Draining brain's debris enhances Alzheimer's therapies in mice: study

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CHICAGO, April 28 (Xinhua) -- A study led by researchers at Washington University School of Medicine in St. Louis in mice has shown that some investigational Alzheimer's therapies are more effective when paired with a treatment geared toward improving drainage of fluid or debris from the brain.

In this study, the researchers took an indirect approach to checking the drainage system, known as the meningeal lymphatics, in the brains of Alzheimer's patients. Thinking that the effects of a clogged drain might spill over onto microglia, the cells that serve as the brain's cleanup crew, the researchers looked for evidence of lymphatic damage in the form of altered patterns of microglial gene expression.

The researchers disabled the meningeal lymphatics of a group of mice genetically prone to forming amyloid plaques, leaving the lymphatics functional in another group of mice for comparison, and analyzed the patterns of genes expressed by microglia.

Lymphatic dysfunction shifted microglia toward a state that was more likely to promote neurodegeneration. Further, when researchers compared the gene-expression patterns in microglia from mice and people, including 53 people who died with Alzheimer's disease and nine who died with healthy brains, the people's microglia most resembled those from mice with damaged lymphatics.

Another cell type, endothelial cells that line the inside of lymphatic vessels, provided additional evidence for the importance of the brain's drainage system. The researchers identified the genes most highly expressed in lymphatic endothelial cells from mice, and discovered that genetic variations in many of the same genes have been linked to Alzheimer's in people, suggesting that problems with the lymphatics might contribute to the disease.

"In the end, even though we're looking at specific cell types and specific pathways, the brain is one big organ," said co-senior author Carlos Cruchaga, a professor of psychiatry, of genetics and of neurology. "The lymphatic system is how the garbage is cleaned out of the brain. If it's not working, everything gets gummed up. If it starts working better, then everything in the brain works better. I think this is a very good example of how everything is connected, everything impacts brain health."

To find out whether bolstering lymphatic function could help treat Alzheimer's disease, the researchers studied mice genetically prone to developing amyloid plaques and whose lymphatics were impaired due to age or injury. They treated the animals with mouse versions of the experimental Alzheimer's drugs aducanumab or BAN2401, along with vascular endothelial growth factor C, a compound that promotes the growth of lymphatic vessels. Combination therapy reduced amyloid deposits more than the anti-amyloid drugs alone.

"There have been several antibodies that appear very effective at reducing amyloid deposits in mouse studies and now in humans," said co-author David Holtzman, professor and director of the Department of Neurology. "Some now also appear to slow cognitive decline in people with very mild dementia or mild cognitive impairment due to Alzheimer's. However, the cognitive effects are not large, and one wonders if meningeal lymphatic system dysfunction may be related in part to the somewhat limited effects on cognition currently being observed. The meningeal lymphatic system seems to be influencing not just the progression of the amyloid component of Alzheimer's pathology but also the response to immunotherapy."

Maybe an understanding of this system is a part of what the field of Alzheimer's drug development has been missing. "With increased attention to it we will better translate some of these promising drug candidates into therapies that provide meaningful benefits to people living with this devastating disease," Holtzman added.

Sticky plaques of the protein amyloid start forming in the brains of people with Alzheimer's two decades or more before symptoms such as forgetfulness and confusion arise.

The findings are published Wednesday in the journal Nature. Enditem

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