{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T11:16:28Z","timestamp":1792062988943,"version":"4.4.0"},"reference-count":82,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T00:00:00Z","timestamp":1740700800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T00:00:00Z","timestamp":1740700800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100010127","name":"J\u00fcrgen Manchot Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010127","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003042","name":"Else Kr\u00f6ner-Fresenius-Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004350","name":"Studienstiftung des Deutschen Volkes","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004350","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Human tau protein, composed of six brain\u2010specific isoforms, is a major driver of Alzheimer's disease (AD). The role of its isoforms however remains unclear and human AD models are scarce.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We generated human\n                      <jats:italic>MAPT<\/jats:italic>\n                      \u2013 (tau\u2013) knockout (KO) induced pluripotent stem cells (iPSC) using CRISPR\/Cas9, differentiated these into glutamatergic neurons, and assessed isoform\u2010specific functions of tau in these neurons. We used omic\u2010 approaches, live\u2010cell imaging, subcompartmental analysis, and lentivirus\u2010based reintroduction of specific tau isoforms to investigate isoform\u2010mediated neuronal dysfunction in an AD model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Tau KO human iPSC\u2010derived neurons showed decreased neurite outgrowth and axon initial segment length and, notably, resisted amyloid beta oligomer (A\u03b2O)\u2013induced neuronal activity reduction. Introducing the 1N4R\u2010tau isoform, but not other isoforms, confers A\u03b2O vulnerability and increases KxGS phosphorylation of tau, without altering neuronal activity or microtubule modifications.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>While tau KO impacts neuronal development and activity, tau\u2010KO also confers resistance against A\u03b2O insult. 1N4R\u2010tau likely mediates A\u03b2O\u2010induced and phosphorylated tau toxicity, representing a novel prime therapeutic target for AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Tau knockout alters neurite growth and axon initial segment formation in human neurons.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Tau isoforms show differential axonal localization in human neurons.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Tau depletion protects against amyloid beta oligomer (A\u03b2O)\u2013mediated neurotoxicity.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>1N4R tau mediates A\u03b2O\u2010induced toxicity in human neurons.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.14403","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T08:50:55Z","timestamp":1741683055000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["The tau isoform 1N4R confers vulnerability of\n                    <i>MAPT<\/i>\n                    knockout human iPSC\u2010derived neurons to amyloid beta and phosphorylated tau\u2010induced neuronal dysfunction"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3636-1364","authenticated-orcid":false,"given":"Sarah","family":"Buchholz","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC) University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Aghyad Al","family":"Kabbani","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC) University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Bell\u2010Simons","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC) University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Kluge","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC) University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cagla","family":"Cagmak","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC) University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Klimek","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC) University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natja","family":"Haag","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics and Genomic Medicine, Medical Faculty RWTH Aachen University Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas C.","family":"Iohan","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lille Inserm, CHU Lille, Institut Pasteur de Lille, U1167\u2010RID\u2010AGE\u2010 Risk factors and molecular determinants of aging\u2010related diseases Lille France"},{"name":"Bioinformatics Multidisciplinary Environment (BIoME) Federal University of Rio Grande do Norte, Campus Universit\u00e1rio, Lagoa Nova Natal Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Coulon","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lille Inserm, CHU Lille, Institut Pasteur de Lille, U1167\u2010RID\u2010AGE\u2010 Risk factors and molecular determinants of aging\u2010related diseases Lille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4928-2163","authenticated-orcid":false,"given":"Marcos R.","family":"Costa","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lille Inserm, CHU Lille, Institut Pasteur de Lille, U1167\u2010RID\u2010AGE\u2010 Risk factors and molecular determinants of aging\u2010related diseases Lille France"},{"name":"Brain Institute Federal University of Rio Grande do Norte, Campus Universit\u00e1rio, Lagoa Nova Natal Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3321-5203","authenticated-orcid":false,"given":"Devrim","family":"Kilinc","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lille Inserm, CHU Lille, Institut Pasteur de Lille, U1167\u2010RID\u2010AGE\u2010 Risk factors and molecular determinants of aging\u2010related diseases Lille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7510-3077","authenticated-orcid":false,"given":"Hans","family":"Zempel","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC) University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,28]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13784"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.TCB.2019.02.007"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/873270"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.114.6.1179"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2018.05.045"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/343461a0"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.11\u201006\u201001515.1991"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.18\u201021\u201008660.1998"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/EMBOJ.2013.207"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ALZ.052863"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/BRAIN\/AWZ090"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.NEUROBIOLAGING.2009.04.002"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(199903)45:3"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000063311.58879.01"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0B013E31825018F7"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.092136199"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/SCIENCE.1141736"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.2610\u201010.2011"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aag0481"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1126\/SCIENCE.1194653"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896\u20106273(89)90210\u20109"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00158a027"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/HMG\/DDS238"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.IJDEVNEU.2009.06.001"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.20255"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0084849"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.784702"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.643115"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673\u20105374.389644"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/S00415\u2010024\u201012314\u20103"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/S00401\u2010016\u20101662\u2010X"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2840"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2017.08.019"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20100716\u20103629\u20109_31\/FIGURES\/2"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22042034"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-3629-9_31"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.STEM.2018.05.020"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010019\u20100638\u2010x"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/NMETH.3901"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20104939\u20106598\u20104_20"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-3629-9_29"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/CYTO.A.20022"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PONE.0033093"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.11.8463\u20108471.1998"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201024900\u20104"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3519"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.7563.2"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/S13059\u2010014\u20100550\u20108\/FIGURES\/9"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1101\/060012"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541\u20107786.MCR\u201016\u20100459\/14585\/AM\/THE\u2010LANDSCAPE\u2010OF\u2010ISOFORM\u2010SWITCHES\u2010IN\u2010HUMAN"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1073\/PNAS.1307202110\/SUPPL_FILE\/SD01.PDF"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKX428"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKR1065"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010019\u20100036\u2010z"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/PROT.25674"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.NEUROSCIENCE.2021.01.041"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2890"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4562\u201006.2007"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2018.1509607"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.06.036"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/EMBOJ.2010.211"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572\u2010021\u201000269\u2010y"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1126\/SCIENCE.AAI8764\/SUPPL_FILE\/MOVIES_S5\u2010S10.ZIP"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.NEULET.2021.135656"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380\u2010024\u201002463\u20102"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460\u20102075.1989.tb03390.x"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1101\/2024.06.28.601286"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.376"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2021.12.041\/ATTACHMENT\/418D38D8\u20106F98\u20104567\u2010AE33\u201002B961DF13F7\/MMC6.XLSX"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1074\/JBC.M115.641902"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2357\u201010.2010"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.BBAMCR.2018.07.018"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.NEUROBIOLAGING.2014.10.020"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.3389\/FNSYN.2023.1129036\/BIBTEX"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.3389\/FCELL.2022.969547\/BIBTEX"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.ARR.2021.101417"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.1117\/1.NPH.7.1.011402"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1990.tb07870.x"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1074\/JBC.M112.364067"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.NEURON.2018.06.003"},{"key":"e_1_2_8_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.TINS.2014.08.004"},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.4261\u201013.2014"}],"container-title":["Alzheimer's &amp; Dementia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/alz.14403","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/alz.14403","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/alz.14403","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T11:28:59Z","timestamp":1789558139000},"score":1,"resource":{"primary":{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/10.1002\/alz.14403"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,28]]},"references-count":82,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["10.1002\/alz.14403"],"URL":"https:\/\/doi.org\/10.1002\/alz.14403","archive":["Portico"],"relation":{},"ISSN":["1552-5260","1552-5279"],"issn-type":[{"value":"1552-5260","type":"print"},{"value":"1552-5279","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,28]]},"assertion":[{"value":"2024-06-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e14403"}}