Neurons burdened by DNA double-strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration

Sci Adv. 2022 Sep 30;8(39):eabo4662. doi: 10.1126/sciadv.abo4662. Epub 2022 Sep 28.

Abstract

DNA double-strand breaks (DSBs) are linked to neurodegeneration and senescence. However, it is not clear how DSB-bearing neurons influence neuroinflammation associated with neurodegeneration. Here, we characterize DSB-bearing neurons from the CK-p25 mouse model of neurodegeneration using single-nucleus, bulk, and spatial transcriptomic techniques. DSB-bearing neurons enter a late-stage DNA damage response marked by nuclear factor κB (NFκB)-activated senescent and antiviral immune pathways. In humans, Alzheimer's disease pathology is closely associated with immune activation in excitatory neurons. Spatial transcriptomics reveal that regions of CK-p25 brain tissue dense with DSB-bearing neurons harbor signatures of inflammatory microglia, which is ameliorated by NFκB knockdown in neurons. Inhibition of NFκB in DSB-bearing neurons also reduces microglia activation in organotypic mouse brain slice culture. In conclusion, DSBs activate immune pathways in neurons, which in turn adopt a senescence-associated secretory phenotype to elicit microglia activation. These findings highlight a previously unidentified role for neurons in the mechanism of disease-associated neuroinflammation.

MeSH terms

  • Animals
  • Antiviral Agents / metabolism
  • DNA / metabolism
  • DNA Breaks, Double-Stranded*
  • Humans
  • Mice
  • Microglia* / metabolism
  • NF-kappa B / metabolism
  • Neurons / metabolism

Substances

  • Antiviral Agents
  • NF-kappa B
  • DNA