The gene expression patterns of DSB-burdened neurons were enriched in excitatory neurons from AD postmortem human brain. This is accompanied by degradation of neuronal identity. We found that DSB-bearing neurons activate innate immune signaling pathways reminiscent of those expressed by senescent cells and neurons infected by virus ( 12– 14). We used fluorescence-activated nuclei sorting (FANS) followed by bulk and single-nucleus RNA sequencing (snRNA-seq) to transcriptionally characterize neurons burdened with DSBs in the CK-p25 mouse model of neurodegeneration. We also investigated how this affects mechanisms of neuroinflammation in age-associated neurodegenerative disease. Here, we sought to characterize the biological consequences of DSB accumulation in neurons. These findings highlight a previously unidentified role for neurons in the mechanism of disease-associated neuroinflammation. In conclusion, DSBs activate immune pathways in neurons, which in turn adopt a senescence-associated secretory phenotype to elicit microglia activation. Inhibition of NFκB in DSB-bearing neurons also reduces microglia activation in organotypic mouse brain slice culture. 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. In humans, Alzheimer’s disease pathology is closely associated with immune activation in excitatory neurons. DSB-bearing neurons enter a late-stage DNA damage response marked by nuclear factor κB (NFκB)–activated senescent and antiviral immune pathways.
Here, we characterize DSB-bearing neurons from the CK-p25 mouse model of neurodegeneration using single-nucleus, bulk, and spatial transcriptomic techniques.
However, it is not clear how DSB-bearing neurons influence neuroinflammation associated with neurodegeneration. DNA double-strand breaks (DSBs) are linked to neurodegeneration and senescence.
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