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Translation dysregulation is linked to multiple neurological disorders characterized by cognitive impairments. Phosphorylation of the translational factor eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K results in inhibition of general protein synthesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>We used genetic and pharmacological methods to suppress eEF2K in two lines of DS mouse models. We further applied multiple approaches to evaluate the effects of eEF2K inhibition on DS pathophysiology.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>We found that eEF2K signaling was overactive in the brain of patients with DS and DS mouse models. Inhibition of eEF2 phosphorylation through suppression of eEF2K in DS model mice improved multiple aspects of DS\u2010associated pathophysiology including <jats:italic>de novo<\/jats:italic> protein synthesis deficiency, synaptic morphological defects, long\u2010term synaptic plasticity failure, and cognitive impairments.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>Our data suggested that eEF2K signaling dysregulation mediates DS\u2010associated synaptic and cognitive impairments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Phosphorylation of the translational factor eukaryotic elongation factor 2 (eEF2) is increased in the Down syndrome (DS) brain.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Suppression of the eEF2 kinase (eEF2K) alleviates cognitive deficits in DS models.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Suppression of eEF2K improves synaptic dysregulation in DS models.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Cognitive and synaptic impairments in DS models are rescued by eEF2K inhibitors.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.13916","type":"journal-article","created":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T07:01:04Z","timestamp":1719471664000},"page":"5357-5374","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Suppression of eEF2 phosphorylation alleviates synaptic failure and cognitive deficits in mouse models of Down syndrome"],"prefix":"10.1002","volume":"20","author":[{"given":"Xin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Gerontology and Geriatric Medicine Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Gerontology and Geriatric Medicine Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueyan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Gerontology and Geriatric Medicine Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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