Lowering PU.1 in microglia shifts them toward an immune-regulating state, with these protective microglia expressing receptors typically found in lymphoid cells and producing widespread anti-inflammatory effects.

These protective microglia show reduced PU.1 and increased CD28 expression, together helping to regulate brain immune activity.

In mouse models, human brain cells, and tissue samples, these microglia preserve memory and survival by dampening brain inflammation.

The study is funded by NIH, European Research Council, Cure Alzheimer’s Fund, and other foundations, with collaboration across institutions including The Rockefeller University and The City University of New York.

Leading researchers include Anne Schaefer and Alexander Tarakhovsky, with Goate providing genetic context; the work highlights cross-institution collaboration and translational potential for immune-based therapies.

Researchers emphasize microglial state plasticity, potential cross-talk with immune regulation, and the importance of international collaboration in advancing this research area.

Genetic context is strengthened by prior work linking a SPI1 (PU.1) variant to lower Alzheimer’s risk, offering a mechanistic explanation for the protective effect.

Alison M. Goate’s work tying a SPI1 variant to reduced Alzheimer’s risk provides a mechanistic link between lower PU.1 levels and protective microglial states.

The genetic findings connect SPI1 variants to lower disease risk through reduced PU.1 levels that promote protective microglial activity.

A Nature report from November 2024 profiles a microglial subset with low PU.1 and high CD28, published by Icahn School of Medicine at Mount Sinai and international partners.

A new study identifies a microglial subset that slows Alzheimer’s by reducing inflammation and limiting amyloid plaques and tau spread, reframing microglia as brain protectors.

The findings point to immunotherapy strategies that target microglial activity via the PU.1–CD28 axis to modulate brain inflammation and disease progression.

Removing CD28 from this protective microglial subset worsens inflammation and accelerates plaque growth, underscoring CD28’s essential role in maintaining their protective state.

CD28 is critical for sustaining the protective microglial state; its removal exacerbates neuroinflammation and plaque development.

Although small, this protective microglial subset contributes to memory preservation and survival in mice, suggesting meaningful therapeutic potential.