Experimental drugs for Alzheimer’s disease have shown little success in slowing the decline of memory and thinking, leaving scientists to search for explanations. But new research in mice has shown that some experimental Alzheimer’s disease therapies are more effective when combined with treatment to improve the drainage of fluids – and debris – from the brain, according to a study by researchers from the Washington University School of Medicine in Saint Louis.
The results, published on April 28 in the journal Nature, suggest that the brain’s drainage system – known as the meningeal lymphatics – plays a critical but underestimated role in neurodegenerative disease, and that repairing faulty drains could be a key to unlocking the potential of certain therapies against Alzheimer’s disease.
“Lymphatics are a sink,” said co-lead author Jonathan Kipnis, PhD, Alan A. and Edith L. Wolff Professor Emeritus of Pathology and Immunology, and BJC researcher. “Alzheimer’s disease and other neurodegenerative diseases such as Parkinson’s disease and frontotemporal dementia are characterized by an aggregation of proteins in the brain. If you break down these aggregates but have no way of getting rid of them because your sink is clogged, you haven’t accomplished much. You have to unclog the sink to really fix the problem. “
Sticky plaques of the amyloid protein begin to form in the brains of people with Alzheimer’s disease two decades or more before symptoms such as forgetfulness and confusion appear. For years, scientists have tried to treat Alzheimer’s disease by developing therapies that remove these plaques, but have had very limited success. One of the most promising candidates, aducanumab, was recently shown to be effective in slowing cognitive decline in one clinical trial, but failed in another, leaving scientists perplexed.
Kipnis, who is also a professor of neurosurgery, neurology, and neuroscience, identified meningeal lymphatics as the brain’s drainage system in 2015. A few years later, in 2018, he demonstrated that damage to the system increases buildup amyloid in mice. He suspects that the mixed and often disappointing performance of anti-amyloid drugs may be explained by differences in lymphatic function in patients with Alzheimer’s disease. But proving this intuition has been difficult, as there are no tools to directly measure the health of a person’s meningeal lymphatics.
In this study, Kipnis and his colleagues took an indirect approach to check the drainage system in the brains of patients with Alzheimer’s disease. The study was undertaken in collaboration with the biotherapy company PureTech Health.
Believing that the effects of a blocked drain could spread to microglia, the cells that serve as the brain’s cleaning crew, the researchers looked for evidence of lymphatic damage in the form of altered patterns of microglial gene expression. Microglia play a complex role in Alzheimer’s disease: it seems to slow the growth of amyloid plaques early in the disease but worsen neurological damage later. The researchers turned off meningeal lymphatics from a group of mice genetically prone to amyloid plaque formation, leaving functional lymphatics in another group of mice for comparison, and analyzed patterns of genes expressed by microglia.
Lymphatic dysfunction has shifted the microglia to a condition more likely to promote neurodegeneration. Additionally, when lead co-author Oscar Harari, PhD, assistant professor of psychiatry and genetics, compared patterns of gene expression in the microglia of mice and people – including 53 people who died of Alzheimer’s disease and nine died with healthy brains – people’s microglia most closely resembled that of mice with damaged lymphatics.
“There was a signature that we found in the microglia of mice with ablated meningeal lymphatics,” Harari said. “When we harmonized the human and murine microglial data, we found the same signature in the human data.”
Another type of cell, the endothelial cells that line the inside of lymphatic vessels, have provided further evidence for the importance of the brain’s drainage system. Co-lead author Carlos Cruchaga, PhD, professor of psychiatry, genetics and neurology, identified the genes most highly expressed in mouse lymphatic endothelial cells. He found that genetic variations in many of the same genes have been linked to Alzheimer’s disease in people, suggesting that problems with lymphatics could contribute to the disease.
“At the end of the day, even as we look at specific cell types and specific pathways, the brain is a big organ,” Cruchaga said. “The lymphatic system is how garbage is cleaned out of the brain. If that doesn’t work, everything gets scrubbed. If it starts to work better, then everything in the brain works better. I think this is a great example of how everything is connected, everything has an impact on brain health. “
To find out if boosting lymphatic function could help treat Alzheimer’s disease, the researchers studied mice genetically prone to developing amyloid plaques and whose lymphatics were altered due to age or injury. They treated the animals with murine versions of the experimental Alzheimer’s disease drugs aducanumab or BAN2401, as well as vascular endothelial growth factor C, a compound that promotes the growth of lymphatic vessels. Combination therapy reduced amyloid deposits more than anti-amyloid drugs alone.
“There have been several antibodies that appear to be very effective in reducing amyloid deposits in studies in mice and now in humans,” said co-author David Holtzman, MD, Professor Andrew B. and Gretchen P. Jones and head of the department of neurology. “Some now appear to slow cognitive decline in people with very mild dementia or mild cognitive impairment due to Alzheimer’s disease. However, the cognitive effects are not significant and it is questioned whether the dysfunction of the meningeal lymphatic system may be partly related to somewhat limited effects. on the cognition currently observed. The meningeal lymphatic system appears to influence not only the progression of the amyloid component of Alzheimer’s disease, but also the response to immunotherapy. Perhaps understanding this system is part of what the field of Alzheimer’s drug development is lacking, and with increased attention to this, we’ll better translate some of these promising drug candidates into therapies that offer significant benefits to people living with this devastating disease. “