A lymphatic waste-disposal system implicated in Alzheimer’s disease

The discovery that a set of lymphatic vessels interacts with blood vessels to remove toxic waste products from the brain has implications for cognition, ageing and disorders such as Alzheimer’s disease.
Melanie D. Sweeney is in the Department of Physiology and Neuroscience and at the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90089–2821, USA.

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Berislav V. Zlokovic is in the Department of Physiology and Neuroscience and at the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90089–2821, USA.

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A network of lymphatic vessels acts in tandem with the blood vasculature to regulate fluid balance in the body1. The brain does not have its own lymphatic network, but the cellular membranes around the brain, known as the meninges, do have a network of lymphatic vessels. This meningeal lymphatic system was first found2 in 1787 and has been ‘rediscovered’ this decade35. Do the meningeal lymphatics have a role in brain diseases, as systemic lymphatic vessels do in systemic diseases such as cancer1? In a paper in Nature, Da Mesquita et al.6 show that meningeal lymphatic vessels help to maintain both cognitive function and the proper levels of proteins in brain fluids (a process called proteostasis). The finding has implications for normal ageing and disorders such as Alzheimer’s disease.

In the body, lymphatic vessels drain tissues of interstitial fluid (ISF), which contains waste products such as cellular debris and toxic molecules. The ISF forms a protein-rich fluid called lymph that circulates through the lymphatic system back to the circulating blood1. On its way, lymph is filtered through the lymph nodes, which can initiate immune responses if foreign particles are detected.

The brain does not have its own lymphatic vessels. As such, proteins and waste from the main body of the brain (the parenchyma) are transported within ISF along the walls of blood vessels to reach the cerebrospinal fluid (CSF), which circulates through the meninges7. It is well established that proteins, metabolic waste products and other molecules in these fluids can be removed from the brain by being transported across the walls of blood vessels, thus crossing the blood–brain barrier7,8 — a process called transvascular clearance. But it was unknown whether the meningeal lymphatic vessels are also involved in waste clearance.

Da Mesquita et al. destroyed the meningeal lymphatic vessels of mice by injecting a vessel-damaging drug into the cisterna magna — a large, CSF-filled space in the meninges. They then administered a fluorescent tracer molecule into the cisterna magna. In mice lacking meningeal lymphatic vessels, the tracer did not reach the deep cervical lymph nodes, to which the meningeal lymphatics normally drain. Similarly, injection of tracers into the brain parenchyma showed reduced ISF drainage into deep cervical lymph nodes. Previous work has shown9 that injecting high concentrations of tracer into CSF can cause the diffusion of tracer into the brain along blood vessels — but this transport was also reduced. The authors confirmed these results through several alternative approaches: using different tracers; surgically closing off drainage to the deep cervical lymph nodes; and examining mice genetically engineered so that their lymphatic-vessel development was impaired.

Destruction of the meningeal lymphatics also led to deficits in spatial orientation and fear memory. The brain’s hippocampus has a key role in these behaviours, and the researchers found changes in gene expression in this region resembling those seen in neurodegenerative disorders. Collectively, these experiments suggest that drainage of brain ISF and CSF by the meningeal lymphatics is necessary for proper cognitive function.

These findings also raise an interesting question: where did the injected tracers go? One study10 has shown that tracers injected into the cisterna magna are primarily transported into the blood, and only secondarily into the lymphatic system. Simultaneous measurements of tracer movements into the meningeal lymphatics, other lymphatic vessels (for instance in the neck) and the blood might reveal whether impairment of the meningeal lymphatics leads to a shift in the pathways used to control brain proteostasis, increasing transvascular removal of waste products across the blood–brain barrier (Fig. 1), or their drainage into the venous system in the meninges7.

Figure 1 | Regulation of waste clearance in the brain. a, The brain does not have its own lymphatic vessels to manage the clearance of waste. Proteins and waste are transported from the brain’s interstitial fluid (ISF) along blood-vessel walls to reach the cerebrospinal fluid (CSF) in a space within the meninges — membranes that cover the brain. Da Mesquita et al.6 report that lymphatic vessels in the meninges drain CSF and ISF containing waste products. b, In a healthy mouse brain, lymphatic drainage of both fluids requires signalling between vascular endothelial growth factor C (VEGF-C) and its receptor VEGFR3 on lymphatic endothelial cells lining the wall of meningeal lymphatic vessels. The protein amyloid-β (Aβ), which is associated with Alzheimer’s disease, is primarily removed from the ISF by blood vessels. c, During ageing, both vessel systems can become impaired. The diameter of the meningeal lymphatic vessels decreases, causing decreased waste clearance by this route. This defect, along with impaired clearance by blood vessels, leads to Aβ accumulation in the brain.

Da Mesquita et al. next observed an ageing-induced decrease in the diameter and coverage of meningeal lymphatic vessels, and decreased drainage of tracers from the ISF and CSF into deep cervical lymph nodes. Lymphatic-vessel growth in mice is promoted by a signalling pathway involving vascular endothelial growth factor C (VEGF-C) and its receptor VEGFR3, whereas impairments in the pathway lead to a loss of meningeal lymphatic vessels1,3. Furthermore, treatment with VEGF-C increases the diameter of meningeal lymphatic vessels, improving lymphatic drainage4. Consistent with these findings, the authors showed that local delivery of the Vegf-c gene into the cisterna magna of old mice using a virus restored the drainage of CSF tracer into deep cervical lymph nodes. This change was accompanied by restoration of spatial orientation in old mice.

Age-related impairments in transvascular clearance of waste have been implicated in the accumulation of amyloid-β protein in the brain7,11,12 — a hallmark of Alzheimer’s disease. Da Mesquita and colleagues investigated the effects of ablating the meningeal lymphatics in two mouse models of Alzheimer’s disease, in which amyloid-β protein is produced in neurons and secreted into the ISF. Ablation led to amyloid-β accumulation in the meninges, accelerated amyloid-β deposition in the brain parenchyma and cognitive deficits. The authors also showed that amyloid-β had accumulated in the meninges of people who had Alzheimer’s disease, pointing to the potential relevance of these findings for humans.

Notably, the researchers found that the mouse models did not develop any apparent structural or functional changes in the meningeal lymphatics at the time when amyloid-β deposition in the brain parenchyma first became apparent. Viral delivery of Vegf-c at this time point could not prevent the cognitive impairments in either model, suggesting that the early amyloid-β deposition and cognitive impairments in these animals were caused by disruption in another clearance pathway — most likely transvascular clearance. As transvascular-clearance routes gradually deteriorate with age, an increasing burden is probably put on the meningeal lymphatic system. If the capacity of the lymphatic system is reached, this might lead to faulty lymphatic drainage of amyloid-β and other proteins from the ISF and CSF (Fig. 1). Thus, a dynamic relationship between the meningeal lymphatics and blood vessels seems to regulate proteostasis in the brain.

Future work should aim to improve our understanding of waste-clearance pathways from the brain, how the ISF and CSF drain into the meningeal lymphatics, and how these lymphatic vessels interact with the blood vessels at the blood–brain barrier. Such analyses will open up fresh directions for research into cognition, neurodegeneration and Alzheimer’s disease. Da Mesquita et al. showed that strategies that promote local growth of lymphatic vessels have the potential to improve clearance by meningeal lymphatics to rebuild brain proteostasis, and might lessen amyloid-β deposition. It remains to be determined whether treatments directed at the meningeal lymphatics can also improve the impaired function of blood vessels with age, and whether enhancing clearance at the blood–brain barrier can improve lymphatic drainage function.

Nature 560, 172-174 (2018)


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