A study published November 5 in Nature reports that a small subset of microglia marked by low PU.1 and expression of the receptor CD28 can dampen neuroinflammation and curb amyloid pathology in Alzheimer’s models, pointing to microglia-focused immunotherapy. The work draws on mouse experiments, human cells, and analyses of human brain tissue.
Researchers from the Icahn School of Medicine at Mount Sinai, together with collaborators at the Max Planck Institute for Biology of Ageing in Cologne, The Rockefeller University, and The City University of New York, report a distinct, neuroprotective state of microglia—the brain’s immune cells—that appears to slow features of Alzheimer’s disease progression. The Nature paper was published November 5, 2025. (dx.doi.org)
The team identified plaque-associated microglia with reduced levels of the transcription factor PU.1 (encoded by SPI1) and induction of lymphoid-like receptors, notably CD28, a co‑stimulatory protein best known for its role in T‑cell activation. In Alzheimer’s mouse models, experimentally lowering PU.1 drove this immune‑regulatory program and was associated with less severe amyloid pathology. (dx.doi.org)
Although these PU.1-low, CD28-expressing cells comprise only a small fraction of total microglia, the study found they exert broad, brain‑wide effects: they preserved synaptic function, improved performance on memory‑related tasks, and extended survival in 5xFAD Alzheimer’s mice compared with controls. (dx.doi.org)
Mechanistic tests underscored CD28’s importance. Deleting CD28 specifically in microglia amplified inflammatory signaling and increased amyloid plaque burden, suggesting this receptor helps restrain disease‑promoting neuroinflammation. (dx.doi.org)
Participating institutions also report that, in the team’s models, the protective microglia state slowed the spread of neurotoxic tau—another key Alzheimer’s hallmark—alongside reducing amyloid buildup. Because that claim appears in institutional releases rather than the article’s abstract, we note it as reported by Mount Sinai and Rockefeller. (mountsinai.org)
“Microglia are not simply destructive responders in Alzheimer’s disease—they can become the brain’s protectors,” said senior author Anne Schaefer of Mount Sinai. Alexander Tarakhovsky of Rockefeller added that molecules long studied in lymphocytes also regulate microglia, “pav[ing] the way for immunotherapeutic strategies” in Alzheimer’s. (sciencedaily.com)
The findings align with earlier human genetics work from Alison M. Goate and colleagues linking a common SPI1 variant—associated with lower PU.1 expression—to reduced Alzheimer’s risk and delayed onset, providing a mechanistic rationale for those observations. (dx.doi.org)
The research was supported by agencies and foundations including the U.S. National Institutes of Health and the Alzheimer’s Association. While the results highlight a potentially druggable immune circuit in microglia, they are primarily preclinical; translating these insights into therapies will require further validation and safety studies. (sciencedaily.com)
