In a study published in the journal Nature, Mount Sinai’s Alison Goate, DPhil, and Anne Schaefer, MD, PhD, in concert with a team of international collaborators, reported a striking finding about microglia, the brain's immune cells. A specific subset of microglia, characterized by reduced expression of a protein called PU.1 and co-expression of a receptor known as CD28, actively limits neuroinflammation and slows the buildup of amyloid plaques and toxic tau proteins, the major hallmarks of Alzheimer's disease.

PU.1 is a protein that binds to specific DNA sequences to control the translation of genetic information, determining when and how genes are turned on or off. CD28 is a co-stimulatory receptor found on the surface of T cells that helps initiate and sustain an effective adaptive immune response. 

Using Alzheimer’s mouse models, human cells, and human brain tissue, the researchers demonstrated that lowering PU.1 promotes the expression of lymphoid immunoregulatory receptor proteins on microglia. Despite being present in small numbers, these neuroprotective microglia exert a brain-wide suppressive impact on inflammation and protect cognitive function and survival in mice. The researchers found that deleting CD28 from this small subset of microglia amplified inflammation and accelerated plaque growth, highlighting CD28’s key role in protective microglial activity.