{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:13:40Z","timestamp":1785413620804,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,17]]},"group-title":"Neuroscience","reference-count":68,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["EY028158"],"award-info":[{"award-number":["EY028158"]}],"id":[{"id":"https:\/\/ror.org\/03wkg3b53","id-type":"ROR","asserted-by":"publisher"}]},{"award":["EY032488"],"award-info":[{"award-number":["EY032488"]}],"id":[{"id":"https:\/\/ror.org\/03wkg3b53","id-type":"ROR","asserted-by":"publisher"}]},{"name":"James Fickel Alzheimer's disease research fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder characterized by \u03b2-amyloid (A\u03b2) accumulation and oxidative stress, with aging being its greatest risk factor. Age-related decline in antioxidant defenses, particularly glutathione (GSH), may increase neuronal vulnerability to A\u03b2-mediated toxicity; however, the mechanisms linking redox dysregulation to neuronal death remain incompletely understood. In this study, we investigated how impaired GSH homeostasis influences neuronal susceptibility to A\u03b2-associated injury. Human SH-SY5Y neuron-like cells were engineered to express either wild-type APP\n                  <jats:sub>695<\/jats:sub>\n                  or the familial AD-associated APP\n                  <jats:sub>Swe\/Ind<\/jats:sub>\n                  mutant, and intracellular GSH depletion was induced using both pharmacological and genetic approaches. GSH depletion markedly sensitized APP\n                  <jats:sub>Swe\/Ind<\/jats:sub>\n                  -expressing cells to cell death, accompanied by increased plasma membrane lipid peroxidation, elevated malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels, and enhanced lactate dehydrogenase (LDH) release. This cell death was not prevented by the pan-caspase inhibitor Z-VAD-FMK but was effectively rescued by the ferroptosis inhibitors ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1), indicating a ferroptotic mechanism. Similar ferroptotic responses were observed when A\u03b2 oligomers were combined with intracellular GSH depletion. Mechanistically, A\u03b2 and GSH depletion synergistically increased transferrin receptor-1 expression and intracellular iron levels while markedly suppressing glutathione peroxidase 4 (GPX4), a central regulator of ferroptosis. Importantly, inhibition of autophagy with bafilomycin A1 restored GPX4 expression and rescued cells from ferroptotic death, suggesting that autophagy-mediated GPX4 degradation contributes to this process. Collectively, our findings demonstrate that GSH dysregulation synergizes with A\u03b2 to induce lipid peroxidation and ferroptosis in neuron-like cells. These results identify impaired redox homeostasis as a critical driver of neuronal vulnerability in AD and suggest that preserving GSH levels or targeting ferroptotic pathways may offer promising therapeutic strategies for neurodegeneration.\n                <\/jats:p>","DOI":"10.64898\/2026.04.15.718809","type":"posted-content","created":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T07:30:18Z","timestamp":1776497418000},"source":"Crossref","is-referenced-by-count":0,"title":["\u03b2-Amyloid and Glutathione Dysregulation Cooperatively Drive Lipid Peroxidation and Ferroptosis in Neuron-Like Cells"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5977-6028","authenticated-orcid":false,"given":"Kazi Rafsan","family":"Radeen","sequence":"first","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caili","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongbo","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingjun","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026042111201095000_2026.04.15.718809v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12213"},{"key":"2026042111201095000_2026.04.15.718809v1.2","doi-asserted-by":"crossref","unstructured":"Huang, X . (2023) A Concise Review on Oxidative Stress-Mediated Ferroptosis and Cuproptosis in Alzheimer\u2019s Disease, Cells. 12.","DOI":"10.3390\/cells12101369"},{"key":"2026042111201095000_2026.04.15.718809v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2015.04.005"},{"key":"2026042111201095000_2026.04.15.718809v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0244-7"},{"key":"2026042111201095000_2026.04.15.718809v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.039"},{"key":"2026042111201095000_2026.04.15.718809v1.6","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1354.065"},{"key":"2026042111201095000_2026.04.15.718809v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2022.101619"},{"key":"2026042111201095000_2026.04.15.718809v1.8","doi-asserted-by":"crossref","unstructured":"Trofin, D. M. , Sardaru, D. P. , Trofin, D. , Onu, I. , Tutu, A. , Onu, A. , Onita, C. , Galaction, A. I. & Matei, D. V . (2025) Oxidative Stress in Brain Function, Antioxidants (Basel ). 14.","DOI":"10.3390\/antiox14030297"},{"key":"2026042111201095000_2026.04.15.718809v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-019-0132-6"},{"key":"2026042111201095000_2026.04.15.718809v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.104795"},{"key":"2026042111201095000_2026.04.15.718809v1.11","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201606210"},{"key":"2026042111201095000_2026.04.15.718809v1.12","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072994"},{"key":"2026042111201095000_2026.04.15.718809v1.13","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.04426.x"},{"key":"2026042111201095000_2026.04.15.718809v1.14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2007.05072.x"},{"key":"2026042111201095000_2026.04.15.718809v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2009.06.012"},{"key":"2026042111201095000_2026.04.15.718809v1.16","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1297.059"},{"key":"2026042111201095000_2026.04.15.718809v1.17","doi-asserted-by":"publisher","DOI":"10.1002\/nbm.1646"},{"key":"2026042111201095000_2026.04.15.718809v1.18","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/nbm.1583","article-title":"Noninvasive quantification of T2 and concentrations of ascorbate and glutathione in the human brain from the same double-edited spectra","volume":"24","year":"2011","journal-title":"NMR Biomed"},{"key":"2026042111201095000_2026.04.15.718809v1.19","doi-asserted-by":"publisher","DOI":"10.1155\/S1110724302203010"},{"key":"2026042111201095000_2026.04.15.718809v1.20","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1017\/S0317167100012609","article-title":"Untangling the vascular web from Alzheimer disease and oxidative stress","volume":"39","year":"2012","journal-title":"Can J Neurol Sci"},{"key":"2026042111201095000_2026.04.15.718809v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2013.01.005"},{"key":"2026042111201095000_2026.04.15.718809v1.22","first-page":"3751","article-title":"Multiple neurotransmitter synthesis by human neuroblastoma cell lines and clones","volume":"38","year":"1978","journal-title":"Cancer Res"},{"key":"2026042111201095000_2026.04.15.718809v1.23","first-page":"741","article-title":"Coordinate morphological and biochemical interconversion of human neuroblastoma cells","volume":"71","year":"1983","journal-title":"J Natl Cancer Inst"},{"key":"2026042111201095000_2026.04.15.718809v1.24","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4701-07.2007"},{"key":"2026042111201095000_2026.04.15.718809v1.25","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/s41419-021-03683-y","article-title":"Cellular FLICE-like inhibitory protein (cFLIP) critically maintains apoptotic resistance in human lens epithelial cells","volume":"12","year":"2021","journal-title":"Cell Death Dis"},{"key":"2026042111201095000_2026.04.15.718809v1.26","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adl1088"},{"key":"2026042111201095000_2026.04.15.718809v1.27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M210207200"},{"key":"2026042111201095000_2026.04.15.718809v1.28","doi-asserted-by":"crossref","first-page":"e2407842121","DOI":"10.1073\/pnas.2407842121","article-title":"Deficiency in glutathione peroxidase 4 (GPX4) results in abnormal lens development and newborn cataract","volume":"121","year":"2024","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026042111201095000_2026.04.15.718809v1.29","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.freeradbiomed.2021.02.010","article-title":"Aging lens epithelium is susceptible to ferroptosis","volume":"167","year":"2021","journal-title":"Free Radic Biol Med"},{"key":"2026042111201095000_2026.04.15.718809v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.378"},{"key":"2026042111201095000_2026.04.15.718809v1.31","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awq386"},{"key":"2026042111201095000_2026.04.15.718809v1.32","doi-asserted-by":"crossref","unstructured":"Li, B. , Hai, E. , Song, Y. & Zhang, J. (2025) Autophagic Degradation of GPX4 Mediates Ferroptosis During Sheep Sperm Cryopreservation, Vet Sci. 12.","DOI":"10.3390\/vetsci12050490"},{"key":"2026042111201095000_2026.04.15.718809v1.33","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.redox.2016.11.004","article-title":"Inhibition of autophagy with bafilomycin and chloroquine decreases mitochondrial quality and bioenergetic function in primary neurons","volume":"11","year":"2017","journal-title":"Redox Biol"},{"key":"2026042111201095000_2026.04.15.718809v1.34","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/s13073-015-0232-5","article-title":"The age factor in Alzheimer\u2019s disease","volume":"7","year":"2015","journal-title":"Genome Med"},{"key":"2026042111201095000_2026.04.15.718809v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.05.011"},{"key":"2026042111201095000_2026.04.15.718809v1.36","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.2174\/1389450110607011505","article-title":"The deficit in low molecular weight thiols as a target for antiageing therapy","volume":"7","year":"2006","journal-title":"Curr Drug Targets"},{"key":"2026042111201095000_2026.04.15.718809v1.37","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1093\/gerona\/61.10.1030","article-title":"Age-related influence on thiol, disulfide, and protein-mixed disulfide levels in human plasma","volume":"61","year":"2006","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"2026042111201095000_2026.04.15.718809v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2005.02.005"},{"key":"2026042111201095000_2026.04.15.718809v1.39","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.110.003483"},{"key":"2026042111201095000_2026.04.15.718809v1.40","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2009.033"},{"key":"2026042111201095000_2026.04.15.718809v1.41","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1089\/ars.2012.4996","article-title":"Functional consequences of age-dependent changes in glutathione status in the brain","volume":"19","year":"2013","journal-title":"Antioxid Redox Signal"},{"key":"2026042111201095000_2026.04.15.718809v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2016.12.022"},{"key":"2026042111201095000_2026.04.15.718809v1.43","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1093\/hmg\/ddx040","article-title":"Gclc deficiency in mouse CNS causes mitochondrial damage and neurodegeneration","volume":"26","year":"2017","journal-title":"Hum Mol Genet"},{"key":"2026042111201095000_2026.04.15.718809v1.44","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.redox.2018.08.003","article-title":"Hippocampal neurons require a large pool of glutathione to sustain dendrite integrity and cognitive function","volume":"19","year":"2018","journal-title":"Redox Biol"},{"key":"2026042111201095000_2026.04.15.718809v1.45","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2298-2"},{"key":"2026042111201095000_2026.04.15.718809v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2023.05.003"},{"key":"2026042111201095000_2026.04.15.718809v1.47","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1016\/j.chembiol.2020.10.010","article-title":"Using the Oxytosis\/Ferroptosis Pathway to Understand and Treat Age-Associated Neurodegenerative Diseases","volume":"27","year":"2020","journal-title":"Cell Chem Biol"},{"key":"2026042111201095000_2026.04.15.718809v1.48","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1007\/s00702-004-0255-3","article-title":"Oxidative stress potentiates BACE1 gene expression and Abeta generation","volume":"112","year":"2005","journal-title":"J Neural Transm (Vienna"},{"key":"2026042111201095000_2026.04.15.718809v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.042"},{"key":"2026042111201095000_2026.04.15.718809v1.50","doi-asserted-by":"crossref","first-page":"101082","DOI":"10.1016\/j.redox.2018.101082","article-title":"Lipids and lipoxidation in human brain aging. Mitochondrial ATP-synthase as a key lipoxidation target","volume":"23","year":"2019","journal-title":"Redox Biol"},{"key":"2026042111201095000_2026.04.15.718809v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-07152-0"},{"key":"2026042111201095000_2026.04.15.718809v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2012.01.003"},{"key":"2026042111201095000_2026.04.15.718809v1.53","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1039\/C7MT00066A","article-title":"Cellular copper homeostasis: current concepts on its interplay with glutathione homeostasis and its implication in physiology and human diseases","volume":"9","year":"2017","journal-title":"Metallomics"},{"key":"2026042111201095000_2026.04.15.718809v1.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtemb.2013.08.001"},{"key":"2026042111201095000_2026.04.15.718809v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(14)70117-6"},{"key":"2026042111201095000_2026.04.15.718809v1.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2008.03.012"},{"key":"2026042111201095000_2026.04.15.718809v1.57","doi-asserted-by":"crossref","first-page":"13704","DOI":"10.1016\/S0021-9258(18)33504-X","article-title":"Mechanism of action, metabolism, and toxicity of buthionine sulfoximine and its higher homologs, potent inhibitors of glutathione synthesis","volume":"257","year":"1982","journal-title":"J Biol Chem"},{"key":"2026042111201095000_2026.04.15.718809v1.58","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaf7694"},{"key":"2026042111201095000_2026.04.15.718809v1.59","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.02.049"},{"key":"2026042111201095000_2026.04.15.718809v1.60","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.18.9866"},{"key":"2026042111201095000_2026.04.15.718809v1.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.021"},{"key":"2026042111201095000_2026.04.15.718809v1.62","doi-asserted-by":"crossref","first-page":"101494","DOI":"10.1016\/j.redox.2020.101494","article-title":"Iron dyshomeostasis, lipid peroxidation and perturbed expression of cystine\/glutamate antiporter in Alzheimer\u2019s disease: Evidence of ferroptosis","volume":"32","year":"2020","journal-title":"Redox Biol"},{"key":"2026042111201095000_2026.04.15.718809v1.63","doi-asserted-by":"crossref","first-page":"287","DOI":"10.3233\/JAD-2011-101005","article-title":"Region- and age-specific changes in glutamate transport in the AbetaPP23 mouse model for Alzheimer\u2019s disease","volume":"24","year":"2011","journal-title":"J Alzheimers Dis"},{"key":"2026042111201095000_2026.04.15.718809v1.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2012.11.020"},{"key":"2026042111201095000_2026.04.15.718809v1.65","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3181cb5af4"},{"key":"2026042111201095000_2026.04.15.718809v1.66","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.redox.2017.01.021","article-title":"Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration","volume":"12","year":"2017","journal-title":"Redox Biol"},{"key":"2026042111201095000_2026.04.15.718809v1.67","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1819728116"},{"key":"2026042111201095000_2026.04.15.718809v1.68","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/s41419-023-05978-8","article-title":"Autophagy mediates an amplification loop during ferroptosis","volume":"14","year":"2023","journal-title":"Cell Death Dis"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.04.15.718809","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T18:20:22Z","timestamp":1776795622000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.04.15.718809"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,17]]},"references-count":68,"URL":"https:\/\/doi.org\/10.64898\/2026.04.15.718809","relation":{},"subject":[],"published":{"date-parts":[[2026,4,17]]},"subtype":"preprint"}}