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

ABSTRACT: 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 available 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 undergo cellular senescence and exhibit elevated type-I-interferon signaling. Mechanistically, knockdown of Hsa21-encoded type I interferon receptors, IFNARs, rescues the DS micr

SUBMITTER: Jin M 

PROVIDER: S-EPMC9345168 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature