{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T21:16:30Z","timestamp":1790284590549,"version":"4.1.0"},"reference-count":70,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T00:00:00Z","timestamp":1659052800000},"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":["R01 AG067258\u201002"],"award-info":[{"award-number":["R01 AG067258\u201002"]}],"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":["R01 NS100704\u201005"],"award-info":[{"award-number":["R01 NS100704\u201005"]}],"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":["R01 NS100704\u2010S2"],"award-info":[{"award-number":["R01 NS100704\u2010S2"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    APOE is an immunomodulator in the brain and the major genetic risk factor for late\u2010onset Alzheimer's disease (AD). Targeted replacement\n                    <jats:italic>APOE<\/jats:italic>\n                    mice (\n                    <jats:italic>APOE<\/jats:italic>\n                    \u2010TR) have been a useful tool to study the effects of\n                    <jats:italic>APOE<\/jats:italic>\n                    isoforms on brain neurochemistry and activity prior to and during AD. We use newly available APOE knock\u2010in mice (JAX\u2010APOE) to compare phenotypes associated with\n                    <jats:italic>APOE4<\/jats:italic>\n                    across models. Similar to APOE4\u2010TR mice, JAX\u2010E4 mouse brains showed 27% lower levels of APOE protein compared with JAX\u2010E3 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001). We analyzed several neuroinflammatory molecules that have been associated with APOE genotype. SerpinA3 was much higher in\n                    <jats:italic>APOE4<\/jats:italic>\n                    \u2010TR mice to\n                    <jats:italic>APOE3<\/jats:italic>\n                    \u2010TR mice, but this effect was not seen in JAX\u2010APOE mice. There were higher levels of IL\u20103 in JAX\u2010E4 brains compared with JAX\u2010E3, but other neuroinflammatory markers (IL6, TNF\u03b1) were not affected by\n                    <jats:italic>APOE<\/jats:italic>\n                    genotype. In terms of neuronal structure, basal dendritic spine density in the entorhinal cortex was 39% lower in JAX\u2010E4 mice compared with JAX\u2010E3 mice (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001), again similar to APOE\u2010TR mice. One\u2010week treatment with ibuprofen significantly increased dendritic spine density in the JAX\u2010E4 mice, consistent with our previous finding in\n                    <jats:italic>APOE<\/jats:italic>\n                    \u2010TR mice. Behaviorally, there was no effect of\n                    <jats:italic>APOE<\/jats:italic>\n                    genotype on Barnes Maze learning and memory in 6\u2010month\u2010old JAX\u2010APOE mice. Overall, the experiments performed in JAX\u2010APOE mice validated findings from\n                    <jats:italic>APOE<\/jats:italic>\n                    \u2010TR mice, identifying particularly strong effects of\n                    <jats:italic>APOE4<\/jats:italic>\n                    genotype on lower APOE protein levels and simplified neuron structure. These data demonstrate pathways that could promote susceptibility of\n                    <jats:italic>APOE4<\/jats:italic>\n                    brains to AD pathological changes.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15665-fig-0006-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.15665","type":"journal-article","created":{"date-parts":[[2022,7,15]],"date-time":"2022-07-15T09:54:05Z","timestamp":1657878845000},"page":"247-259","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Independent\n                    <scp>\n                      <i>APOE4<\/i>\n                    <\/scp>\n                    knock\u2010in mouse models display reduced brain\n                    <scp>APOE<\/scp>\n                    protein, altered neuroinflammation, and simplification of dendritic spines"],"prefix":"10.1111","volume":"163","author":[{"given":"Jordy","family":"Sepulveda","sequence":"first","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Georgetown University Medical Center  Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Georgetown University Medical Center  Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Georgetown University Medical Center  Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christi Anne S.","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Georgetown University Medical Center  Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6276-248X","authenticated-orcid":false,"given":"George\u00a0William","family":"Rebeck","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Georgetown University Medical Center  Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,7,29]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4040\u201010.2010"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195\u2010020\u201000710\u20106"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0887\u201009.2009"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1934"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0169-328X(95)00097-C"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5198\u201013.2014"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2008.05.008"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181a18691"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2020.112534"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2016.04.014"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4026\u201009.2009"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.327.7407.128"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.NEUROBIOLAGING.2015.09.011"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2019.00014"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12123842"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0811879106"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwz084"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2019.104724"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.838436"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306\u20104522(02)00178\u20101"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2004.09.019"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2010.90"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2018.0821"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.4668"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974\u2010021\u201002256\u20102"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI6172"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dadm.2017.01.007"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109\u2010018\u20101632\u2010y"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.439"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23974"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0404.2006.00680.x"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2010.1396"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.11.013"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024\u2010015\u20100002\u20102"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.08.024"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.12.019"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11682\u2010019\u201000069\u20109"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/1742\u20102094\u20103\u201021"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-016-1427-y"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genom.1.1.507"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02621"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007232"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.119.311994"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1097\/WNR.0000000000000811"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl255"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03325217"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.201279298"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(93)90070-8"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1972\u201008.2008"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1101\/lm.030031.112"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1159\/000354777"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/0140\u20106736(93)91709\u2010u"},{"key":"e_1_2_11_55_1","doi-asse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