Language
English
Publication Date
9-30-2022
Journal
Science Advances
DOI
10.1126/sciadv.abo4662
PMID
36170369
PMCID
PMC9519048
PubMedCentral® Posted Date
9-28-2022
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Animals, Antiviral Agents, DNA, DNA Breaks, Double-Stranded, Humans, Mice, Microglia, NF-kappa B, Neurons
Published Open-Access
yes
Recommended Citation
Welch, Gwyneth M; Boix, Carles A; Schmauch, Eloi; et al., "Neurons Burdened by Dna Double-Strand Breaks Incite Microglia Activation Through Antiviral-Like Signaling in Neurodegeneration" (2022). Faculty, Staff and Students Publications. 8559.
https://digitalcommons.library.tmc.edu/baylor_docs/8559