[221014 Àú³Î¹ßÇ¥] Neurons burdened by DNA double-strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration Á¤¼±¿ì ¦¢ 2022-10-13 HIT 47411 |
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Welch et al., Sci. Adv. 8, eabo4662 (2022) Science Advances, 28 Sep 2022, Vol 8, Issue 39 REARCH ARTICLE NEUROSCIENCE Neurons burdened by DNA double-strand breaks incite microglia activation through antiviral-like signaling in neurodegenerationAbstract 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 ¥êB (NF¥êB)–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 NF¥êB knockdown in neurons. Inhibition of NF¥êB 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. |
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