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

  • Cell Stem Cell. 2022 Jul 7;29(7):1135-1153.e8. doi: 10.1016/j.stem.2022.06.007.
Mengmeng Jin  1 ,  Ranjie Xu  1 ,  Le Wang  2 ,  Mahabub Maraj Alam  1 ,  Ziyuan Ma  1 ,  Sining Zhu  1 ,  Alessandra C Martini  3 ,  Azadeh Jadali  1 ,  Matteo Bernabucci  2 ,  Ping Xie  1 ,  Kelvin Y Kwan  1 ,  Zhiping P Pang  2 ,  Elizabeth Head  3 ,  Ying Liu  4 ,  Ronald P Hart  1 ,  Peng Jiang  5
Affiliations
  • 1. Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
  • 2. Department of Neuroscience and Cell Biology and Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
  • 3. Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697, USA.
  • 4. Department of Neurosurgery and Center for Stem Cell and Regenerative Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Center for Translational Science, Florida International University, Miami, FL 34987, USA.
  • 5. Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: [email protected].
PMID: 35803230 DOI: 10.1016/j.stem.2022.06.007
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 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 microglial functions and prevent senescence.

Keywords
Alzheimer's disease; Down syndrome; human induced pluripotent stem cells; microglia; senescence; synaptic pruning; type I interferon.