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Cytoplasmic dsRNA (cdsRNA) triggers a type-I interferon response in human neural cells, leading to their death, and is found in neurons of\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    -ALS patients. Here, we report the spatial coincidence of cdsRNA and pTDP-43 inclusions in human postmortem tissue with Alzheimer\u2019s disease pathology, and upregulated interferon response genes in affected regions. CdsRNA also accumulates in a human TDP-43 G298S iPSC cortical neuronal model. We use cryptic exon detection as a proxy for TDP-43 mislocalization and demonstrate that FDA-approved JAK inhibitors baricitinib and ruxolitinib, which block interferon signaling, show protective effects only in brains with elevated cryptic exon expression. A CRISPR screen reveals\n                    <jats:italic>TYK2<\/jats:italic>\n                    as a top hit, and\n                    <jats:italic>TYK2<\/jats:italic>\n                    knockdown and the selective TYK2 inhibitor deucravacitinib rescue cdsRNA-induced toxicity. We find parallel neuroinflammatory mechanisms, dependent on TYK2 - a potential disease-modifying target - for TDP-43-associated Alzheimer\u2019s disease and\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    -ALS.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-70243-3","type":"journal-article","created":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T14:24:49Z","timestamp":1773498289000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TYK2 mediates neuroinflammation in Alzheimer\u2019s disease brains with TDP-43 pathology"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8154-4226","authenticated-orcid":false,"given":"Laura 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