Altered astrocyte-microglia interactions have been implicated in the pathogenesis of Alzheimer’s disease, but the underpinning mechanisms remain unclear. Zhang and colleagues show that astrocytic PAD2-mediated citrullination of vimentin activates microglia, worsens Aβ accumulation, and exacerbates cognitive deficits. These findings highlight astrocyte-microglia crosstalk as a potential therapeutic target for Alzheimer’s disease.