{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:25:59Z","timestamp":1786976759700,"version":"build-2736575974"},"reference-count":38,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T00:00:00Z","timestamp":1718755200000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Anim Models and Exp Med"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Apolipoprotein E4 (\n                      <jats:italic>ApoE4<\/jats:italic>\n                      ) allele is the strongest genetic risk factor for late\u2010onset Alzheimer's disease, and it can aggravate depressive symptoms in non\u2010AD patients. However, the impact of ApoE4 on AD\u2010associated depression\u2010like behaviors and its underlying pathogenic mechanisms remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study developed a 5xFAD mouse model overexpressing human\n                      <jats:italic>ApoE4<\/jats:italic>\n                      (E4FAD). Behavioral assessments and synaptic function tests were conducted to explore the effects of ApoE4 on cognition and depression in 5xFAD mice. Changes in peripheral and central lipid metabolism, as well as the levels of serotonin (5\u2010HT) and \u03b3\u2010aminobutyric acid (GABA) neurotransmitters in the prefrontal cortex, were examined. In addition, the protein levels of 24\u2010dehydrocholesterol reductase\/glycogen synthase kinase\u20103 beta\/mammalian target of rapamycin (DHCR24\/GSK3\u03b2\/mTOR) and postsynaptic density protein 95\/calmodulin\u2010dependent protein kinase II\/brain\u2010derived neurotrophic factor (PSD95\/CaMK\u2010II\/BDNF) were measured to investigate the molecular mechanism underlying the effects of\n                      <jats:italic>ApoE4<\/jats:italic>\n                      on AD mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Compared with 5xFAD mice, E4FAD mice exhibited more severe depression\u2010like behaviors and cognitive impairments. These mice also exhibited increased amyloid\u2010beta deposition in the hippocampus, increased astrocyte numbers, and decreased expression of depression\u2010related neurotransmitters 5\u2010HT and GABA in the prefrontal cortex. Furthermore, lipid metabolism disorders were observed in E4FAD, manifesting as elevated low\u2010density lipoprotein cholesterol and reduced high\u2010density lipoprotein cholesterol in peripheral blood, decreased cholesterol level in the prefrontal cortex, and reduced expression of key enzymes and proteins related to cholesterol synthesis and homeostasis. Abnormal expression of proteins related to the DHCR24\/GSK3\u03b2\/mTOR and PSD95\/CaMK\u2010II\/BDNF pathways was also observed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study found that\n                      <jats:italic>ApoE4<\/jats:italic>\n                      overexpression exacerbates depression\u2010like behaviors in 5xFAD mice and confirmed that\n                      <jats:italic>ApoE4<\/jats:italic>\n                      reduces cognitive function in these mice. The mechanism may involve the induction of central and peripheral lipid metabolism disorders. Therefore, modulating\n                      <jats:italic>ApoE<\/jats:italic>\n                      expression or function to restore cellular lipid homeostasis may be a promising therapeutic target for AD comorbid with depression. This study also provided a better animal model for studying AD comorbid with depression.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ame2.12446","type":"journal-article","created":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T05:15:20Z","timestamp":1718774120000},"page":"347-361","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Apolipoprotein E4 interferes with lipid metabolism to exacerbate depression\u2010like behaviors in 5xFAD mice"],"prefix":"10.1002","volume":"7","author":[{"given":"Yanju","family":"Gong","sequence":"first","affiliation":[{"name":"iNHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and lnnovation of Animal Model, Comparative Medicine Center, Institute of Laboratory Animal Sciences Chinese Academy of Medical Sciences 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