Newly Discovered Brain Immune Cells Offer Potential Defense Against Alzheimer’s Disease
A groundbreaking study reveals a previously unknown population of immune cells in the brain that may act as natural defenders against Alzheimer’s disease, offering a new avenue for potential therapies.
A subset of microglia—the brain’s resident immune cells—can transition to an anti-inflammatory state, shielding neurons from damage, according to research published this week in Nature. This discovery reveals surprising similarities between the brain’s immune system and the B and T cells that protect the rest of the body. Researchers demonstrated that bolstering this protective state in mouse models reduced brain inflammation, slowed the spread of toxic tau proteins, and diminished amyloid plaque buildup.
The findings illuminate a molecular pathway that could explain variations in Alzheimer’s susceptibility and suggest innovative strategies for leveraging the brain’s own immune system to combat neurodegeneration. “It is remarkable to see that molecules long known to immunologists for their roles in B and T lymphocytes also regulate microglial activity,” stated a senior researcher involved in the study. “This discovery comes at a time when regulatory T cells have achieved major recognition as master regulators of immunity, highlighting a shared logic of immune regulation across cell types. It also paves the way for immunotherapeutic strategies for Alzheimer’s disease.”
The Dual Role of Microglia in Alzheimer’s
Microglia are critical players in Alzheimer’s disease, exhibiting a complex duality—acting both as protectors and aggressors. Their function hinges on gene expression; at times, they clear toxic amyloid deposits, while at other times, they contribute to chronic inflammation. The central question driving this research was identifying the specific molecular signals that determine whether microglia adopt a helpful or harmful role.
Previous research had indicated that the transcription factor PU.1 was a likely key component. Genetic analyses revealed that a common mutation in the gene encoding PU.1 reduces its expression in myeloid cells—a lineage that includes microglia—and individuals carrying this mutation tend to experience later onset and milder symptoms of Alzheimer’s. Earlier work also demonstrated that PU.1 regulates Alzheimer’s-related genes in human microglia and that even slight changes in its activity can alter cellular responses to inflammation. However, the precise molecular mechanism linking PU.1, microglia, and Alzheimer’s progression remained unclear.
Unveiling the PU.1-CD28 Axis
To address these questions, the research team combined molecular profiling, genetic manipulation in mice, and analysis of human brain tissue to map the PU.1 pathway. Imaging revealed a small group of microglia with low levels of PU.1 clustering around amyloid plaques in both mice and humans. These immune cells exhibited unusual resilience—a drug typically used to destroy microglia had minimal impact on this population. Further examination of these surviving cells revealed that microglia with low PU.1 levels also activated CD28, alongside a suite of molecules known for their anti-inflammatory properties elsewhere in the body. These results suggest that these microglia had entered a protective state to stabilize the brain’s environment and limit further damage.
Subsequent experiments elucidated how this protective shift in microglia is triggered. When plaque-sensing receptors on microglia—including TREM2 and CLEC7A, which detect debris and abnormal proteins—were activated, they initiated a signaling cascade through two key molecules, SYK and PLCγ2. This cascade lowered PU.1 levels and activated the microglia’s protective mode.
The team further found that simply reducing PU.1 levels was sufficient to activate CD28 and other anti-inflammatory genes in mice, while increasing PU.1 levels promoted inflammation.
Striking Results in Mouse Models
In mice genetically engineered to exhibit Alzheimer’s-like symptoms, the effect was profound. The low-PU.1 state suppressed harmful immune pathways that typically release toxic molecules, reduced markers of cellular stress in microglia, compacted amyloid plaques into less damaging forms, prevented the spread of the tau protein responsible for neuronal death, and ultimately preserved memory and extended lifespan. However, when the CD28 gene was deleted in these mice, the protective effects were lost. Inflammation returned, amyloid plaques expanded, and the disease progressed more rapidly, despite the low-PU.1 state of the microglia.
Together, the results revealed a critical PU.1-CD28 axis. Signals from plaque-sensing receptors activate a pathway that lowers PU.1 levels and switches on CD28, driving microglia into a neuroprotective state that suppresses inflammation, limits amyloid and tau buildup, preserves brain function and lifespan, and relies entirely on CD28 to maintain these effects.
“This finding extends our earlier observations on the remarkable plasticity of microglia states and their important roles in diverse brain functions,” said Anne Schaefer, senior author and director of the Max Planck Institute for Biology of Ageing.
A New Understanding of Brain Immunity
In a broader sense, the findings reshape our understanding of immunity within the brain itself, revealing that the same molecular logic governing the body’s general immune system may also operate in the central nervous system. Molecules like CD28, previously thought to be exclusive to T and B lymphocytes, were shown to regulate microglial activity. This discovery underscores the surprising parallels between how suppressor T cells prevent autoimmunity and how PU.1-low, CD28-positive microglia limit neuroinflammation in the brain. These insights suggest that the brain’s immune system is not an isolated entity but rather an integral part of a broader, evolutionarily conserved network of checks and balances designed to maintain tissue health.
The discovery of the PU.1–CD28 axis in microglia also provides a blueprint for how the brain’s immune system defends itself against Alzheimer’s. By uncovering an internal circuit of immune regulation that can be steered toward protection rather than inflammation, the work points to the potential for therapies that train the brain’s own defenses to fight neurodegeneration. Future research focusing on how PU.1-low, CD28-positive microglia interact with neighboring cells could pave the way for a new generation of immune-based strategies to preserve brain health.
The research appears in Nature. Additional researchers from the Max Planck Institute, the Icahn School of Medicine at Mount Sinai, The City University of New York, and other institutions contributed to the work.
Source: Rockefeller University
