Microglia Switch Into Protective Mode That Slows Alzheimer’s in Mice — Potential Immunotherapy Target

New research finds that certain brain immune cells, called microglia, can adopt a distinct protective state when they encounter amyloid‑beta plaques — a hallmark of Alzheimer’s disease. In mouse models, this state reduced the accumulation of both amyloid‑beta and tau protein aggregates, suggesting a new possible avenue for therapies that encourage microglia to protect, rather than damage, neurons.

An international team led by neuroscientists Pinar Ayata and colleagues used Alzheimer’s mouse models to track how microglia change as they approach amyloid‑beta deposits. They identified a subtype of microglia with two defining molecular features: lower levels of the transcription factor PU.1 and higher expression of the immune receptor CD28.

"Microglia are not simply destructive responders in Alzheimer's disease — they can become the brain's protectors," said Anne Schaefer, neuroscientist.

Microglia with reduced PU.1 and elevated CD28 were more effective at limiting plaque growth and also helped restrain tau aggregation in these mouse brains. To test causality, the researchers experimentally blocked CD28 production: this caused an increase in inflammation‑promoting microglia and a higher amyloid‑beta plaque burden, linking CD28 activity with the protective phenotype.

The findings align with prior genetic studies showing that people with variants associated with lower PU.1 expression in specific cells tend to develop Alzheimer’s later than average. "These results provide a mechanistic explanation for why lower PU.1 levels are linked to reduced Alzheimer's disease risk," said geneticist Alison Goate.

Although the observed microglial state appears to be a natural defense, the authors emphasize it is not sufficient on its own to stop disease progression. The team cautions that these results come from mouse models and that it is essential to confirm whether the same mechanisms operate in humans before translating the approach into clinical therapies.

The study also highlights connections between brain‑resident immune regulation and systemic immunity. The protective microglia share functional similarities with regulatory T cells, suggesting a broader, shared logic of immune regulation that might be harnessed for immunotherapeutic strategies.

"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," said epigeneticist Alexander Tarakhovsky.

The research, which adds important mechanistic detail to how microglia states influence Alzheimer’s pathology, was published in the journal Nature. Researchers say future work should focus on confirming these findings in human tissue and on developing safe ways to shift microglia into this neuroprotective mode without triggering damaging inflammation.