For decades, scientists have generally viewed the brain's immune system as a sort of gated community, separate from the body's main defenses. The brain has its own specialized immune cells and a blood-brain barrier that keeps out unwanted visitors, much like a bouncer at an exclusive club. But new research from Stanford is challenging that picture, finding that large numbers of immune cells from elsewhere in the body enter the human brain as people age. The discovery could reshape our understanding of brain aging and potentially open new avenues for treating neurological diseases. The work, supported in part by the Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, was published in the journal Nature.
"We usually think of the brain as a closed system," said Julia Belk, a postdoctoral scholar in pathology at Stanford Medicine and first author on the study. "What we found is that actually a lot of immune cells enter the human brain during aging." Belk's interdisciplinary background - she started in computer science and trained through Sarafan ChEM-H's Chemistry/Biology Interface Predoctoral Training Program - led to a collaboration with Siddhartha Jaiswal, an associate professor of pathology and senior author, who had previously shown that certain clones of immune cells from mutated blood stem cells were associated with a lower risk of Alzheimer's. That raised the possibility that these unusual cells might interact with the brain, and further research suggested they could actually enter it. The team then asked a bigger question: Could immune cells from the blood routinely enter the brains of people as they age?
"Unlike most immune cells, which are continuously replenished by blood stem cells from the bone marrow, immune cells in the brain were presumed to renew themselves throughout the lifespan without contribution from outside the brain," said Jaiswal. "Our first study showed that this might not always be the case."
For years, many researchers believed that the brain's specialized immune cells, known as microglia, were established at birth and remained a self-sustaining population. But Belk and colleagues considered the possibility that outside immune cells could enter the brain in more people than just those with rare mutations - maybe it's a regular feature of human aging. The idea that blood-based immune cells could play a role in Alzheimer's was both unusual and controversial, so in 2022, Jaiswal and colleagues sought support from the Knight Initiative for Brain Resilience, which funds research intended to rethink how we study brain resilience and neurodegenerative disease.
With support from a Knight Initiative Innovation Award, the team - including co-senior author Howard Chang, the Virginia and D. K. Ludwig Professor of Cancer Research - set out to determine whether blood immune cells truly could replenish microglia in the brain. They studied human brain tissue from the Stanford Rapid Autopsy Center (led by co-author Jody Hooper) and the University of Washington's Alzheimer's Disease Sequencing Project, which provided both blood and post-mortem brain tissue from people with and without Alzheimer's. This allowed them to directly compare immune cells from the bloodstream with those in brain tissue.
The challenge was tracing the origins of immune cells in the brain. Because immune cells divide continuously, the scientists used shared mutations as biological markers of ancestry, much like a consumer ancestry testing service. Random mutations accumulate in blood stem cells as people age, and immune cells produced by those stem cells inherit the same mutations. If two groups of immune cells carry matching mutations, they likely share the same origin. Using techniques developed during their 2023 research, Belk and colleagues compared paired blood and brain samples and found the genetic signatures matched, showing that immune cells from the body had entered the brain, with the process occurring as early as middle age.
Further experiments revealed another striking development: once the peripheral immune cells entered the brain, they transformed into specialized microglia. And this process does not appear to occur in mice or non-human primates. "Now that we know that these immune cells actually can get into the brain, we can think about all kinds of new engineering strategies to have those peripheral immune cells do useful things," Belk said. One possibility is engineering immune cells to target and break down amyloid and tau aggregates associated with neurodegenerative diseases, potentially given to people preventively before damage accumulates.
The discovery could also broaden research into how the health and history of blood stem cells affect the brain. "Our findings suggest that the life history of blood stem cells could influence the risk of brain diseases by altering the microglia," Jaiswal said. 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."
Materials provided by Stanford University. Note: Content may be edited for style and length.