The brain’s lymphatic drainage system removes cellular debris and other waste. The system was recently discovered in 2015 by Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff distinguished professor of pathology and immunology, and a BJC investigator at Washington University in St. Louis. Now new research by Kipnis and colleagues suggest that immunotherapies for Alzheimer’s such as BAN2401 or aducanumab might be more effective when the brain’s lymphatic system can better drain the amyloid-beta protein that accumulates in the brain. Major funding for the research was provided by the National Institute on Aging (NIA), part of the National Institutes of Health.

The findings are published in the journal Nature in a paper titled, “Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy,” and led by researchers from Washington University in St. Louis and the University of Virginia.

“Alzheimer’s disease (AD) is the most prevalent cause of dementia,” wrote the researchers. “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 behavioral deficits.”

“The lymphatics are a sink,” explained Kipnis. “Alzheimer’s and other neurodegenerative diseases such as Parkinson’s and frontotemporal dementia are characterized by protein aggregation in the brain. If you break up these aggregates but you have no way to get rid of the debris because your sink is clogged, you didn’t accomplish much. You have to unclog the sink to really solve the problem.”

In 2018, Kipnis demonstrated that damage to the system increases amyloid buildup in mice. In the new study, the researchers sought to determine whether changing how the lymphatic drainage works in the brain could affect the levels of amyloid-beta and the success of treatments that target amyloid-beta.

Study of mouse brain shows the meningeal lymphatics system (purple and pink) could help reduce amyloid. [Sandro Da Mesquita]
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 the mice and control group with injections of monoclonal antibody therapies, including a mouse version of aducanumab.

Mice with less functional lymphatic systems had a greater buildup of amyloid-beta plaques. 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 observed that the genetic fingerprints of the microglia, were very similar between people with the disease and mice with defective lymphatic vessels.

The researchers also sought to determine whether enhancing the brain’s lymphatic system could reverse these changes. The mice not only showed lower accumulations of amyloid-beta, but also expansion of some parts of the lymphatic system in the brain’s meninges.

“These findings suggest that supporting the meningeal lymphatic system in people with Alzheimer’s—and starting treatment early in the disease, when this system is more intact—could lead to better outcomes,” said Molly V. Wagster, PhD, chief of the behavioral and systems neuroscience branch in NIA’s division of neuroscience.

The researchers believe that future studies may help identify how well the brain’s lymphatic system is working as we age.

NIA director Richard J. Hodes, MD, added “…While this study’s findings require further confirmation, the link it has identified between a well-functioning lymphatic system in the brain and the ability to reduce amyloid-beta accumulation may be a significant step forward in pursuing this class of therapeutics.”

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