Type I Interferon Signaling Drives Microglial Dysfunction and Senescence in Human iPSC Models of Down Syndrome and Alzheimers Disease

Jin, M.; Xu, R.; Alam, M. M.; Ma, Z.; Zhu, S.; Wang, L.; Martini, A. C.; Bernabucci, M.; Xie, P.; Kwan, K.; Pang, Z. P.; Head, E.; Liu, Y.; Hart, R. P.; Jiang, P.

doi:10.1101/2021.12.22.473858

bioRxiv · 10.1101/2021.12.22.473858

Type I Interferon Signaling Drives Microglial Dysfunction and Senescence in Human iPSC Models of Down Syndrome and Alzheimers Disease

Jin, M.·Xu, R.·Alam, M. M.·Ma, Z.·Zhu, S.·Wang, L.·Martini, A. C.·Bernabucci, M.·Xie, P.·Kwan, K.·Pang, Z. P.·Head, E.·Liu, Y.·Hart, R. P.·Jiang, P.

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Abstract

Microglia are critical for brain development and play a central role in Alzheimers disease (AD) etiology. Down syndrome (DS), also known as trisomy 21, is the most common genetic origin of intellectual disability and the most common risk factor for AD. Surprisingly, little information is available on the impact of trisomy of human chromosome 21 (Hsa21) on microglia in DS brain development and AD in DS (DSAD). Using our new induced pluripotent stem cell (iPSC)-based human microglia-containing cerebral organoid and chimeric mouse brain models, here we report that DS microglia exhibit enhanced synaptic pruning function during brain development. Consequently, electrophysiological recordings demonstrate that DS microglial mouse chimeras show impaired synaptic functions, as compared to control microglial chimeras. Upon being exposed to human brain tissue-derived soluble pathological tau, DS microglia display dystrophic phenotypes in chimeric mouse brains, recapitulating microglial responses seen in human AD and DSAD brain tissues. Further flow cytometry, single-cell RNA- sequencing, and immunohistological analyses of chimeric mouse brains demonstrate that DS microglia undergo cellular senescence and exhibit elevated type I interferon signaling after being challenged by pathological tau. Mechanistically, we find that shRNA-mediated knockdown of Hsa21encoded type I interferon receptor genes, IFNARs, rescues the defective DS microglial phenotypes both during brain development and in response to pathological tau. Our findings provide first in vivo evidence supporting a paradigm shifting theory that human microglia respond to pathological tau by exhibiting accelerated senescence and dystrophic phenotypes. Our results further suggest that targeting IFNARs may improve microglial functions during DS brain development and prevent human microglial senescence in DS individuals with AD.

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Jin, M., Xu, R., Alam, M. M., Ma, Z., Zhu, S., Wang, L., Martini, A. C., Bernabucci, M., Xie, P., Kwan, K., Pang, Z. P., Head, E., Liu, Y., Hart, R. P., Jiang, P.. 2021-12-23. Type I Interferon Signaling Drives Microglial Dysfunction and Senescence in Human iPSC Models of Down Syndrome and Alzheimers Disease. https://doi.org/10.1101/2021.12.22.473858

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