{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:03:39Z","timestamp":1782281019886,"version":"3.54.5"},"posted":{"date-parts":[[2025,10,7]]},"group-title":"Cell Biology","reference-count":106,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH","award":["R01NS080967"],"award-info":[{"award-number":["R01NS080967"]}]},{"name":"NIH","award":["RF1\/R01AG069941"],"award-info":[{"award-number":["RF1\/R01AG069941"]}]},{"name":"NIH","award":["R21AG085473"],"award-info":[{"award-number":["R21AG085473"]}]},{"name":"CUIMC TIGER award"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Chronic stress, marked by prolonged elevation of glucocorticoid (GC) stress hormones, is a major risk factor for Alzheimer\u2019s disease (AD) and accelerates AD pathology in mouse models. A key mechanism contributing to AD progression is the release of small extracellular vesicles (sEVs) carrying pathogenic proteins (e.g., tau, amyloid-beta) between brain regions, but the role of GCs in sEV biogenesis and release is unknown. Using total internal reflection fluorescence (TIRF) microscopy and the pH-sensitive marker mCh-CD63-pHluorin to visualize sEV release, we show that GCs stimulate sEV secretion in a neuronal cell line. This process requires the GTPase Rab27a and the enzyme neutral sphingomyelinase 2 (nSMase2), which catalyzes ceramide production and drives sEV formation. We further demonstrate that GCs promote sEV release by activating nSMase2 downstream of mitochondrial reactive oxygen species production and opening of the mitochondrial permeability transition pore (mPTP). These findings link GC-induced mitochondrial damage, specifically mPTP opening, to nSMase2 activation and enhanced sEV release by neuronal cells.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:p>This study reveals a mechanism by which glucocorticoid stress hormones promote extracellular vesicle release from neuronal cells by activating the enzyme neutral sphingomyelinase 2. These findings provide a possible explanation for how stress accelerates the spread of Alzheimer\u2019s pathology in the brain.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"680983v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.07.680983","type":"posted-content","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T05:07:01Z","timestamp":1759900021000},"source":"Crossref","is-referenced-by-count":1,"title":["Glucocorticoids regulate small extracellular vesicle (sEV) release via activation of nSMase2"],"prefix":"10.64898","author":[{"given":"Mia","family":"Burke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4263-5576","authenticated-orcid":false,"given":"Clarissa","family":"Waites","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025101011401052000_2025.10.07.680983v1.1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-023-01308-4"},{"key":"2025101011401052000_2025.10.07.680983v1.2","doi-asserted-by":"publisher","DOI":"10.2174\/15672050113109990137"},{"key":"2025101011401052000_2025.10.07.680983v1.3","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.163.12.2164"},{"issue":"11","key":"2025101011401052000_2025.10.07.680983v1.4","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/j.tins.2024.08.015","article-title":"The multiple roles of chronic stress and glucocorticoids in Alzheimer\u2019s disease pathogenesis","volume":"47","year":"2024","journal-title":"Trends Neurosci"},{"key":"2025101011401052000_2025.10.07.680983v1.5","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2797-06.2006"},{"key":"2025101011401052000_2025.10.07.680983v1.6","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000264930.97061.82"},{"issue":"1","key":"2025101011401052000_2025.10.07.680983v1.7","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41419-024-06458-3","article-title":"Glucocorticoid stress hormones stimulate vesicle-free Tau secretion and spreading in the brain","volume":"15","year":"2024","journal-title":"Cell Death Dis"},{"issue":"1","key":"2025101011401052000_2025.10.07.680983v1.8","doi-asserted-by":"crossref","first-page":"4862","DOI":"10.1038\/s41467-021-25193-3","article-title":"Author Correction: Spread of pathological tau proteins through communicating neurons in human Alzheimer\u2019s disease","volume":"12","year":"2021","journal-title":"Nat Commun"},{"key":"2025101011401052000_2025.10.07.680983v1.9","doi-asserted-by":"crossref","unstructured":"Pignataro, A. and S. 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