Neurons burdened by DNA double-strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration
Name
sciadv.abo4662.pdf
Description
Published version
Size
9.4 MB
Format
Adobe PDF
Checksum (MD5)
342bd874528ab5a249a047a0738fd91e
Author(s)
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
Date Issued
2022
Journal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Welch, Gwyneth M, Boix, Carles A, Schmauch, Eloi, Davila-Velderrain, Jose, Victor, Matheus B et al. 2022. "Neurons burdened by DNA double-strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration." Science Advances, 8 (39).
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Terms of Use
Creative Commons Attribution NonCommercial License 4.0
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DOI of Published Version
https://doi.org/10.1126/SCIADV.ABO4662
