A new study from Washington University School of Medicine in St. Louis points to an unexpected source outside the brain. In experiments involving mice, researchers found that T cells appear to receive signals from lymph nodes that prepare them to enter the brain and cause damage. When scientists disrupted those signals, neurodegeneration was dramatically reduced.

The findings reveal a previously unrecognized immune pathway that could eventually offer a way to slow or potentially prevent damage associated with Alzheimer’s disease and primary tauopathies. These disorders are characterized by the accumulation of twisted tau proteins in the brain.

The study was published September 3 in Nature Neuroscience.

Alzheimer’s disease pathways may begin outside the brain

David M. Holtzman, M.D., the Barbara Barton Professor and the Reuben M. Morris III Distinguished Professor in the Department of Neurology at Washington University School of Medicine, is the study’s lead author. He said the findings are especially important because they identify disease-related processes that begin outside the brain, where they may be more accessible and better understood.

“One of the challenges in developing treatments for neurological diseases is that therapeutic drugs need to be engineered to reach the brain and cross the blood-brain barrier, but in reality it may not be necessary to introduce drugs into the central nervous system to reduce neurodegeneration,” Holtzman said. “While there are many ways to manipulate T cells that have been widely studied and approved for treatment of other diseases, there are still many that have not been studied for neurodegenerative diseases.”

Researchers trace Alzheimer’s-related T cells to lymph nodes

Holtzman’s lab has played a leading role in studying how the immune system contributes to neurodegenerative disease. In a previous study, the researchers showed that removing T cells from the brains of mice prevented much of the neurodegeneration that typically occurs in models of tau-related damage seen in Alzheimer’s disease and primary tauopathies.

The next questions were where those immune cells originate and what directs them to the brain.

The new study was led by Dr. Hao Fu, a postdoctoral researcher, and included co-senior author Jason Ulrich, Ph.D., a professor of neurology, along with collaborators.

Some T cells depend on other immune cells, known as dendritic cells, to identify molecular targets. A related group called classical dendritic cell type 1, or cDC1, is almost absent from the brain. The cDC1 cells that are present also do not appear to interact with the T cells that emerge after tau tangles develop.

This evidence suggested that the activation of both dendritic cells and T cells occurs somewhere outside the brain.

Blocking immune signals reduces brain damage in mice

To test this possibility, the researchers removed dendritic cells from lymph nodes and other areas in mice that normally develop tau tangles and neurodegeneration.

The results were striking. The increased number of T cells—particularly CD8 T cells—in the brain nearly disappeared, along with the associated brain damage. However, the amount of tau tangles in the brain did not change.

The mice also maintained their cognitive abilities. The findings suggest that suppressing T-cell activity, even when tau tangles are present, could potentially slow or reduce the cognitive decline associated with Alzheimer’s disease.

How tau-related brain injury may trigger an immune attack

Researchers still do not know the exact signals that cause dendritic cells to activate T cells.

Holtzman said one possibility is that tau-related damage causes brain cells to release a substance. That material could travel to lymph nodes in the neck, where dendritic cells identify it and present it as a target to T cells.

The activated T cells could then be directed to the brain, where their activity may contribute to neurodegeneration.

Could immune cells outside the brain become a treatment target?

Because this immune pathway operates outside the brain, it may provide several potential targets for future Alzheimer’s disease treatments.

Holtzman’s team is now testing whether interfering with dendritic cell activity during middle age—when tau tangles begin to appear—can provide the same protection as inhibiting dendritic cells from birth in this study.

The researchers are also working to identify the specific signals that guide T cells to the brain. Finding that signal could offer another way to prevent immune cells from entering brain tissue and contributing to damage.

“Until recently, most people, including myself, did not think that immune responses were involved in neurodegenerative diseases caused by protein buildup in the brain,” Holtzman said. “It is interesting that these dendritic cells are involved in neurodegenerative diseases. We have shown that they are important and are potential targets for future treatments.”