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."

Tracing T Cells Back to the Lymph Nodes

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.

Certain T cells rely on other immune cells, known as dendritic cells, to identify the molecular targets they should attack. Very few of the relevant dendritic cells, known as classical dendritic cells type 1 (cDC1), are found in the brain. Those that are present also do not appear to interact with the T cells that emerge after tau tangles develop.

That evidence suggested that both the dendritic cells and the T cell activation process were originating somewhere outside the brain.

Blocking Immune Signals Reduced Brain Damage

To test that possibility, the researchers eliminated dendritic cells from the lymph nodes and other locations in mice that would normally develop tau tangles and neurodegeneration.

The result was striking. Elevated numbers of T cells in the brain, particularly CD8 T cells, largely disappeared, along with the associated brain damage. Yet the amount of tau tangles in the brain did not change.

The mice also preserved their cognitive abilities. That finding suggests that suppressing T cell activity could potentially slow or reduce the cognitive decline associated with Alzheimer's disease, even when tau tangles remain present.

How Brain Damage May Trigger an Immune Attack

Researchers still do not know the exact signal that causes dendritic cells to activate the T cells.

Holtzman said one possibility is that damage caused by tau releases material from brain cells. That material may then travel to lymph nodes in the neck, where dendritic cells identify it and present it as a target for T cells.

The T cells could then be directed toward the brain, where their activity contributes to neurodegeneration.

A Potential New Route for Alzheimer's Treatment

Because this immune pathway operates outside the brain, it may provide several new therapeutic targets.

Holtzman's team is now testing whether interfering with dendritic cell activity in midlife, around the time tau tangles begin to emerge, can produce the same protection seen when the cells were blocked from birth in this study.

The researchers are also working to identify the specific signal that guides T cells toward the brain. If that signal can be determined, it could offer another way to prevent the immune cells from reaching brain tissue and contributing to damage.

"Until not that long ago, most people, including myself, did not think that the immune response was even involved in neurodegenerative diseases that are due to protein accumulation in the brain," Holtzman said. "That these dendritic cells are involved in neurodegenerative disease is exciting; we've shown they're important, and that they are a potential target for future therapy."