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Seizures in AD have been shown to occur more often with early\u2010onset disease, particularly when there is a familial presenilin I (PS1) mutation or abnormal expression of amyloid precursor protein (APP). AD patients with seizures have been associated with a faster decline in cognitive functions. However, it remains unclear how seizures exacerbate neurodegeneration in AD. Here, we showed that, using a kainic acid\u2010induced acute seizure model, mitochondrial function is enhanced and the reactive oxygen species (ROS) are reduced in the brain of wild\u2010type (WT) mice but not in an AD mouse model, APP\/PS1 mice. These data suggest a lack of protective mechanism following seizures in APP\/PS1 mice. Mechanistically, we found that an E3 ubiquitin ligase, the neural precursor cell\u2010expressed developmentally downregulated protein 4\u2010like (Nedd4\u20102), is elevated but stays dephosphorylated in APP\/PS1 mice upon seizure inductions. Immunocytochemistry and sub\u2010cellular fractionation experiments demonstrate an interaction between Nedd4\u20102 and mitochondria. Unbiased proteomics analysis suggests that Nedd4\u20102 regulates the expression of multiple mitochondrial proteins including one of the key mitochondrial outer membrane proteins, Mitofusin 2 (MFN2). Upon seizure induction, Nedd4\u20102 exhibits elevated interaction with mitochondria and downregulates MFN2 in APP\/PS1 mice but not in WT mice. These data suggest that seizures aggravate mitochondrial dysfunction in AD, and Nedd4\u20102, which acts as a negative mitochondrial regulator, contributes to this effect. Altogether, our findings illustrate a potential mechanism by which seizures exacerbate neurodegeneration in AD and suggest Nedd4\u20102 as a novel therapeutic target for AD patients with comorbid seizures.<\/jats:p>\n                  <jats:p>\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\/jnc70440-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70440","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T06:22:10Z","timestamp":1776234130000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>E3<\/scp>\n                    Ubiquitin Ligase Nedd4\u20102 Exacerbates Seizure\u2010Induced Mitochondrial Defects in an Alzheimer's Disease Mouse Model"],"prefix":"10.1111","volume":"170","author":[{"given":"Yingxin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Molecular and Integrative Physiology School of Molecular and Cellular Biology, University of Illinois at Urbana\u2010Champaign  Urbana Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiuhe","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology School of Molecular and Cellular Biology, University of Illinois at 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