Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer’s disease

Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer’s disease (AD). The microglial response to amyloid plaques can be either neuroprotective or neurotoxic. Here we show that the protective function of microglia is associated with and functionally linked to a transcriptional shift toward lymphoid gene expression. Microglial contact with the plaques induces downregulation of PU.1, a lineage-specifying transcription factor. PU.1 downregulation plays a key role in mitigating the severity of AD, as evidenced by a reduction in neurotoxic microglia activation, preservation of neuronal connections, maintenance of cognitive function, and increased survival in mice with genetically reduced PU.1 expression in microglia. The neuroprotective effect of PU.1 downregulation is linked to the de-repression of lymphoid-specific proteins, particularly CD28—a surface protein critical for T cell activation. Microglia-specific deficiency in CD28, which is expressed exclusively in a small subset of plaque-associated PU.1low microglia, promotes an inflammatory microglial state and associated increase in amyloid plaque load. Our findings suggest that PU.1low lymphoid/CD28-expressing microglia that emerge in response to AD pathology exert a suppressive, anti-inflammatory effect during AD. This novel role of CD28 -and potentially other lymphoid co-stimulatory or co-inhibitory receptor proteins- in governing microglia responses in AD points to possible new immunotherapy approaches for AD treatment.