{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T22:40:42Z","timestamp":1776379242629,"version":"3.51.2"},"reference-count":48,"publisher":"Wiley","license":[{"start":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T00:00:00Z","timestamp":1600646400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Advanced Microscopy Facility UC","award":["SLT006\/17\/00040"],"award-info":[{"award-number":["SLT006\/17\/00040"]}]},{"name":"Advanced Microscopy Facility UC","award":["MDM-2014-0370"],"award-info":[{"award-number":["MDM-2014-0370"]}]},{"name":"Advanced Microscopy Facility UC","award":["180084"],"award-info":[{"award-number":["180084"]}]},{"name":"Advanced Microscopy Facility UC","award":["AFB170005"],"award-info":[{"award-number":["AFB170005"]}]},{"name":"Advanced Microscopy Facility UC","award":["11611065"],"award-info":[{"award-number":["11611065"]}]},{"name":"Advanced Microscopy Facility UC","award":["SAF2014-52228-R"],"award-info":[{"award-number":["SAF2014-52228-R"]}]},{"name":"Advanced Microscopy Facility UC","award":["SAF2017-83372-R"],"award-info":[{"award-number":["SAF2017-83372-R"]}]},{"name":"Health Deparment of the Generalitat de Catalunya","award":["SLT006\/17\/00040"],"award-info":[{"award-number":["SLT006\/17\/00040"]}]},{"name":"Health Deparment of the Generalitat de Catalunya","award":["MDM-2014-0370"],"award-info":[{"award-number":["MDM-2014-0370"]}]},{"name":"Health Deparment of the Generalitat de Catalunya","award":["180084"],"award-info":[{"award-number":["180084"]}]},{"name":"Health Deparment of the Generalitat de Catalunya","award":["AFB170005"],"award-info":[{"award-number":["AFB170005"]}]},{"name":"Health Deparment of the Generalitat de Catalunya","award":["11611065"],"award-info":[{"award-number":["11611065"]}]},{"name":"Health Deparment of the Generalitat de Catalunya","award":["SAF2014-52228-R"],"award-info":[{"award-number":["SAF2014-52228-R"]}]},{"name":"Health Deparment of the Generalitat de Catalunya","award":["SAF2017-83372-R"],"award-info":[{"award-number":["SAF2017-83372-R"]}]},{"name":"Mar\u00eda de Maeztu Programme for Units of Excellence in R&D","award":["SLT006\/17\/00040"],"award-info":[{"award-number":["SLT006\/17\/00040"]}]},{"name":"Mar\u00eda de Maeztu Programme for Units of Excellence in R&D","award":["MDM-2014-0370"],"award-info":[{"award-number":["MDM-2014-0370"]}]},{"name":"Mar\u00eda de Maeztu Programme for Units of Excellence in R&D","award":["180084"],"award-info":[{"award-number":["180084"]}]},{"name":"Mar\u00eda de Maeztu Programme for Units of Excellence in R&D","award":["AFB170005"],"award-info":[{"award-number":["AFB170005"]}]},{"name":"Mar\u00eda de Maeztu Programme for Units of Excellence in R&D","award":["11611065"],"award-info":[{"award-number":["11611065"]}]},{"name":"Mar\u00eda de Maeztu Programme for Units of Excellence in R&D","award":["SAF2014-52228-R"],"award-info":[{"award-number":["SAF2014-52228-R"]}]},{"name":"Mar\u00eda de Maeztu Programme for Units of Excellence in R&D","award":["SAF2017-83372-R"],"award-info":[{"award-number":["SAF2017-83372-R"]}]},{"name":"Chilean Government","award":["SLT006\/17\/00040"],"award-info":[{"award-number":["SLT006\/17\/00040"]}]},{"name":"Chilean Government","award":["MDM-2014-0370"],"award-info":[{"award-number":["MDM-2014-0370"]}]},{"name":"Chilean Government","award":["180084"],"award-info":[{"award-number":["180084"]}]},{"name":"Chilean Government","award":["AFB170005"],"award-info":[{"award-number":["AFB170005"]}]},{"name":"Chilean Government","award":["11611065"],"award-info":[{"award-number":["11611065"]}]},{"name":"Chilean Government","award":["SAF2014-52228-R"],"award-info":[{"award-number":["SAF2014-52228-R"]}]},{"name":"Chilean Government","award":["SAF2017-83372-R"],"award-info":[{"award-number":["SAF2017-83372-R"]}]},{"name":"Chilean Government","award":["SLT006\/17\/00040"],"award-info":[{"award-number":["SLT006\/17\/00040"]}]},{"name":"Chilean Government","award":["MDM-2014-0370"],"award-info":[{"award-number":["MDM-2014-0370"]}]},{"name":"Chilean Government","award":["180084"],"award-info":[{"award-number":["180084"]}]},{"name":"Chilean Government","award":["AFB170005"],"award-info":[{"award-number":["AFB170005"]}]},{"name":"Chilean Government","award":["11611065"],"award-info":[{"award-number":["11611065"]}]},{"name":"Chilean Government","award":["SAF2014-52228-R"],"award-info":[{"award-number":["SAF2014-52228-R"]}]},{"name":"Chilean Government","award":["SAF2017-83372-R"],"award-info":[{"award-number":["SAF2017-83372-R"]}]},{"name":"Chilean Government","award":["SLT006\/17\/00040"],"award-info":[{"award-number":["SLT006\/17\/00040"]}]},{"name":"Chilean Government","award":["MDM-2014-0370"],"award-info":[{"award-number":["MDM-2014-0370"]}]},{"name":"Chilean Government","award":["180084"],"award-info":[{"award-number":["180084"]}]},{"name":"Chilean Government","award":["AFB170005"],"award-info":[{"award-number":["AFB170005"]}]},{"name":"Chilean Government","award":["11611065"],"award-info":[{"award-number":["11611065"]}]},{"name":"Chilean Government","award":["SAF2014-52228-R"],"award-info":[{"award-number":["SAF2014-52228-R"]}]},{"name":"Chilean Government","award":["SAF2017-83372-R"],"award-info":[{"award-number":["SAF2017-83372-R"]}]},{"name":"Spanish Ministry of Economy and Business","award":["SLT006\/17\/00040"],"award-info":[{"award-number":["SLT006\/17\/00040"]}]},{"name":"Spanish Ministry of Economy and Business","award":["MDM-2014-0370"],"award-info":[{"award-number":["MDM-2014-0370"]}]},{"name":"Spanish Ministry of Economy and Business","award":["180084"],"award-info":[{"award-number":["180084"]}]},{"name":"Spanish Ministry of Economy and Business","award":["AFB170005"],"award-info":[{"award-number":["AFB170005"]}]},{"name":"Spanish Ministry of Economy and Business","award":["11611065"],"award-info":[{"award-number":["11611065"]}]},{"name":"Spanish Ministry of Economy and Business","award":["SAF2014-52228-R"],"award-info":[{"award-number":["SAF2014-52228-R"]}]},{"name":"Spanish Ministry of Economy and Business","award":["SAF2017-83372-R"],"award-info":[{"award-number":["SAF2017-83372-R"]}]},{"name":"Spanish Ministry of Economy and Business","award":["SLT006\/17\/00040"],"award-info":[{"award-number":["SLT006\/17\/00040"]}]},{"name":"Spanish Ministry of Economy and Business","award":["MDM-2014-0370"],"award-info":[{"award-number":["MDM-2014-0370"]}]},{"name":"Spanish Ministry of Economy and Business","award":["180084"],"award-info":[{"award-number":["180084"]}]},{"name":"Spanish Ministry of Economy and Business","award":["AFB170005"],"award-info":[{"award-number":["AFB170005"]}]},{"name":"Spanish Ministry of Economy and Business","award":["11611065"],"award-info":[{"award-number":["11611065"]}]},{"name":"Spanish Ministry of Economy and Business","award":["SAF2014-52228-R"],"award-info":[{"award-number":["SAF2014-52228-R"]}]},{"name":"Spanish Ministry of Economy and Business","award":["SAF2017-83372-R"],"award-info":[{"award-number":["SAF2017-83372-R"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Oxidative Medicine and Cellular Longevity"],"published-print":{"date-parts":[[2020,9,21]]},"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is tightly linked to oxidative stress since amyloid beta-peptide (A<jats:italic>\u03b2<\/jats:italic>) aggregates generate free radicals. Moreover, the aggregation of A<jats:italic>\u03b2<\/jats:italic> is increased by oxidative stress, and the neurotoxicity induced by the oligomers and fibrils is in part mediated by free radicals. Interestingly, it has been reported that oxidative stress can also induce BACE1 transcription and expression. BACE1 is the key enzyme in the cleavage of the amyloid precursor protein to produce A<jats:italic>\u03b2<\/jats:italic>, and the expression of this enzyme has been previously shown to be enhanced in the brains of Alzheimer\u2019s patients. Here, we have found that BACE1 expression is increased in the hippocampi from AD patients at both the early (Braak stage II) and late (Braak stage VI) stages of the disease as studied by immunohistochemistry and western blot. To address the role of A<jats:italic>\u03b2<\/jats:italic> and oxidative stress in the regulation of BACE1 expression, we have analyzed the effect of subtoxic concentrations of A<jats:italic>\u03b2<\/jats:italic> oligomers (0.25\u2009<jats:italic>\u03bc<\/jats:italic>M) and H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> (10\u2009mM) on a human neuroblastoma cell line. Firstly, our results show that A<jats:italic>\u03b2<\/jats:italic> oligomers and H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> induce an increase of <jats:italic>BACE1<\/jats:italic> mRNA as we studied by qPCR. Regarding BACE1 translation, it is dependent on the phosphorylation of the eukaryotic initiation factor 2<jats:italic>\u03b1<\/jats:italic> (eIF2<jats:italic>\u03b1<\/jats:italic>), since <jats:italic>BACE1<\/jats:italic> mRNA bears a 5<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M1\"><mml:msup><mml:mrow\/><mml:mrow><mml:mo>\u2032<\/mml:mo><\/mml:mrow><\/mml:msup><\/mml:math>UTR that avoids its translation under basal conditions. BACE1 5<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M2\"><mml:msup><mml:mrow\/><mml:mrow><mml:mo>\u2032<\/mml:mo><\/mml:mrow><\/mml:msup><\/mml:math>UTR contains four upstream initiating codons (uAUGs), and its translation is activated when eIF2<jats:italic>\u03b1<\/jats:italic> is phosphorylated. Consistently, we have obtained that A<jats:italic>\u03b2<\/jats:italic> oligomers and H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> increase the levels of BACE1 and p-eIF2<jats:italic>\u03b1<\/jats:italic> assayed by western blot and confocal microscopy. Our results suggest that A<jats:italic>\u03b2<\/jats:italic> oligomers increase BACE1 translation by phosphorylating eIF2<jats:italic>\u03b1<\/jats:italic> in a process that involves oxidative stress and conforms a pathophysiological loop, where the A<jats:italic>\u03b2<\/jats:italic> once aggregated favors its own production continuously by the increase in BACE1 expression as observed in AD patients.<\/jats:p>","DOI":"10.1155\/2020\/2739459","type":"journal-article","created":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T23:30:37Z","timestamp":1600731037000},"page":"1-12","source":"Crossref","is-referenced-by-count":19,"title":["Amyloid Beta-Peptide Increases BACE1 Translation through the Phosphorylation of the Eukaryotic Initiation Factor-2<i>\u03b1<\/i>"],"prefix":"10.1155","volume":"2020","author":[{"given":"Pol","family":"Pic\u00f3n-Pag\u00e8s","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela A.","family":"Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Cell Signaling Laboratory, Centro UC de Envejecimiento y Regeneraci\u00f3n (CARE), Department of Cellular and Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Cat\u00f3lica de Chile, Santiago, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro","family":"Barranco-Almohalla","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Crepin","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Tajes","sequence":"additional","affiliation":[{"name":"Group of Biomedical Research in Heart Diseases, Hospital del Mar-Medical Research Institute (IMIM), Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerard","family":"ILL-Raga","sequence":"additional","affiliation":[{"name":"Division of Physiological Sciences, Federal University of Esp\u00edrito Santo, Vit\u00f3ria, Esp\u00edrito Santo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesc X.","family":"Guix","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurobiology, Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d, CSIC-UAM, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Men\u00e9ndez","sequence":"additional","affiliation":[{"name":"Cancer Research Programm, Hospital del Mar-Medical Research Institute (IMIM), Parc de Salut Mar, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Montserrat","family":"Arum\u00ed-Ur\u00eda","sequence":"additional","affiliation":[{"name":"Servicio de Anatom\u00eda Patol\u00f3gica, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rub\u00e9n","family":"Vicente","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandra R.","family":"\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Cell Signaling Laboratory, Centro UC de Envejecimiento y Regeneraci\u00f3n (CARE), Department of Cellular and Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Cat\u00f3lica de Chile, Santiago, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1343-3599","authenticated-orcid":true,"given":"Francisco J.","family":"Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","reference":[{"key":"1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(84)80190-4"},{"key":"2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.12.4245"},{"key":"3","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2009-0957"},{"key":"4","doi-asserted-by":"publisher","DOI":"10.2174\/156801505774913053"},{"issue":"6","key":"5","first-page":"1633","volume":"152","year":"1998","journal-title":"The American Journal of Pathology"},{"key":"6","doi-asserted-by":"publisher","DOI":"10.1038\/nm0896-864"},{"key":"7","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201200243"},{"key":"8","doi-asserted-by":"publisher","DOI":"10.1021\/bi00069a001"},{"key":"9","doi-asserted-by":"publisher","DOI":"10.1126\/science.8191290"},{"key":"10","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(00)01749-5"},{"key":"11","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2012.00464"},{"key":"12","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.17074"},{"key":"13","doi-asserted-by":"publisher","DOI":"10.1021\/bi990438f"},{"key":"14","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(00)00015-0"},{"key":"15","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2018.11.007"},{"key":"16","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.2002.0515"},{"key":"17","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2007.01.009"},{"key":"18","doi-asserted-by":"publisher","DOI":"10.1096\/fj.03-1378fje"},{"key":"19","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.2.865-874.2004"},{"key":"20","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKH348"},{"key":"21","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.7400166"},{"key":"22","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.26.9.3353-3364.2006"},{"key":"23","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm191"},{"key":"24","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.10.047"},{"key":"25","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.22113"},{"key":"26","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2014.6080"},{"key":"27","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.10.12.8903508"},{"key":"28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0021456"},{"key":"29","doi-asserted-by":"publisher","DOI":"10.4236\/nm.2011.23031"},{"key":"30","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11417"},{"key":"31","doi-asserted-by":"publisher","DOI":"10.1038\/nm0103-3"},{"key":"32","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.59.9.1381"},{"key":"33","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10208"},{"key":"34","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000260698.46517.8f"},{"key":"35","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(97)00062-2"},{"key":"36","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.12.6839"},{"key":"37","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(02)00801-8"},{"key":"38","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M411936200"},{"key":"39","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2010-100474"},{"key":"40","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2766-05.2005"},{"key":"41","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2440-08.2008"},{"key":"42","doi-asserted-by":"publisher","DOI":"10.1007\/BF00964863"},{"key":"43","doi-asserted-by":"publisher","DOI":"10.1016\/0047-6374(90)90040-M"},{"key":"44","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.23.7971-7980.2001"},{"key":"45","doi-asserted-by":"publisher","DOI":"10.1021\/bi020397e"},{"key":"46","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfi205"},{"key":"47","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.05164-11"},{"key":"48","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2005.09.018"}],"container-title":["Oxidative Medicine and Cellular Longevity"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/downloads.hindawi.com\/journals\/omcl\/2020\/2739459.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/omcl\/2020\/2739459.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/omcl\/2020\/2739459.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T23:30:49Z","timestamp":1600731049000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.hindawi.com\/journals\/omcl\/2020\/2739459\/"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,21]]},"references-count":48,"alternative-id":["2739459","2739459"],"URL":"https:\/\/doi.org\/10.1155\/2020\/2739459","relation":{},"ISSN":["1942-0900","1942-0994"],"issn-type":[{"value":"1942-0900","type":"print"},{"value":"1942-0994","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,21]]}}}