That the brain has a lymphatic system that drains into the body is a comparatively recently discovery, a development of the last decade of research. It isn't the only way in which fluids drain from the brain - see, for example, the work on the cribriform plate path for drainage of cerebrospinal fluid - but there are a limited number of such pathways outside the vascular system. The vascular system itself is separated from the brain by the blood-brain barrier that surrounds every blood vessel that passes through the central nervous system. This barrier controls the entry and exit of molecules and cells, limiting the degree to which forms of undesirable molecular waste can be removed.
Cerebrospinal fluid and lymphatic fluid leaving the brain can carry away molecular waste, such as the protein aggregates of various forms (amyloid-β, tau, α-synuclein, and so on) that are associated with the development of neurodegenerative conditions. These pathways of drainage decline in effectiveness with age. This is coming to be seen as a meaningful contribution to the buildup of protein aggregates in the brain, and thus consequent pathology. This makes mechanisms of drainage an important consideration in the development of neurodegeneration, and a potential target for therapies.
Abnormal buildup of amyloid-beta is one hallmark of Alzheimer's disease. The brain's lymphatic drainage system, which removes cellular debris and other waste, plays an important part in that accumulation. A 2018 study showed a link between impaired lymphatic vessels and increased amyloid-beta deposits in the brains of aging mice, suggesting these vessels could play a role in age-related cognitive decline and Alzheimer's. The lymphatic system is made up of vessels which run alongside blood vessels and which carry immune cells and waste to lymph nodes. Lymphatic vessels extend into the brain's meninges, which are membranes that surround the brain and spinal cord.
For this new study, the research team sought to determine whether changing how well the lymphatic drainage works in the brain could affect the levels of amyloid-beta and the success of antibody treatments that target amyloid-beta. Using a mouse model of early-onset Alzheimer's, researchers removed some of the lymphatic vessels in the brains of one group of mice. They treated these mice, as well as a control group, with injections of monoclonal antibody therapies, including a mouse version of aducanumab.
Mice with less functional lymphatic systems had greater buildup of amyloid-beta plaques and of other immune cells that cause inflammation, which is another factor in Alzheimer's pathology. Moreover, when the researchers compared immune cells in the brains of human Alzheimer's patients with those of the mice whose meningeal lymphatic system had been diminished, they found that the genetic fingerprints of certain immune cells in the brain, the microglia, were very similar between people with the disease and mice with defective lymphatic vessels. These mice also performed more poorly on a test of learning and memory performance, suggesting that dysfunctional lymphatic drainage in the brain contributes to cognitive impairment and increases difficulties for antibodies that target amyloid-beta.
Alzheimer's disease (AD) is the most prevalent cause of dementia. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD.
Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD.
Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.