Immune cells that usually defend the body by attacking infected or foreign cells appear in unusually high numbers in the brains of people with Alzheimer's disease and related conditions. Evidence suggests these cells contribute to neurodegeneration, but researchers have not known where they originate or what prompts them to gather in the brain. A new study from Washington University School of Medicine in St.
Louis points to an unexpected source outside the brain. In experiments with mice, researchers found that T cells receive signals from lymph nodes that appear to prepare them to enter the brain and contribute to damage. When the scientists disrupted those signals, neurodegeneration was dramatically reduced.
The findings reveal a previously unrecognized immune pathway that may offer a way to slow or potentially halt damage associated with Alzheimer's disease and primary tauopathies. These disorders are marked by twisted accumulations of tau protein in the brain. The study was published Sept. 3 in Nature Neuroscience.
An Alzheimer's Pathway Outside the Brain David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor in WashU Medicine's Department of Neurology and senior author of the study, said the discovery is especially intriguing because it identifies a disease related process that begins outside the brain.
That could make it possible to target mechanisms that are easier to reach and better understood. "One of the issues in developing treatments for neurological diseases is that you need to engineer your treatment so that it gets into the brain and past the blood-brain barrier, but we might not actually need to get the drugs into the central nervous system to mitigate neurodegeneration," Holtzman said. "There are lots of ways to manipulate T cells that have been studied extensively and that are approved treatments for other diseases, but many haven't yet been explored for neurodegenerative diseases." Holtzman's laboratory has played a leading role in investigating how the immune system contributes to neurodegenerative disease.
In a previous study, the team showed that removing T cells from the brain prevented much of the neurodegeneration that normally develops in mice modeling the tau related damage seen in Alzheimer's disease and primary tauopathies. The next question was where those immune cells came from and what caused them to move into the brain. In the new study, Holtzman's team included Hao Hu, PhD, a postdoctoral fellow and the study's first author; co-senior author Jason Ulrich, PhD, a professor of neurology; and their collaborators.
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