch as this pathway is used in clearing the amyloid, coupled with the aging effect on the lymphatics that they’ve shown, one can presume there may be a link between dysfunction of this system and the accumulation of Aβ in the brain.”—Gwyneth Dickey Zakaib
- Lymphatic Vessels Found in Human Brain
- Brain Drain—“Glymphatic” Pathway Clears Aβ, Requires Water Channel
Research Models Citations
- Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM, Contarino C, Onengut-Gumuscu S, Farber E, Raper D, Viar KE, Powell RD, Baker W, Dabhi N, Bai R, Cao R, Hu S, Rich SS, Munson JM, Lopes MB, Overall CC, Acton ST, Kipnis J. Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature. 2018 Aug;560(7717):185-191. Epub 2018 Jul 25 PubMed.