Summary: Scientists have identified a new immune mechanism in Alzheimer’s disease showing that the brain’s immune cells, microglia, can act as protectors rather than only contributors to damage. Lowering the transcription factor PU.1 in microglia induces expression of lymphoid-like immunoregulatory receptors, including CD28, which reduces inflammation, slows amyloid plaque accumulation, and preserves cognitive function in mouse models.
When CD28 was specifically removed from this protective subset of microglia, the benefit disappeared: neuroinflammation increased and plaque growth accelerated. This PU.1–CD28 signaling axis therefore defines a molecular route by which microglia can adopt neuroprotective roles and suggests new directions for microglia-targeted immunotherapies for Alzheimer’s disease.
Key takeaways
- Microglial protection: Reducing PU.1 levels shifts some microglia into a state that suppresses inflammation and protects brain tissue and cognitive function.
- Critical role of CD28: CD28 expression on these PU.1-low microglia is essential for their suppressive, protective activity; deleting CD28 reverses protection and worsens pathology.
- Therapeutic implications: The PU.1–CD28 axis is a promising molecular target for new immunotherapies aimed at promoting protective microglial states in Alzheimer’s disease.
This research used a combination of Alzheimer’s mouse models, experiments with human cells, and analyses of human brain tissue to show that lowering PU.1 encourages microglia to express lymphoid immunoregulatory receptors. Although the protective CD28-expressing microglia form only a small subset of plaque-associated cells, they have a widespread suppressive effect on inflammation that benefits brain health and survival in mice.
The study reframes how we think about microglia in Alzheimer’s disease. Rather than being uniformly harmful or reactive, microglia display plasticity and can transition into immune-regulatory states that restrain damaging inflammation. The transcription factor PU.1 acts as a central controller in this process: microglial contact with amyloid plaques reduces PU.1 expression, and experimentally lowering PU.1 drives a protective program associated with lymphoid receptor expression.
Senior author Anne Schaefer emphasized that microglia are capable of protective behavior in Alzheimer’s disease and that recognizing this plasticity is vital for developing therapeutic strategies. Co-author Alexander Tarakhovsky noted the surprise and significance of finding classical lymphoid molecules, such as CD28, functioning in microglia—paralleling mechanisms known from B and T cell regulation and suggesting a shared logic of immune regulation across cell types.
Alison Goate, a senior co-author whose earlier genetic studies identified a common variant in SPI1 (the gene encoding PU.1) linked to lower Alzheimer’s risk, described the current findings as a mechanistic explanation for how reduced PU.1 levels can be protective. Together, these insights provide a clearer map of the molecular pathways that allow microglia to limit neuroinflammation and slow disease progression.
Key questions answered
A: They found that lowering PU.1 activates a small subset of microglia that express lymphoid immunoregulatory receptors and that these protective microglia suppress inflammation and protect against Alzheimer’s-related damage in mouse models.
A: CD28 is one of the lymphoid receptors expressed by PU.1-low microglia and is essential for their suppressive function. Removing CD28 from these cells increased inflammation and amyloid plaque formation, showing CD28’s crucial role.
A: The identification of the PU.1–CD28 axis highlights a new immunological pathway that could be targeted to promote protective microglial states, offering a potential avenue for immunotherapy to slow or prevent Alzheimer’s progression.
About this Alzheimer’s disease research news
Author: Maren Berghof
Source: Max Planck Institute
Contact: Maren Berghoff – Max Planck Institute
Image: Image credited to Neuroscience News
Original research: Open access. Title: “Lymphoid gene expression supports neuroprotective microglia function” by Anne Schaefer et al., published in Nature. DOI: 10.1038/s41586-025-09662-z
Abstract
Lymphoid gene expression supports neuroprotective microglia function
Microglia, the brain’s innate immune cells, influence the course of Alzheimer’s disease through a spectrum of responses to amyloid plaques, ranging from protective to damaging. This study demonstrates that microglial protective function is regulated by the transcription factor PU.1, which becomes downregulated in plaque-associated microglia.
Lowering PU.1 expression in microglia in experimental models reduces the severity of amyloid pathology and correlates with increased expression of immunoregulatory lymphoid receptor proteins, notably CD28. A microglia-specific loss of CD28 in this PU.1-low population shifts microglia toward a broadly inflammatory state and increases amyloid plaque burden.
These results suggest that PU.1-low, CD28-expressing microglia act as suppressive, neuroprotective cells that can mitigate Alzheimer’s-related neuroinflammation. The involvement of CD28 and related lymphoid co-stimulatory and co-inhibitory receptors in microglial regulation points to potential immunotherapeutic strategies that aim to promote protective microglial functions and alter the course of Alzheimer’s disease.