In this issue of Cell Stem Cell, Jin et al. report that human Down syndrome microglia exhibit enhanced synaptic engulfment and accelerated tau-induced cellular senescence in human-mouse chimeric brains. They show that inhibiting interferon signaling rescues both developmental and tau-associated phenotypes, rendering it a potential therapeutic target for Down syndrome. In this issue of Cell Stem Cell, Jin et al. report that human Down syndrome microglia exhibit enhanced synaptic engulfment and accelerated tau-induced cellular senescence in human-mouse chimeric brains. They show that inhibiting interferon signaling rescues both developmental and tau-associated phenotypes, rendering it a potential therapeutic target for Down syndrome.