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Normally, the innate immune system mounts a robust response to infectious stimuli. However, unintentional activation by host-derived factors, such as aggregated proteins associated with neurodegenerative disorders or by cytoplasmic genomic or mitochondrial DNA, can elicit aberrant immune responses. One such immune response is represented by the cytosolic GMP-AMP synthase\u2013stimulator of interferon genes (cGAS-STING) pathway. Using redox chemical biology and mass spectrometry approaches, we identified\n                  <jats:italic>S<\/jats:italic>\n                  -nitrosylation of STING cysteine 148 as a novel posttranslational redox modification underlying aberrant type 1 interferon signaling in Alzheimer\u2019s disease (AD). Critically, we observed\n                  <jats:italic>S<\/jats:italic>\n                  -nitrosylated STING (SNO-STING) in postmortem human AD brains, in hiPSC-derived microglia (hiMG) exposed to amyloid-\u03b2 (A\u03b2)\/\u03b1-synuclein (\u03b1Syn) aggregates, and in 5xFAD transgenic mice. Mechanistically, our findings reveal that STING\n                  <jats:italic>S<\/jats:italic>\n                  -nitrosylation is critical in initiating signaling cascades by promoting the formation of disulfide-bonded STING oligomers. This leads to neuroinflammation early in the course of disease\n                  <jats:italic>in vivo<\/jats:italic>\n                  in 5xFAD mice with consequent synaptic loss. Collectively, our research supports the role of SNO-STING in neuroinflammation associated with AD, and points to a novel druggable cysteine residue in STING to prevent this\n                  <jats:italic>S<\/jats:italic>\n                  -nitrosylation reaction with its inherent inflammatory response.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>\n                    <jats:italic>S<\/jats:italic>\n                    -Nitrosylation of STING triggers activation of cGAS-STING signaling in Alzheimer\u2019s disease brain and subserves a novel link between excessive nitrosative stress and dysregulated innate immunity, thus contributing to disease progression.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.08.674963","type":"posted-content","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T17:25:14Z","timestamp":1757438714000},"source":"Crossref","is-referenced-by-count":0,"title":["Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer\u2019s disease brain"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0451-0481","authenticated-orcid":false,"given":"Lauren N.","family":"Carnevale","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piu","family":"Banerjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jazmin","family":"Navarro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlene K","family":"Raspur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parth","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Schahrer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nhi","family":"Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolene K.","family":"Diedrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda J.","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"John R.","family":"Yates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart A.","family":"Lipton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025091112351134000_2025.09.08.674963v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23592"},{"key":"2025091112351134000_2025.09.08.674963v1.2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI133737"},{"key":"2025091112351134000_2025.09.08.674963v1.3","doi-asserted-by":"crossref","unstructured":"Hussain, B. et al. 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