biostudies-literatureUnknown121(17)Arvanitaki ESDNA damage and neurodegenerative disorders are intimately linked but the underlying mechanism remains elusive. Here, we show that persistent DNA lesions in tissue-resident macrophages carrying an XPF-ERCC1 DNA repair defect trigger neuroinflammation and neuronal cell death in mice. We find that microglia accumulate dsDNAs and chromatin fragments in the cytosol, which are sensed thereby stimulating a viral-like immune response in <i>Er1^Cx/-</i> and naturally aged murine brain. Cytosolic DNAs are packaged into extracellular vesicles (EVs) that are released from microglia and discharge their dsDNA cargo into IFN-responsive neurons triggering cell death. To remove cytosolic dsDNAs and prevent inflammation, we developed targeting EVs to deliver recombinant DNase I to <i>Er1^Cx/-</i> brain microglia in vivo. We show that EV-mediated elimination of cytosolic dsDNAs is sufficient to prevent neuroinflammation, reduce neuronal apoptosis, and delay the onset of neurodegenerative symptoms in <i>Er1^Cx/-</i> mice. Together, our findings unveil a causal mechanism leading to neuroinflammation and provide a rationalized therapeutic strategy against age-related neurodegeneration.Proceedings of the National Academy of Sciences of the United States of Americae2317402121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11047102biostudies-literatureMicroglia-derived extracellular vesicles trigger age-related neurodegeneration upon DNA damage.PMC11047102Tsakani EGarinis GAArvanitaki ESNenedaki EKalafatakis IXydias DPsilodimitrakopoulos SGkirtzimanaki KNiotis GGoulielmaki ERouska IKaragogeos DStratakis EKefalogianni MSchumacher BfalseMicroglia-derived extracellular vesicles trigger age-related neurodegeneration upon DNA damage.DNA damage and neurodegenerative disorders are intimately linked but the underlying mechanism remains elusive. Here, we show that persistent DNA lesions in tissue-resident macrophages carrying an XPF-ERCC1 DNA repair defect trigger neuroinflammation and neuronal cell death in mice. We find that microglia accumulate dsDNAs and chromatin fragments in the cytosol, which are sensed thereby stimulating a viral-like immune response in <i>Er1^Cx/-</i> and naturally aged murine brain. Cytosolic DNAs are packaged into extracellular vesicles (EVs) that are released from microglia and discharge their dsDNA cargo into IFN-responsive neurons triggering cell death. To remove cytosolic dsDNAs and prevent inflammation, we developed targeting EVs to deliver recombinant DNase I to <i>Er1^Cx/-</i> brain microglia in vivo. We show that EV-mediated elimination of cytosolic dsDNAs is sufficient to prevent neuroinflammation, reduce neuronal apoptosis, and delay the onset of neurodegenerative symptoms in <i>Er1^Cx/-</i> mice. Together, our findings unveil a causal mechanism leading to neuroinflammation and provide a rationalized therapeutic strategy against age-related neurodegeneration.2024-01-01T00:00:00Z2024 Apr2025-04-26T07:58:22.249Z2025-04-06T12:31:06.079ZS-EPMC110471023863563210.1073/pnas.2317402121