Breaking Down Barriers: Immune Cells in the Aging Brain

For decades, scientists have believed that the brain’s immune system operates independently of the rest of the body. However, new research from Stanford University is challenging this long-held view. A team of researchers led by Julia Belk, a postdoctoral scholar in pathology at Stanford Medicine, has discovered that large numbers of immune cells from elsewhere in the body enter the human brain as people age.

This groundbreaking finding could reshape our understanding of brain aging and may eventually lead to new possibilities for treating neurological diseases. The research, supported in part by the Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, was published recently in the journal Nature.

Tracing the Origins of Immune Cells

To investigate the entry of immune cells into the brain, the researchers studied human brain tissue. They used samples from the Stanford Rapid Autopsy Center and the University of Washington’s Alzheimer’s Disease Sequencing Project. These programs collect both blood and post-mortem brain tissue from people with and without Alzheimer’s, providing the team with a unique opportunity to directly compare immune cells found in the bloodstream with those present in brain tissue after death.

The challenge was determining exactly where the immune cells inside the brain had originated. Because immune cells divide continuously, the scientists needed to trace their cellular family trees. Their goal was to distinguish cells descended from the original population of microglia that had been present since birth from cells descended from blood stem cells in the bone marrow later in life.

The researchers found a way to do this by comparing DNA from immune cells in the blood with DNA from immune cells in the brain. They used shared mutations as biological markers of ancestry, somewhat like a consumer ancestry testing service. By analyzing the genetic signatures of immune cells from paired blood and brain samples, the team was able to show that immune cells from the body had entered the brain, with the process occurring as early as middle age.

A New Route for Brain Immunotherapy

The discovery that immune cells from the blood can enter the brain and transform into specialized microglia opens up new possibilities for developing treatments aimed at the brain. One possibility is to engineer immune cells so they could target and break down amyloid and tau aggregates associated with neurodegenerative diseases. Such cells might eventually be given to people preventively, before those damaging aggregates begin accumulating.

The finding also broadens research into how the health and history of blood stem cells affect the brain. Because many microglia in aging humans appear to originate from blood stem cells, anything that changes cells in the blood or bone marrow could potentially influence the brain as well.

A Uniquely Human Feature of Aging

For Belk, the results are also notable because they reveal an aspect of brain aging that appears to be distinctly human. ‘I think this is exciting because this is also a uniquely human feature of aging that we had no idea about,’ she said.

As the research continues to unfold, it has the potential to challenge our understanding of brain aging and provide new insights into the complex relationships between the immune system, the brain, and age-related diseases.