{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:23:21Z","timestamp":1789986201835,"version":"4.0.1"},"reference-count":54,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2019,11,23]],"date-time":"2019-11-23T00:00:00Z","timestamp":1574467200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2020,1,7]]},"abstract":"<jats:p>Hyperbilirubinemia may increase the risk of Alzheimer\u2019s disease (AD) but its mechanistic role in AD pathogenesis remains obscure. Here, we used animal models to investigate the short- and long-term effects of neonatal systemic exposure to bilirubin on brain histology and function as well as the acute effect of lateral ventricle injection of bilirubin in adult rats. We found that three days exposure to bilirubin in newborn rats could induce AD-like pathological changes in late life, including tau protein hyperphosphorylation at multiple sites, increased A\u03b2 production in brain tissues, and spatial learning and memory injury. Bilirubin activated the activities of several protein kinases (GSK-3\u03b2, CDK5, and JNK), which were positively correlated with hyperphosphorylated tau; simultaneously increased the expression of A\u03b2PP \u03b3-secretase PS2 and decreased the expression of \u03b1-secretase ADAM17, which were positively correlated with A\u03b2 production. The above results were well replicated in primary hippocampal cell cultures. These data demonstrate that bilirubin encephalopathy is an AD-like disease, suggesting a potent role of bilirubin in AD.<\/jats:p>","DOI":"10.3233\/jad-190945","type":"journal-article","created":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T11:12:28Z","timestamp":1574766748000},"page":"277-295","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":16,"title":["Short Term Exposure to Bilirubin Induces Encephalopathy Similar to Alzheimer\u2019s Disease in Late Life"],"prefix":"10.1177","volume":"73","author":[{"given":"Haoyu","family":"Chen","sequence":"first","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Liang","sequence":"additional","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Xu","sequence":"additional","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Xu","sequence":"additional","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leyi","family":"Yao","sequence":"additional","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Li","sequence":"additional","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufan","family":"Tan","sequence":"additional","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofen","family":"Li","sequence":"additional","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingtian","family":"Huang","sequence":"additional","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenjun","family":"Yang","sequence":"additional","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawen","family":"Wu","sequence":"additional","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghong","family":"Chen","sequence":"additional","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbiao","family":"Huang","sequence":"additional","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejun","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-E.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinbao","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,11,23]]},"reference":[{"key":"ref001","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.04212.x"},{"key":"ref002","doi-asserted-by":"publisher","DOI":"10.1111\/imj.12572"},{"key":"ref003","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.13.4913"},{"key":"ref004","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)38495-8"},{"key":"ref005","first-page":"131","volume":"414","author":"Cabral-Miranda F","year":"2018","journal-title":"Curr Top Microbiol Immunol"},{"key":"ref006","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.43.7.1377"},{"key":"ref007","first-page":"101","volume":"50","author":"Pluta R","year":"2012","journal-title":"Folia Neuropathol"},{"key":"ref008","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-013-8439-1"},{"key":"ref009","first-page":"146","volume":"2","author":"Tai HC","year":"2014","journal-title":"Acta Neuropathol Commun"},{"key":"ref010","doi-asserted-by":"publisher","DOI":"10.2174\/1871527313666140917095514"},{"key":"ref011","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-013-0022-9"},{"key":"ref012","doi-asserted-by":"publisher","DOI":"10.1159\/000447239"},{"key":"ref013","doi-asserted-by":"publisher","DOI":"10.2174\/1567205011666140331161027"},{"key":"ref014","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2011.00525.x"},{"key":"ref015","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.274"},{"key":"ref016","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-198608000-00018"},{"key":"ref017","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2362.2003.01261.x"},{"key":"ref018","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jp.7210634"},{"key":"ref019","doi-asserted-by":"publisher","DOI":"10.1111\/jgs.12678"},{"key":"ref020","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(00)00128-7"},{"key":"ref021","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2013.00161"},{"key":"ref022","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0889-12.2012"},{"key":"ref023","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0149-16.2017"},{"key":"ref024","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2003.01645.x"},{"key":"ref025","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-142772"},{"key":"ref026","doi-asserted-by":"publisher","DOI":"10.2174\/156720512799361691"},{"key":"ref027","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2010.10.020"},{"key":"ref028","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.419135"},{"key":"ref029","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2013.07.014"},{"key":"ref030","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2016.00051"},{"key":"ref031","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-141134"},{"key":"ref032","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2014.07.035"},{"key":"ref033","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2011-0066"},{"key":"ref034","doi-asserted-by":"publisher","DOI":"10.1016\/0197-4580(94)90077-9"},{"key":"ref035","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2015.06.013"},{"key":"ref036","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2009.07.009"},{"key":"ref037","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-180772"},{"key":"ref038","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-018-0116-6"},{"key":"ref039","doi-asserted-by":"publisher","DOI":"10.1126\/science.292.5521.1552"},{"key":"ref040","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3250"},{"key":"ref041","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1206786109"},{"key":"ref042","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5659-11.2012"},{"key":"ref043","first-page":"41","volume":"18","author":"Wang H","year":"2014","journal-title":"Discov Med"},{"key":"ref044","doi-asserted-by":"publisher","DOI":"10.2174\/1567202053586767"},{"key":"ref045","doi-asserted-by":"publisher","DOI":"10.1016\/j.arcmed.2014.11.015"},{"key":"ref046","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0155022"},{"key":"ref047","doi-asserted-by":"publisher","DOI":"10.1542\/peds.114.1.e130"},{"key":"ref048","first-page":"227","volume":"184","author":"Xu J","year":"1994","journal-title":"J Anat"},{"key":"ref049","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2001.281.5.H1976"},{"key":"ref050","first-page":"819","volume":"6","author":"Sassa S","year":"2004","journal-title":"Antioxid Redox Signal"},{"key":"ref051","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(95)01511-6"},{"key":"ref052","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-015-9666-4"},{"key":"ref053","doi-asserted-by":"publisher","DOI":"10.2174\/1381612824666180717160623"},{"key":"ref054","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-180451"}],"container-title":["Journal of Alzheimer\u2019s Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.3233\/JAD-190945","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.3233\/JAD-190945","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.3233\/JAD-190945","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T10:07:17Z","timestamp":1777370837000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.3233\/JAD-190945"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,23]]},"references-count":54,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,1,7]]}},"alternative-id":["10.3233\/JAD-190945"],"URL":"https:\/\/doi.org\/10.3233\/jad-190945","relation":{},"ISSN":["1387-2877","1875-8908"],"issn-type":[{"value":"1387-2877","type":"print"},{"value":"1875-8908","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,23]]}}}