{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:01:09Z","timestamp":1790704869816,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,24]]},"group-title":"Neuroscience","reference-count":106,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["RF1AG091371"],"award-info":[{"award-number":["RF1AG091371"]}]},{"name":"National Institutes of Health","award":["R01AA028947"],"award-info":[{"award-number":["R01AA028947"]}]},{"name":"National Institutes of Health","award":["R35GM118337"],"award-info":[{"award-number":["R35GM118337"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Extracellular cold-inducible RNA-binding protein (eCIRP) is a crucial neuroinflammatory mediator in ischemic stroke and alcohol-induced memory impairment. We have recently discovered that amyloid-\u03b2 causes microglia to release eCIRP, prompting us to investigate its role in Alzheimer\u2019s disease (AD). We found that eCIRP levels were significantly elevated in the cerebrospinal fluid (CSF) and plasma of AD patients compared with age-matched non-AD subjects, as well as in hTau.P301S mice (a model of AD tauopathy) compared with wildtype control mice. Plasma eCIRP strongly correlated with astrocyte activation marker glial fibrillary acidic protein (GFAP) in AD patients. eCIRP induced neurotoxic astrocyte-specific genes and astrocyte release of proinflammatory and neurotoxic factors in C8-D1a cells, primary murine astrocytes and intracerebroventricular eCIRP-injected C57BL\/6 mice brains. In particular, eCIRP increased Complement 3, an astrocytic marker involved in neuroinflammation-associated neurodegeneration. Primary astrocytes from TREM-1 knockout mice were resistant to eCIRP induction of neurotoxic astrocytes. eCIRP increased TREM-1 expression and activation in astrocytes. Blocking CIRP\/TREM-1 interaction using peptide M3, effectively attenuated eCIRP\u2019s induction of neurotoxic astrocytes. Thus, eCIRP strongly correlates with astrocyte reactivity in AD patients, and eCIRP induces neurotoxic astrocytes via TREM-1, which is attenuated by M3, suggesting a novel therapeutic opportunity to target neurotoxic astrocytes in AD.<\/jats:p>","DOI":"10.64898\/2026.09.18.752724","type":"posted-content","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:10:12Z","timestamp":1790309412000},"source":"Crossref","is-referenced-by-count":0,"title":["Extracellular CIRP induces neurotoxic astrocytes via TREM-1 in Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4745-0220","authenticated-orcid":false,"given":"Archna","family":"Sharma","sequence":"first","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, USA"},{"name":"Department of Molecular Medicine, Zucker School of Medicine at Hofstra\/Northwell, Manhasset, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3237-9724","authenticated-orcid":false,"given":"Dilara","family":"Aylar","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitriy","family":"Lapin","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, USA"},{"name":"Department of Molecular Medicine, Zucker School of Medicine at Hofstra\/Northwell, Manhasset, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8983-1497","authenticated-orcid":false,"given":"Philippe","family":"Marambaud","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Zucker School of Medicine at Hofstra\/Northwell, Manhasset, NY, USA"},{"name":"Litwin-Zucker Center for Alzheimer\u2019s Disease Research, The Feinstein Institutes for Medical Research, Manhasset, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1557-0394","authenticated-orcid":false,"given":"Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, USA"},{"name":"Department of Molecular Medicine, Zucker School of Medicine at Hofstra\/Northwell, Manhasset, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092910502634000_2026.09.18.752724v1.1","unstructured":"Alzheimer\u2019s Association. 2026 Alzheimer\u2019s disease facts and figures. 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