Type-I-interferon signaling drives microglial dysfunction and senescence in human iPSC models of Down syndrome and Alzheimer’s disease

With human iPSC-based brain organoids and mouse chimeras, Jin and colleagues demonstrate that upregulated type-I-interferon (IFN-I) signaling in Down syndrome microglia causes elevated synaptic pruning during development and accelerated senescence, rather than massive activation/inflammation, in response to pathological tau. These phenotypes can be rescued by inhibiting IFN-I receptors.