{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T07:27:54Z","timestamp":1786433274078,"version":"build-2736575974"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is increasingly recognized as a disorder of proteostatic failure characterized by progressive disruption of neuronal protein quality control, culminating in amyloid-\u03b2 (A\u03b2) accumulation and synaptic dysfunction. Chronic activation of the endoplasmic reticulum (ER) stress response represents one of the earliest molecular alterations detected in vulnerable brain regions and correlates with Braak progression before overt plaque deposition. Inositol-requiring enzyme 1 alpha (IRE1\u03b1), the most evolutionarily conserved sensor of the unfolded protein response (UPR), functions as a signaling rheostat within this network through its divergent downstream outputs. Under moderate proteotoxic stress, adaptive IRE1\u03b1- X-box binding protein 1 (XBP1) signaling supports ER proteostasis, preserves amyloid precursor protein (APP) quality control, and favors non-amyloidogenic \u03b1-secretase processing. Persistent ER stress, however, drives sustained IRE1\u03b1 hyperactivation and engages regulated IRE1\u03b1-dependent decay (RIDD), which destabilizes microRNA (miRNA) networks that normally constrain beta-site APP-cleaving enzyme 1 (BACE1) expression, thereby favoring amyloidogenic APP processing. Accumulating evidence suggests that aging progressively compromises ER proteostatic capacity, thereby redirecting IRE1\u03b1 signaling away from adaptive XBP1s-mediated responses toward a predominantly RIDD-driven state. This shift may reinforce a self-sustaining cycle in which accumulating A\u03b2 further amplifies ER stress signaling. Here, we examine how dynamic changes in IRE1\u03b1 signaling bias contribute to amyloidogenic progression in AD and consider whether selective modulation of adaptive versus maladaptive IRE1\u03b1 outputs may offer stage-dependent therapeutic benefit.<\/jats:p>","DOI":"10.3389\/fmolb.2026.1903849","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T06:31:04Z","timestamp":1786429864000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Adaptive-to-maladaptive IRE1\u03b1 signaling as a driver of amyloidogenic APP processing in Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"13","author":[{"given":"Daniel","family":"Wang","sequence":"first","affiliation":[{"name":"Bullis School","place":["Potomac, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinan","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Cancer Institute, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology","place":["Luoyang, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.3389\/fmolb.2019.00011","article-title":"Structure and molecular mechanism of ER stress signaling by the unfolded protein response signal activator IRE1","volume":"6","author":"Adams","year":"2019","journal-title":"Front. Mol. Biosci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1038\/s41419-022-05153-5","article-title":"ER stress and UPR in Alzheimer\u2019s disease: mechanisms, pathogenesis, treatments","volume":"13","author":"Ajoolabady","year":"2022","journal-title":"Cell Death Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"4421","DOI":"10.1523\/jneurosci.19-11-04421.1999","article-title":"Role of phosphorylation of Alzheimer's amyloid precursor protein during neuronal differentiation","volume":"19","author":"Ando","year":"1999","journal-title":"J. Neurosci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2919","DOI":"10.1038\/s41380-019-0410-8","article-title":"Familial Alzheimer\u2019s disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta","volume":"25","author":"Arber","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"B5","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":"B6","doi-asserted-by":"publisher","first-page":"e74342","DOI":"10.7554\/elife.74342","article-title":"Endoplasmic reticulum stress activates human IRE1\u03b1 through reversible assembly of inactive dimers into small oligomers","volume":"11","author":"Belyy","year":"2022","journal-title":"Elife"},{"key":"B7","doi-asserted-by":"publisher","first-page":"2314","DOI":"10.1038\/s41467-023-37437-5","article-title":"Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers","volume":"14","author":"Brase","year":"2023","journal-title":"Nat. Commun."},{"key":"B8","doi-asserted-by":"publisher","first-page":"3258","DOI":"10.1007\/s12035-020-01950-1","article-title":"Synaptic loss, ER stress and neuro-inflammation emerge late in the lateral temporal cortex and associate with progressive tau pathology in Alzheimer\u2019s disease","volume":"57","author":"Buchanan","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e111952","DOI":"10.15252\/embj.2022111952","article-title":"Unfolded protein response IRE1\/XBP1 signaling is required for healthy Mammalian brain aging","volume":"41","author":"Cabral-Miranda","year":"2022","journal-title":"Embo J."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2146","DOI":"10.1038\/s41467-020-16074-2","article-title":"Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer\u2019s disease","volume":"11","author":"Calvo-Rodriguez","year":"2020","journal-title":"Nat. Commun."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2144","DOI":"10.1093\/hmg\/ddr100","article-title":"The ER stress factor XBP1s prevents amyloid-beta neurotoxicity","volume":"20","author":"Casas-Tinto","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"614556","DOI":"10.3389\/fncel.2021.614556","article-title":"IRE1\u03b1-XBP1 affects the mitochondrial function of A\u03b225-35-Treated SH-SY5Y cells by regulating mitochondria-associated endoplasmic reticulum membranes","volume":"15","author":"Chu","year":"2021","journal-title":"Front. Cell Neurosci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"185","DOI":"10.3389\/fnins.2017.00185","article-title":"Protein quality control by molecular chaperones in neurodegeneration","volume":"11","author":"Ciechanover","year":"2017","journal-title":"Front. Neurosci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1038\/s41380-022-01926-8","article-title":"Golgi apparatus, endoplasmic reticulum and mitochondrial function implicated in Alzheimer\u2019s disease through polygenic risk and RNA sequencing","volume":"28","author":"Crawford","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"B15","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1007\/s00401-017-1694-x","article-title":"IRE1 signaling exacerbates Alzheimer\u2019s disease pathogenesis","volume":"134","author":"Duran-Aniotz","year":"2017","journal-title":"Acta Neuropathol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2240","DOI":"10.1016\/j.ymthe.2023.03.028","article-title":"The unfolded protein response transcription factor XBP1s ameliorates Alzheimer\u2019s disease by improving synaptic function and proteostasis","volume":"31","author":"Duran-Aniotz","year":"2023","journal-title":"Mol. Ther."},{"key":"B17","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.neurobiolaging.2017.09.012","article-title":"A decay of the adaptive capacity of the unfolded protein response exacerbates Alzheimer\u2019s disease","volume":"63","author":"Gerakis","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"B18","doi-asserted-by":"publisher","first-page":"37436","DOI":"10.1038\/srep37436","article-title":"A\u03b242 oligomers modulate \u03b2-secretase through an XBP-1s-dependent pathway involving HRD1","volume":"6","author":"Gerakis","year":"2016","journal-title":"Sci. Rep."},{"key":"B19","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1016\/j.cell.2014.07.002","article-title":"Allosteric inhibition of the IRE1\u03b1 RNase preserves cell viability and function during endoplasmic reticulum stress","volume":"158","author":"Ghosh","year":"2014","journal-title":"Cell"},{"key":"B20","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1212\/WNL.0000000000001702","article-title":"Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease","volume":"85","author":"Goetzl","year":"2015","journal-title":"Neurology"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.20390","article-title":"Experimental reconstitution of chronic ER stress in the liver reveals feedback suppression of BiP mRNA expression","volume":"5","author":"Gomez","year":"2016","journal-title":"Elife"},{"key":"B22","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1038\/s41420-021-00518-9","article-title":"IRE1\u03b1 RIDD activity induced under ER stress drives neuronal death by the degradation of 14-3-3 \u03b8 mRNA in cortical neurons during glucose deprivation","volume":"7","author":"G\u00f3mora-Garc\u00eda","year":"2021","journal-title":"Cell Death Discov."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1038\/s41589-020-0584-z","article-title":"Pharmacologic IRE1\/XBP1s activation confers targeted ER proteostasis reprogramming","volume":"16","author":"Grandjean","year":"2020","journal-title":"Nat. Chem. Biol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"20230017","DOI":"10.59368\/agingbio.20230017","article-title":"Early and late chaperone intervention therapy boosts XBP1s and ADAM10, restores proteostasis, and rescues learning in Alzheimer's disease mice","volume":"1","author":"Hafycz","year":"2023","journal-title":"Aging Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/j.biopsych.2020.02.001","article-title":"The \u03b2-Secretase BACE1 in Alzheimer's disease","volume":"89","author":"Hampel","year":"2021","journal-title":"Biol. Psychiatry"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.180024","article-title":"Critical review: involvement of endoplasmic reticulum stress in the aetiology of Alzheimer's disease","volume":"8","author":"Hashimoto","year":"2018","journal-title":"Open Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"6415","DOI":"10.1073\/pnas.0710263105","article-title":"Loss of microRNA cluster miR-29a\/b-1 in sporadic Alzheimer\u2019s disease correlates with increased BACE1\/beta-secretase expression","volume":"105","author":"H\u00e9bert","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B28","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.molcel.2017.06.017","article-title":"The unfolded protein response and cell fate control","volume":"69","author":"Hetz","year":"2018","journal-title":"Mol. Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"2294","DOI":"10.1101\/gad.1830709","article-title":"XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy","volume":"23","author":"Hetz","year":"2009","journal-title":"Genes Dev."},{"key":"B30","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/s41580-020-0250-z","article-title":"Mechanisms, regulation and functions of the unfolded protein response","volume":"21","author":"Hetz","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1083\/jcb.200903014","article-title":"Regulated Ire1-dependent decay of messenger RNAs in Mammalian cells","volume":"186","author":"Hollien","year":"2009","journal-title":"J. Cell Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.2353\/ajpath.2009.080814","article-title":"The unfolded protein response is activated in pretangle neurons in Alzheimer\u2019s disease hippocampus","volume":"174","author":"Hoozemans","year":"2009","journal-title":"Am. J. Pathol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"4372","DOI":"10.1093\/brain\/awaf222","article-title":"Early proteasome downregulation and dysfunction drive proteostasis failure in Alzheimer\u2019s disease","volume":"148","author":"Jiang","year":"2025","journal-title":"Brain"},{"key":"B34","doi-asserted-by":"publisher","first-page":"3106","DOI":"10.1021\/acschembio.0c00802","article-title":"Kinase photoaffinity labeling reveals low selectivity profile of the IRE1 targeting Imidazopyrazine-Based KIRA6 inhibitor","volume":"15","author":"Korovesis","year":"2020","journal-title":"ACS Chem. Biol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"7310","DOI":"10.1038\/s41467-021-27597-7","article-title":"Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1\u03b1","volume":"12","author":"Le Thomas","year":"2021","journal-title":"Nat. Commun."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2140427","DOI":"10.1155\/2019\/2140427","article-title":"Upregulation of miR-34a by inhibition of IRE1\u03b1 has protective effect against A\u03b2-Induced injury in SH-SY5Y cells by targeting Caspase-2","volume":"2019","author":"Li","year":"2019","journal-title":"Oxid. Med. Cell Longev."},{"key":"B37","doi-asserted-by":"publisher","first-page":"108563","DOI":"10.1016\/j.celrep.2020.108563","article-title":"A molecular mechanism for turning off IRE1\u03b1 signaling during endoplasmic reticulum stress","volume":"33","author":"Li","year":"2020","journal-title":"Cell Rep."},{"key":"B38","doi-asserted-by":"publisher","first-page":"937486","DOI":"10.3389\/fnagi.2022.937486","article-title":"Global, regional, and national burden of Alzheimer\u2019s disease and other dementias, 1990-2019","volume":"14","author":"Li","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"105719","DOI":"10.1016\/j.jbc.2024.105719","article-title":"RACK1 and IRE1 participate in the translational quality control of amyloid precursor protein in Drosophila models of Alzheimer\u2019s disease","volume":"300","author":"Li","year":"2024","journal-title":"J. Biol. Chem."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1894","DOI":"10.1021\/acschemneuro.0c00808","article-title":"Berberine improves behavioral and cognitive deficits in a mouse model of Alzheimer's disease via regulation of \u03b2-Amyloid production and endoplasmic reticulum stress","volume":"12","author":"Liang","year":"2021","journal-title":"ACS Chem. Neurosci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1038\/s41419-019-1523-3","article-title":"The unfolded protein response modulators GSK2606414 and KIRA6 are potent KIT inhibitors","volume":"10","author":"Mahameed","year":"2019","journal-title":"Cell Death Dis."},{"key":"B42","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.neurobiolaging.2017.08.012","article-title":"Amyloid-\u03b242 clearance and neuroprotection mediated by X-box binding protein 1 signaling decline with aging in the Drosophila brain","volume":"60","author":"Marcora","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"B43","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.tibs.2014.02.008","article-title":"Getting RIDD of RNA: IRE1 in cell fate regulation","volume":"39","author":"Maurel","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1186\/s40478-019-0857-5","article-title":"Kinesin light chain-1 serine-460 phosphorylation is altered in Alzheimer\u2019s disease and regulates axonal transport and processing of the amyloid precursor protein","volume":"7","author":"M\u00f3rotz","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"B45","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.arr.2009.03.001","article-title":"ER and aging-protein folding and the ER stress response","volume":"8","author":"Naidoo","year":"2009","journal-title":"Ageing Res. Rev."},{"key":"B46","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1007\/s12035-012-8256-y","article-title":"TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid-\u03b2 deposition in APP\/PS1 mice","volume":"45","author":"Nunes","year":"2012","journal-title":"Mol. Neurobiol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"9679","DOI":"10.1074\/jbc.RA119.008263","article-title":"Pathogenic tau does not drive activation of the unfolded protein response","volume":"294","author":"Pitera","year":"2019","journal-title":"J. Biol. Chem."},{"key":"B48","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s12865-018-0283-7","article-title":"Treatment of established TH2 cells with 4\u03bc8c, an inhibitor of IRE1\u03b1, blocks IL-5 but not IL-4 secretion","volume":"20","author":"Poe","year":"2019","journal-title":"BMC Immunol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1096\/fj.13-234864","article-title":"Unfolded protein response signaling by transcription factor XBP-1 regulates ADAM10 and is affected in Alzheimer\u2019s disease","volume":"28","author":"Reinhardt","year":"2014","journal-title":"Faseb J."},{"key":"B50","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1038\/s41418-021-00853-5","article-title":"Stress-induced inflammation evoked by immunogenic cell death is blunted by the IRE1\u03b1 kinase inhibitor KIRA6 through HSP60 targeting","volume":"29","author":"Rufo","year":"2022","journal-title":"Cell Death Differ."},{"key":"B51","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/1742-2094-6-41","article-title":"ER stress in Alzheimer\u2019s disease: a novel neuronal trigger for inflammation and Alzheimer\u2019s pathology","volume":"6","author":"Salminen","year":"2009","journal-title":"J. Neuroinflammation"},{"key":"B52","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1007\/s00401-015-1462-8","article-title":"The unfolded protein response in neurodegenerative diseases: a neuropathological perspective","volume":"130","author":"Scheper","year":"2015","journal-title":"Acta Neuropathol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1001\/jama.2023.13239","article-title":"Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial","volume":"330","author":"Sims","year":"2023","journal-title":"Jama"},{"key":"B54","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1056\/nejmoa2212948","article-title":"Lecanemab in early Alzheimer\u2019s disease","volume":"388","author":"van Dyck","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"B55","doi-asserted-by":"publisher","first-page":"2245","DOI":"10.1093\/hmg\/dds040","article-title":"Targeting the UPR transcription factor XBP1 protects against Huntington\u2019s disease through the regulation of FoxO1 and autophagy","volume":"21","author":"Vidal","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"B56","doi-asserted-by":"publisher","first-page":"4628","DOI":"10.1073\/pnas.1217611110","article-title":"Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains","volume":"110","author":"Volmer","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B57","doi-asserted-by":"publisher","first-page":"4443","DOI":"10.1038\/s41467-019-12070-3","article-title":"Constitutive XBP-1s-mediated activation of the endoplasmic reticulum unfolded protein response protects against pathological tau","volume":"10","author":"Waldherr","year":"2019","journal-title":"Nat. Commun."},{"key":"B58","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1038\/s42003-024-06570-2","article-title":"Endoplasmic reticulum unfolded protein response transcriptional targets of XBP-1s mediate rescue from tauopathy","volume":"7","author":"Waldherr","year":"2024","journal-title":"Commun. Biol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1523\/JNEUROSCI.5065-07.2008","article-title":"The expression of microRNA miR-107 decreases early in Alzheimer\u2019s disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1","volume":"28","author":"Wang","year":"2008","journal-title":"J. Neurosci."},{"key":"B60","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/s13024-024-00771-3","article-title":"Increased expression of mesencephalic astrocyte-derived neurotrophic factor (MANF) contributes to synapse loss in Alzheimer's disease","volume":"19","author":"Zhang","year":"2024","journal-title":"Mol. Neurodegener."}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1903849\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T06:31:05Z","timestamp":1786429865000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1903849\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":60,"alternative-id":["10.3389\/fmolb.2026.1903849"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2026.1903849","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]},"article-number":"1903849"}}