Immune Cells Flood Into the Aging Brain, Stanford Scientists Discover

For many years, the brain's immune system was largely considered distinct from the rest of the body's defenses. The brain possesses its own specialized immune cells and is protected by the blood-brain barrier, which limits the entry of many substances and cells into brain tissue.

However, new research from Stanford is questioning this established understanding. Scientists have found that as people age, substantial numbers of immune cells from elsewhere in the body infiltrate the human brain. This groundbreaking discovery may fundamentally alter how scientists view brain aging and could potentially lead to novel treatments for neurological disorders. This research, partly supported by the Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, was recently published in the journal Nature.

"We typically perceive the brain as an isolated system," stated Julia Belk, a postdoctoral scholar in pathology at Stanford Medicine and the lead author of the new study. "Our findings indicate that a considerable number of immune cells actually enter the human brain during the aging process."

An Unexpected Path Into Brain Research

Belk's initial interest in neuroscience emerged during her graduate studies in Computer Science at Stanford's School of Humanities and Sciences. During this period, she also participated in Sarafan ChEM-H's Chemistry/Biology Interface Predoctoral Training Program. She considers this experience crucial in fostering an interdisciplinary approach that integrates fundamental science, computer science, and medicine.

This training eventually led to a collaborative effort with Siddhartha Jaiswal, a senior author of the study and an associate professor of pathology at Stanford Medicine, as well as a member of the Institute for Stem Cell Biology and Regenerative Medicine.

In prior investigations, the researchers analyzed genetic data from thousands of individuals, some of whom had been monitored for decades. The team demonstrated that individuals carrying specific immune cell clones, originating from mutated blood stem cells, exhibited a significantly reduced likelihood of developing Alzheimer's disease. This observation suggested the possibility that these unusual immune cells might interact with the brain in some way.

The researchers subsequently discovered evidence indicating that some of these mutant cells could indeed enter the brain itself. The mutations involved are linked to clonal hematopoiesis of indeterminate potential, a condition present in only a fraction of the population. Nevertheless, this discovery prompted the team to explore a broader question: could immune cells from the bloodstream routinely enter the brains of individuals as they get older?

"Unlike most immune cells, which are continuously replenished by blood stem cells from the bone marrow, it was presumed that immune cells within the brain renewed themselves throughout life without external contributions," explained Jaiswal. "Our initial study suggested that this assumption might not always hold true."

Challenging a Longstanding View of Microglia

For many years, a prevalent belief among researchers was that the brain's specialized immune cells, known as microglia, were established at birth and maintained a self-sustaining population throughout an individual's life. According to this model, immune cells from outside the brain were not expected to migrate into the brain and integrate into this population.

Belk and her colleagues began to consider an alternative possibility. If peripheral immune cells could enter the brain in some individuals, perhaps this process was not an anomaly but rather a common characteristic of human aging.

The notion that blood-derived immune cells could play a role in Alzheimer's was both unconventional and contentious. In 2022, Jaiswal and his colleagues secured support from the Knight Initiative for Brain Resilience, an organization that funds research aimed at re-evaluating approaches to studying brain resilience and neurodegenerative diseases.

With partial funding from a Knight Initiative Innovation Award, Belk, Jaiswal, and co-senior author Howard Chang, the Virginia and D. K. Ludwig Professor of Cancer Research and a professor of genetics at Stanford Medicine, embarked on an investigation into why peripheral immune cells appeared to enhance resilience to Alzheimer's. However, before addressing this question, they first needed to confirm whether immune cells from the blood could genuinely replenish microglia in the brain.

Tracing Immune Cells From Blood to Brain

To conduct their investigation, the researchers examined human brain tissue. They utilized samples from the Stanford Rapid Autopsy Center, overseen by co-author Jody Hooper, a professor of pathology at Stanford Medicine, as well as samples from the University of Washington's Alzheimer's Disease Sequencing Project.

These programs gather both blood and post-mortem brain tissue from individuals with and without Alzheimer's disease. This dual collection provided the team with a unique opportunity to directly compare immune cells found in the bloodstream with those present in brain tissue after death.

The primary challenge was to precisely determine the origin of the immune cells found within the brain. Given that immune cells undergo continuous division, the scientists needed to trace their cellular lineages. Their objective was to differentiate cells derived from the initial microglial population present since birth from those originating from blood stem cells in the bone marrow later in life.

The researchers devised a method for this by comparing DNA from immune cells in the blood with DNA from immune cells in the brain. They employed shared mutations as biological markers of ancestry, akin to how consumer ancestry testing services operate.

Random mutations gradually accumulate in blood stem cells over time. Immune cells produced by these stem cells inherit the same mutations. Consequently, if two sets of immune cells share identical mutations, they are highly likely to share a common origin.

"If we observe the same mutations in both the blood and the brain's microglia, then we can be highly confident that the immune cells in the brain are descendants of those immune cells in the blood," Belk stated.

Employing this methodology and techniques developed in their 2023 research, Belk and her colleagues compared immune cells from paired blood and brain samples. The genetic signatures matched, indicating that immune cells from the body had entered the brain, with this process commencing as early as middle age.

Further experiments revealed another significant finding. Once peripheral immune cells entered the brain, they differentiated into specialized microglia. The researchers noted that this process does not appear to occur in other species, such as mice or non-human primates.

A Possible New Route for Brain Immunotherapy

Beyond challenging established concepts of brain immunity, this discovery holds the potential to offer a novel strategy for developing brain-centric therapies.

"Now that we know these immune cells can actually enter the brain, we can envision a variety of new engineering approaches to direct these peripheral immune cells to perform beneficial functions."

One potential application could involve engineering immune cells to target and break down amyloid and tau aggregates associated with neurodegenerative diseases. Such engineered cells could potentially be administered preventively, before these detrimental aggregates begin to accumulate.

This discovery may also expand research into how the health and history of blood stem cells influence the brain. Since many microglia in aging humans appear to originate from blood stem cells, any factor that affects cells in the blood or bone marrow could potentially impact the brain as well.

"Our findings suggest that the life history of blood stem cells could influence the risk of brain diseases by modifying microglia," Jaiswal commented.

For Belk, these results are particularly noteworthy as they unveil an aspect of brain aging that seems to be uniquely human.

"I believe this is exciting because it represents a uniquely human feature of aging that we were previously unaware of."