{"doi":"10.1101/2021.12.23.474002","title":"Neurons burdened by DNA double strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration","abstract":"DNA double strand breaks (DSBs) are linked to aging, neurodegeneration, and senescence 1,2 . However, the role played by neurons burdened with DSBs in disease-associated neuroinflammation is not well understood. Here, we isolate neurons harboring DSBs from the CK-p25 mouse model of neurodegeneration through fluorescence-activated nuclei sorting (FANS), and characterize their transcriptomes using single-nucleus, bulk, and spatial sequencing techniques. We find that neurons harboring DSBs enter a late-stage DNA damage response marked by the activation of senescent and antiviral-like immune pathways. We identify the NFkB transcription factor as a master regulator of immune gene expression in DSB-bearing neurons, and find that the expression of cytokines like Cxcl10 and Ccl2 develop in DSB-bearing neurons before glial cell types. Alzheimer’s Disease pathology is significantly associated with immune activation in excitatory neurons, and direct purification of DSB-bearing neurons from Alzheimer’s Disease brain tissue further validates immune gene upregulation. Spatial transcriptomics reveal that regions of brain tissue dense with DSB-bearing neurons also harbor signatures of inflammatory microglia, which is ameliorated by NFkB knock down in neurons. Inhibition of NFkB or depletion of Ccl2 and Cxcl10 in DSB-bearing neurons also reduces microglial activation in organotypic brain slice culture. In conclusion, we find that in the context of age-associated neurodegenerative disease, DSBs activate immune pathways in neurons, which in turn adopt a senescence associated secretory phenotype to elicit microglia activation. These findings highlight a novel role for neurons in the mechanism of age-associated neuroinflammation. <h4>Summary</h4> It is unclear how age-associated DNA double strand break (DSB) accumulation in neurons influences the progression of cellular senescence and neurodegenerative disease. Here, we leverage mouse models of neurodegeneration, single-nucleus, bulk, and spatial transcriptomics from Alzheimer’s disease patients, mouse models, and primary neuron cultures to dissect the immune signaling pathways initiated by DSB-bearing neurons that trigger neuroinflammation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":3400,"datarank":0.46205772671733025,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.13247404011689726,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.13247404011689726,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":6,"citers_with_citation_signal":5,"citers_with_endowment":5,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0419,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-12-23","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":4960,"name":"Carles B. Adsera","orcid":"0000-0001-9212-856X","position":1,"is_corresponding":false},{"id":5683,"name":"Eloi Schmauch","orcid":"0000-0002-2123-8777","position":2,"is_corresponding":false},{"id":1204,"name":"José Dávila-Velderrain","orcid":"0000-0003-0271-6267","position":3,"is_corresponding":false},{"id":11603,"name":"Matheus B. Victor","orcid":"0000-0003-4364-4028","position":4,"is_corresponding":false},{"id":16445,"name":"Vishnu Dileep","orcid":"0000-0001-9181-2191","position":5,"is_corresponding":false},{"id":35837,"name":"Lorenzo Bozzelli","orcid":null,"position":6,"is_corresponding":false},{"id":16447,"name":"Qiao Su","orcid":"0000-0002-7882-6182","position":7,"is_corresponding":false},{"id":16448,"name":"Jemmie D. Cheng","orcid":null,"position":8,"is_corresponding":false},{"id":16449,"name":"Audrey Lee","orcid":"0000-0002-4830-5781","position":9,"is_corresponding":false},{"id":71429,"name":"Gloria Suella Menchaca","orcid":null,"position":10,"is_corresponding":false},{"id":35838,"name":"Andreas Pfenning","orcid":"0000-0002-7390-5041","position":11,"is_corresponding":false},{"id":14693,"name":"Sharon L. R. Kardia","orcid":"0000-0002-9853-3379","position":12,"is_corresponding":false},{"id":11618,"name":"Li-Huei Tsai","orcid":"0000-0003-1262-0592","position":13,"is_corresponding":false},{"id":16444,"name":"Gwyneth M. Welch","orcid":"0000-0003-1635-1190","position":0,"is_corresponding":true}],"reference_count":94,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}