Neurons burdened by DNA double-strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration.
IF: 14.957
Cited by: 16


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.


Spatial Transcriptomics

MeSH terms

Antiviral Agents
DNA Breaks, Double-Stranded
NF-kappa B


Welch, Gwyneth M
Boix, Carles A
Schmauch, Eloi
Davila-Velderrain, Jose
Victor, Matheus B
Dileep, Vishnu
Bozzelli, P Lorenzo
Su, Qiao
Cheng, Jemmie D
Lee, Audrey
Leary, Noelle S
Pfenning, Andreas R
Kellis, Manolis
Tsai, Li-Huei