{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:19:59Z","timestamp":1787026799828,"version":"build-2736575974"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T00:00:00Z","timestamp":1616630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>\n                    <jats:bold>Background:<\/jats:bold>\n                    Neurotoxicity induced by the amyloid beta (A\u03b2) peptide is one of the most important pathological mechanisms of Alzheimer's disease (AD). Activation of the adaptive IRE1\u03b1-XBP1 pathway contributes to the pathogenesis of AD, making it a potential target for AD therapeutics. However, the mechanism of IRE1\u03b1-XBP1 pathway involvement in AD is unclear. We, therefore, investigated the effect of the IRE1\u03b1-XBP1 axis in an\n                    <jats:italic>in vitro<\/jats:italic>\n                    AD model and explored its potential mechanism.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods:<\/jats:bold>\n                    The human neuroblastoma cell line, SH-SY5Y, was used. Cells were treated with A\u03b225\u201335, with or without 4\u03bc8c, an inhibitor of IRE1\u03b1. Cells were collected and analyzed by Western blotting, quantitative real-time PCR, electron microscopy, fluorescence microscopy, calcium imaging, and other biochemical assays.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results:<\/jats:bold>\n                    A\u03b2-exposed SH-SY5Y cells showed an increased expression of XBP1s and p-IRE1\u03b1. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and calcium imaging analysis showed that the IRE1\u03b1 inhibitor, 4\u03bc8c, reduced A\u03b2-induced cytotoxicity. Increased levels of ATP, restoration of mitochondrial membrane potential, and decreased production of mitochondrial reactive oxygen species after A\u03b2 treatment in the presence of 4\u03bc8c showed that inhibiting the IRE1\u03b1-XBP1 axis effectively mitigated A\u03b2-induced mitochondrial dysfunction in SH-SY5Y cells. Furthermore, A\u03b2 treatment increased the expression and interaction of IP3R, Grp75, and vdac1 and led to an increased endoplasmic reticulum (ER)\u2013mitochondria association, malfunction of mitochondria-associated ER-membranes (MAMs), and mitochondrial dysfunction. These deficits were rescued by inhibiting the IRE1\u03b1-XBP1 axis.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusion:<\/jats:bold>\n                    These findings demonstrate that A\u03b2 peptide induces the activation of the IRE1\u03b1-XBP1 axis, which may aggravate cytotoxicity and mitochondrial impairment in SH-SY5Y cells by targeting MAMs. Inhibition of the IRE1\u03b1-XBP1 axis provides the protection against A\u03b2-induced injury in SH-SY5Y cells and may, therefore, be a new treatment strategy.\n                  <\/jats:p>","DOI":"10.3389\/fncel.2021.614556","type":"journal-article","created":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T01:39:54Z","timestamp":1616636394000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["IRE1\u03b1-XBP1 Affects the Mitochondrial Function of A\u03b225\u201335-Treated SH-SY5Y Cells by Regulating Mitochondria-Associated Endoplasmic Reticulum Membranes"],"prefix":"10.3389","volume":"15","author":[{"given":"Bingcong","family":"Chu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maoyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rulong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suqin","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianzhong","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/s41419-017-0215-0","article-title":"A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease","volume":"9","author":"Area-Gomez","year":"2018","journal-title":"Cell Death Dis"},{"key":"B2","doi-asserted-by":"publisher","first-page":"4106","DOI":"10.1038\/emboj.2012.202","article-title":"Upregulated function of mitochondria-associated ER membranes in Alzheimer disease","volume":"31","author":"Area-Gomez","year":"2012","journal-title":"EMBO J"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1038\/nm.3735","article-title":"Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity","volume":"20","author":"Arruda","year":"2014","journal-title":"Nat. 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