New Stanford Research Reveals Immune Cells from Blood Enter the Aging Human Brain

Researchers at Stanford University have challenged long-standing beliefs about the brain’s immune system. For decades, scientists have considered the brain’s immune defenses largely separate from those in the rest of the body, owing largely to the presence of specialized immune cells and the blood-brain barrier that restricts external substances and cells. Their recent study reveals that a significant number of immune cells from the bloodstream enter the human brain as individuals age, potentially reshaping our understanding of brain aging and neurological disease treatment.

“We usually think of the brain as a closed system,” said Julia Belk, a postdoctoral scholar in pathology at Stanford Medicine and first author of the study published in the journal Nature. “What we found is that actually a lot of immune cells enter the human brain during aging.”

A Convergence of Disciplines

Belk’s journey into neuroscience began during her graduate studies in the Department of Computer Science at Stanford Humanities and Sciences. She participated in the Sarafan ChEM-H’s Chemistry/Biology Interface Predoctoral Training Program, which influenced her interdisciplinary approach that integrates basic science, computer science, and medicine. Collaborating with Siddhartha Jaiswal, a senior author of the study and an associate professor of pathology at Stanford Medicine, Belk’s previous research examined genetic data from thousands of people. They noted that those carrying certain clones of immune cells derived from mutated blood stem cells had a notably reduced risk of developing Alzheimer’s disease, hinting at interactions between these immune cells and brain functionality.

Further investigating, the researchers found evidence of these mutant cells entering the brain, a finding linked to clonal hematopoiesis of indeterminate potential, a condition seen in a minority of individuals.

“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 without outside contributions,” Jaiswal said. “Our first study showed that this might not always be the case.”

Revisiting Microglial Beliefs

Traditionally, it was believed that microglia, the brain’s specialized immune cells, were established at birth and remained self-sufficient throughout life. This misconception prevented researchers from considering the migration of external immune cells into the brain.

Belk and her colleagues posited that if external immune cells could infiltrate the brains of some individuals, this process could be a common aspect of human aging. In 2022, Jaiswal and his team sought funding from the Knight Initiative for Brain Resilience to explore this unconventional angle further.

Investigating the Flow of Immune Cells

The researchers utilized samples from the Stanford Rapid Autopsy Center and the University of Washington’s Alzheimer’s Disease Sequencing Project, which provided a unique opportunity to compare immune cells present in blood with those found in post-mortem brain tissue from individuals with and without Alzheimer’s.

Determining the origins of the immune cells within the brain was crucial since these cells divide continuously, making it essential to track their lineage. By analyzing DNA from blood and brain immune cells, they employed shared mutations as biological markers to trace ancestry.

“If we see the same mutations in the blood and in the brain’s microglia, then we can be very confident that immune cells in the brain are descendants of those immune cells in the blood,” Belk explained.

The researchers discovered that immune cells from the bloodstream do enter the brain, with this process beginning in mid-life. Furthermore, upon entering the brain, they transform into specialized microglia—a phenomenon not observed in mice or non-human primates.

Paving the Way for New Therapeutics

This research opens pathways for innovative approaches to brain treatment. “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 noted.

One potential avenue involves engineering these cells to target and dismantle amyloid and tau aggregates associated with neurodegenerative diseases, potentially enabling preventive treatments before these harmful substances accumulate.

The findings also suggest that the history of blood stem cells could influence the brain’s disease risk by altering microglial populations. Jaiswal added, “Our findings suggest that the life history of blood stem cells could influence the risk of brain diseases by altering the microglia.”

Belk remarked on the significance of their findings, stating, “I think this is exciting because this is also a uniquely human feature of aging that we had no idea about.”