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

Microglia are critical in brain development and Alzheimer???s disease (AD) etiology. Down syndrome (DS) is the most common genetic developmental disorder and risk factor for AD. Surprisingly, little information is avail-able on the impact of trisomy of human chromosome 21 (Hsa21) on microglial functions during DS brain development and in AD in DS. Using induced pluripotent stem cell (iPSC)-based organoid and chimeric mouse models, we report that DS microglia exhibit an enhanced synaptic pruning function, which alters neuronal synaptic functions. In response to human brain tissue-derived pathological tau, DS microglia un-dergo cellular senescence and exhibit elevated type-I-interferon signaling. Mechanistically, knockdown of Hsa21-encoded type I interferon receptors, IFNARs, rescues the DS microglial phenotypes both during brain development and in response to pathological tau. Our findings provide in vivo evidence that human microglia respond to pathological tau by exhibiting dystrophic phenotypes. Targeting IFNARs may improve DS micro-glial functions and prevent senescence.

Automated summary

Using iPSC-based organoid and chimeric mouse models, researchers found that microglia in Down syndrome exhibit enhanced synaptic pruning function and elevated type-I interferon signaling, which can be rescued by knocking down the gene encoding type I interferon receptors. This study provides in vivo evidence of human microglial response to pathological tau and suggests that targeting interferon receptors may improve microglial functions.