Enhancing the brain's lymphatic system when administering immunotherapies may lead to better clinical outcomes for Alzheimer's disease patients, according to a new study in mice. Results published April 28 in Nature suggest that treatments such as the immunotherapies BAN2401 or aducanumab might be more effective when the brain's lymphatic system can better drain the amyloid-beta protein that accumulates in the brains of those living with Alzheimer's. Major funding for the research was provided by the National Institute on Aging (NIA), part of the National Institutes of Health, and all study data is now freely available to the broader scientific community.
"A broad range of research on immunotherapies in development to treat Alzheimer's by targeting amyloid-beta has not to date demonstrated consistent results," said NIA Director Richard J. Hodes, M.D. "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."
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 NIA-supported 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.
The researchers also assessed whether boosting the brain's lymphatic system could reverse these changes. They injected mice with amyloid-beta antibody therapies along with a growth factor that enhances the function of the brain's meningeal lymph vessels. The treated mice showed not only 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, Ph.D., chief of the Behavioral & Systems Neuroscience Branch in NIA's Division of Neuroscience.
The research also shows that if lymphatics are removed, the mouse microglia -- "trash collector cells" in the brain -- are much closer to those in humans and that the genes upregulated in microglia upon lymphatic dysfunction are linked to different aspects of Alzheimer's pathology. Writing for the research team, Jonathan Kipnis, Ph.D., at Washington University School of Medicine in St. Louis, notes in the paper that these data demonstrate that it may be possible to devise strategies to therapeutically target microglia and the brain blood vasculature, which are both important in Alzheimer's pathophysiology, by modulating meningeal lymphatic vasculature.
The researchers suggest that future studies may help identify how well the brain's lymphatic system is working as we age. That could result in targeted treatments that could improve how well the lymphatic system drains amyloid-beta and other compounds, in turn slowing the progression of Alzheimer's.
This was funded in part by NIH grants R37AG034113, RF1AG057496, RF1AG053303, RF1AG058501, R01AG057777, R56AG067764, R01AG062734, P30AG066444, P01AG026276, and P01AG03991. It relates to NIH's AD+ADRD Research Implementation Milestone 2.B, "Establish new research programs that employ data-driven, systems-based approaches to understand the interaction between peripheral systems (in particular: immune, metabolic, microbiome) and the brain and the impact of this interaction on brain aging and neurodegeneration."
Reference: Da Mesquita et al. Meningeal lymphatics modify Alzheimer's disease and immunotherapy. Nature. 2021 Apr 28 doi: 10.1038/s41586-021-03489-0
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