The accumulation of amyloid-beta in the brain is believed to be a culprit behind neurodegeneration, but the underlying mechanism of the buildup is not yet clear. The biopharma industry’s endeavor to develop drugs that target the protein has also suffered many setbacks.
But now, scientists might have found a new pathway that plays a key role in both Alzheimer’s and age-related dementia.
The secret lies in meningeal lymphatic vessels, which connect the brain and the immune system. They help keep a healthy fluid balance in the brain and could be a new target for treatment, a team of scientists at the University of Virginia and Virginia Tech reported in a study published in Nature.
For a long time, lymphatic vessels that carry fluid, waste and immune cells were thought to be absent from the mammalian central nervous system. But in 2015, a team led by University of Virginia neuroscientist Jonathan Kipinis discovered such a system in the brains of mice, and an NIH team later extended the findings to people and monkeys. Now Kipinis and several members of that team have returned to study the role of these vessels in aging and Alzheimer’s disease.
They found that meningeal lymphatic vessels drain macromolecules like amyloid-beta from the CNS into the cervical lymph nodes in mice. The scientists damaged the cells that form these vessels and observed a dramatic decline in brain-fluid flow. What’s more, mice with ablated meningeal lymphatic vessels also showed an increased load of harmful amyloid-beta plaque, along with impairments in spatial learning and memory.
“As you age, the fluid movement in your brain slows, sometimes to a pace that’s half of what it was when you were younger,” said Jennifer Munson, a study co-author and an assistant professor at Virginia Tech’s Department of Biomedical Engineering and Mechanics, in a release. “We discovered that the proteins responsible for Alzheimer’s actually do get drained through these lymphatic vessels in the brain along with other cellular debris, so any decrease in flow is going to affect that protein build-up.”
Aging itself increases the risk of neurological disorders, including Alzheimer’s. Old mice experienced reduced brain drainage compared to young mice, and their meningeal lymphatic vessels were also narrower, the team observed.
To see if they could improve the situation, researchers used a compound called vascular endothelial growth factor C (VEGF-C). When they treated healthy aged mice with VEGF-C, they found that the animals' vessels grew larger and drained better, and they observed improved performance on learning and memory tasks, the team reported.
Kipinis at the University of Virginia has exclusively licensed intellectual property related the discovery to biopharma company PureTech Health, which focuses on the brain-immune-gut axis. Together they’ll explore applications in development of new drugs against Alzheimer’s and other age-related cognitive disorders.
“Our work exploring the function of lymphatic vessels has shed light on novel therapeutic approaches that complement the lymphatics focus of PureTech’s research and development work,” said Kipinis in a statement.
So far, many Big Pharmas, including Eli Lilly, Merck & Co. and Pfizer have seen their Alzheimer’s programs targeting amyloid-beta crash in late-stage trials. Biogen and partner Eisai recently reported their amyloid-fighting antibody significantly slowed both cognitive decline and the underlying amyloid buildup. But even that failed to impress many who dug deeper into the data.
In their recent research, Kipinis and his team suggested that the efficacy of current therapies for Alzheimer’s might be improved by repairing aging-related decline in meningeal lymphatic drainage. “Modulation of meningeal lymphatic function in aged individuals might represent a novel preventive therapeutic strategy, not only to delay initiation and progression of Alzheimer’s disease but also for use against other brain proteinopathies that are exacerbated," by the aging process, they wrote.
Editor's Note: This story previously mistakenly stated that an amyloid-beta partnership between Novartis and Amgen also failed in late-stage studies. They're actually working with the Banner Alzheimer’s Institute to test a BACE inhibitor as an Alzheimer's prevention method.