By: Jessica Park
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 neurodegenerative conditions. Evidence suggests these immune cells may contribute to neurodegeneration, but researchers have not fully understood where they originate or what causes them to gather in the brain.
In experiments with mice, researchers at Washington University School of Medicine in St. Louis found that T cells can be activated outside the brain through interactions with immune cells in lymph nodes. These activated T calls can then enter the brain and contribute to brain damage. When researchers disrupted those signals or the immune pathway, neurodegeneration was dramatically reduced, which revealed a previously unrecognized immune pathway that might help slow or potentially halt damage associated with Alzheimer’s disease and primary tauopathies.
Alzheimer’s disease involves several abnormal processes in the brain, including twisted accumulations of a protein called tau. According to David M. Hotzman, MD, Distinguished Professor in the department of Neurology at Washington University of Medicine , “One of the issues in developing treatments for neurological disease is passing the “blood-brain barrier” to get into the brain. Because the blood-brain barrier prevents many substances in the bloodstream from entering brain tissue, drug developers often have to design medicines to cross that barrier.
Holtzan’s laboratory has been investigating how the immune system, particularly T cells, contributes to neurodegenerative disease. They showed that:
- Removing T cells from the brain prevented much of the neurodegeneration that normally develops in mice modelling the tau related damage seen in Alzheimer’s disease and primary tauopathies.
- Because T cells rely on other immune cells, known as dendrite cells, specifically known as classical dendrite calls type 1 (cDC1) in the brain, the researchers eliminated dendritic cells from the lymph nodes in mice that would normally develop tau tangles and neurogeneration. They found 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.
- This 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.
However, researchers still do not know the exact signal that causes dendritic cells to activate the T cells. Holtzman hypothesized that damage caused by tau releases material from brain cells. That material may then travel to lymph nodes in the neck, where dendrite cells identify it and preset it as a target for T cells. The T cells could then be more activated and directed toward the brain, which contributes to neurodegeneration.
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. The research team is also investigating to identify the specific signal that leads 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.
Holtzman said, “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’s research team has shown the influence of dendritic cells, which are immune calls that would help activate and direct other immune calls, may actually play an important role in neurodegenerative diseases like Alzheimer’s disease. These new findings about dendritic cells may open up a new possible way for future therapy targeting neurodegenerative diseases.