{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:06:21Z","timestamp":1791925581683,"version":"4.3.4"},"reference-count":67,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,3,27]],"date-time":"2019-03-27T00:00:00Z","timestamp":1553644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG054429"],"award-info":[{"award-number":["R01AG054429"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["F30AG051327"],"award-info":[{"award-number":["F30AG051327"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32AG20506"],"award-info":[{"award-number":["T32AG20506"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32GM008152"],"award-info":[{"award-number":["T32GM008152"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      The apolipoprotein E (\n                      <jats:italic>APOE<\/jats:italic>\n                      ) E4 isoform is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Although\n                      <jats:italic>APOE<\/jats:italic>\n                      is predominantly expressed by astrocytes in the central nervous system, neuronal expression of\n                      <jats:italic>APOE<\/jats:italic>\n                      is of increasing interest in age\u2010related cognitive impairment, neurological injury, and neurodegeneration. Here, we show that endogenous expression of E4 in stem\u2010cell\u2013derived neurons predisposes them to injury and promotes the release of phosphorylated tau.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Induced pluripotent stem cells from 2 unrelated AD patients carrying the E4 allele were corrected to the E3\/E3 genotype with the CRISPR\/Cas9 system and differentiated into pure cultures of forebrain excitatory neurons without contamination from other cells types.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Compared to unedited E4 neurons, E3 neurons were less susceptible to ionomycin\u2010induced cytotoxicity. Biochemically, E4 cells exhibited increased tau phosphorylation and ERK1\/2 phosphoactivation. Moreover, E4 neurons released increased amounts of phosphorylated tau extracellularly in an isoform\u2010dependent manner by a heparin sulfate proteoglycan\u2013dependent mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Our results demonstrate that endogenous expression of E4 by stem\u2010cell\u2013derived forebrain excitatory neurons predisposes neurons to calcium dysregulation and ultimately cell death. This change is associated with increased cellular tau phosphorylation and markedly enhanced release of phosphorylated tau. Importantly, these effects are independent of glial APOE. These findings suggest that E4 accelerates spreading of tau pathology and neuron death in part by neuron\u2010specific, glia\u2010independent mechanisms. Ann Neurol 2019;85:726\u2013739<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.25455","type":"journal-article","created":{"date-parts":[[2019,3,6]],"date-time":"2019-03-06T11:25:53Z","timestamp":1551871553000},"page":"726-739","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":141,"title":["Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease"],"prefix":"10.1002","volume":"85","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7007-2371","authenticated-orcid":false,"given":"Anil R.","family":"Wadhwani","sequence":"first","affiliation":[{"name":"Department of Neurology Northwestern University  Chicago IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira","family":"Affaneh","sequence":"additional","affiliation":[{"name":"Department of Neurology Northwestern University  Chicago IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Van Gulden","sequence":"additional","affiliation":[{"name":"Department of Neurology Northwestern University  Chicago IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Kessler","sequence":"additional","affiliation":[{"name":"Department of Neurology Northwestern University  Chicago IL"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,3,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8346443"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.5.1977"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature24016"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.11.014"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.11.013"},{"key":"e_1_2_8_7_1","first-page":"779","article-title":"Apolipoprotein E epsilon 4 allele and whole brain atrophy in late\u2010onset Alzheimer's disease","volume":"155","author":"Yasuda M","year":"1998","journal-title":"Am J Psychiatry"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.18.10914"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006312"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.02.040"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2281-14.2014"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.090973"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5476-05.2006"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.06.011"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0004-z"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-9-3"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.143"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2647"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.12.9873-9880.1998"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.05.029"},{"key":"e_1_2_8_21_1","article-title":"PrP\u2010grafted antibodies bind certain amyloid \u03b2\u2010protein aggregates, but do not prevent toxicity","author":"Mengel D","year":"2018","journal-title":"Brain Res"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2017.01.022"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep34904"},{"key":"e_1_2_8_24_1","first-page":"354","article-title":"Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK\u2010dependent changes in gene expression","volume":"12","author":"Reinhardt P","year":"2013","journal-title":"Stem Cell"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-017-0286-y"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature17664"},{"key":"e_1_2_8_27_1","first-page":"1349","article-title":"Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta\u2010analysis","volume":"278","author":"Farrer LA","year":"1997","journal-title":"APOE and alzheimer disease meta analysis consortium. JAMA"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx144"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4026-09.2009"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0059478"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-11-75"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4315-03.2004"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2760(87)90295-5"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2016.12.006"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2959"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00308809"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(94)00596-W"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(16)00070-3"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2015.1285"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.59.8.1267"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.61.1.95"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl269"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.04.056"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.51.36267"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu064"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr394"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0084547"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2013.01.009"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10821"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.2000.7510"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/1098-1136(20010315)33:4<298::AID-GLIA1028>3.0.CO;2-N"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2009.05.011"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3253-07.2008"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2016.12.001"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64788-8"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1529"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0898-6568(02)00007-4"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.23.11183"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M411719200"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4132"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv081"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12481"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2642-12.2013"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.12.044"},{"key":"e_1_2_8_65_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0304-3940(95)12257-5","article-title":"Exposure of rat hippocampal neurons to amyloid \u03b2 peptide (25\u201335) induces the inactivation of phosphatidyl inositol\u20103 kinase and the activation of tau protein kinase I\/glycogen synthase kinase\u20103\u03b2","volume":"203","author":"Takashima A","year":"1996","journal-title":"Neurosci Lett"},{"key":"e_1_2_8_66_1","doi-asserted-by":"crossref","first-page":"23403","DOI":"10.1016\/S0021-9258(17)31529-6","article-title":"Isoform\u2010specific binding of apolipoprotein\u2010E to beta\u2010amyloid","volume":"269","author":"Ladu MJ","year":"1994","journal-title":"J Biol Chem"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-007-0291-9"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2017.00427"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fana.25455","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.25455","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ana.25455","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.25455","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,10]],"date-time":"2023-09-10T08:14:25Z","timestamp":1694333665000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.25455"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,27]]},"references-count":67,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2019,5]]}},"alternative-id":["10.1002\/ana.25455"],"URL":"https:\/\/doi.org\/10.1002\/ana.25455","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,27]]},"assertion":[{"value":"2018-09-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-03-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-03-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}