{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:41:02Z","timestamp":1790905262457,"version":"4.1.0"},"reference-count":74,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["91949205"],"award-info":[{"award-number":["91949205"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31730035"],"award-info":[{"award-number":["31730035"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81721005"],"award-info":[{"award-number":["81721005"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The apolipoprotein E (ApoE) \u03b54 allele and type 2 diabetes mellitus (T2DM) are independent risk factors for Alzheimer's disease (AD), the most prevalent neurodegenerative disorder in the elderly. The T2DM patients carrying the ApoE \u03b54 allele exhibit heightened activation of platelet glycogen synthase kinase\u20103\u03b2 (GSK\u20103\u03b2), a key downstream kinase in the insulin signaling pathway, along with more severe cognitive deficits. This observation suggests an intrinsic link between ApoE \u03b54, GSK\u20103\u03b2, and cognitive dysfunction. However, the precise mechanisms by which ApoE \u03b54 influences GSK\u20103\u03b2 activity and exacerbates brain pathology and cognitive decline in T2DM patients remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To investigate these mechanisms, we developed T2DM mouse models by generating humanized ApoE \u03b53\/\u03b53 and \u03b54\/\u03b54 knock\u2010in mice. The mice were subjected to a high\u2010fat diet combined with multiple low\u2010dose intraperitoneal streptozotocin injections to induce T2DM. We then assessed GSK\u20103\u03b2 expression, AD\u2010like pathologies, and cognitive functions in these models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We observed that GSK\u20103\u03b2 activity was significantly upregulated in ApoE4 mice, accompanied by disruption of the insulin signaling pathway. Notably, ApoE4\u2010T2DM mice exhibited exacerbated AD\u2010related pathologies, including increased accumulation of hyperphosphorylated tau, neuroinflammation, and synaptic loss. These changes were correlated with more severe cognitive impairments compared with ApoE3\u2010T2DM or ApoE4 mice. Furthermore, inhibition of GSK\u20103\u03b2 activity using the selective inhibitor 9\u2010ING\u201041 effectively ameliorated both AD\u2010like pathologies and cognitive deficits in ApoE4\u2010T2DM mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings suggest that ApoE4 exacerbates AD pathogenesis by activating GSK\u20103\u03b2. Furthermore, targeting GSK\u20103\u03b2 may offer a promising therapeutic strategy to halt the progression from T2DM to AD, providing new insights into potential interventions for patients at risk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cns.70575","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T08:50:22Z","timestamp":1756975822000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["<scp>ApoE4<\/scp>\n                    Upregulates\n                    <scp>GSK<\/scp>\n                    \u20103\u03b2 to Aggravate Alzheimer\u2010Like Pathologies and Cognitive Impairment in Type 2 Diabetic Mice"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1741-3559","authenticated-orcid":false,"given":"Yuying","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Ministry of Education for Neurological Disorders, 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Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiazhao","family":"Xie","sequence":"additional","affiliation":[{"name":"Key Laboratory of Ministry of Education for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhipeng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurology Zhongnan Hospital of Wuhan University, Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology Zhongnan Hospital of Wuhan University, Wuhan University  Wuhan 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