Overview
- Lowering the transcription factor PU.1 in microglia induced lymphoid-like receptors including CD28, dampened neuroinflammation, and slowed amyloid and tau pathology in models.
- Removing CD28 from this protective subset boosted inflammation and accelerated amyloid plaque growth, demonstrating CD28’s necessity for the beneficial state.
- The PU.1low CD28+ microglia were rare yet produced brain-wide effects that preserved cognition and extended survival in Alzheimer’s mouse models.
- The protective state was validated across Alzheimer’s mouse models, human cell systems, and postmortem brain tissue, including data consistent with a PU.1-lowering SPI1 allele in humans.
- The work proposes the PU.1–CD28 axis as a candidate target for microglia-directed immunotherapies, with clinical translation and safety evaluation still ahead.