{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T02:51:45Z","timestamp":1772160705770,"version":"3.50.1"},"reference-count":31,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T00:00:00Z","timestamp":1736467200000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["92049107"],"award-info":[{"award-number":["92049107"]}],"id":[{"id":"10.13039\/501100001809","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":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Brain damage induced by ischemia promotes the development of cognitive dysfunction, thus increasing the risk of dementia such as Alzheimer's disease (AD). Studies indicate that cellular acidification\u2010triggered activation of asparagine endopeptidase (AEP) plays a key role in ischemic brain injury, through multiple molecular pathways, including cleavage of its substrates such as SET (inhibitor 2 of PP2A, I\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>PP2A<\/jats:sup>\n                    ) and Tau. However, whether direct targeting AEP can effectively prevent post\u2010stroke cognitive impairment (PSCI) remains unanswered. Here, we explored the therapeutic effect and underlying mechanism of the AEP inhibitor AENK on cognitive impairment of the rats with middle cerebral artery occlusion (MCAO) and on neuronal damage in cultured primary neurons exposed to oxygen and glucose deprivation (OGD). We found that the administration of AENK significantly reduces activated AEP levels in ischemic rat brains, attenuates cognitive deficits, and rescues synaptic dysfunction. For the mechanism, with AEP inhibition, cleavage of SET, inhibition of protein phosphatase 2A (PP2A), and Tau hyperphosphorylation resulted from PP2A inhibition, were all completely or partially reversed. In primary neurons, AENK effectively prevents AEP activation, SET cleavage and cytoplasmic retention, tau hyperphosphorylation and synaptic damage induced by OGD. We conclude that AENK ameliorates cognitive impairment and prevents tau hyperphosphorylation, through inhibiting AEP\u2010mediated cleavage of SET in ischemic brain injury, and direct inhibition of AEP might be a potential therapeutic strategy for preventing synaptic damage and cognitive impairment after stroke.\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\/jnc16283-fig-0007-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16283","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T03:35:58Z","timestamp":1736480158000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>AENK<\/scp>\n                    ameliorates cognitive impairment and prevents Tau hyperphosphorylation through inhibiting\n                    <scp>AEP<\/scp>\n                    \u2010mediated cleavage of\n                    <scp>SET<\/scp>\n                    in rats with ischemic stroke"],"prefix":"10.1111","volume":"169","author":[{"given":"Yi","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry\/Hubei Province of China for Neurological Disorders, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Cognitive and Affective Discorders, Institutes of Biomedical Sciences, School of Medicine Jianghan University  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cuiping","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry\/Hubei Province of China for Neurological Disorders, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"},{"name":"Department of Emergency Medicine, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Bao","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Cognitive and Affective Discorders, Institutes 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