{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T23:52:51Z","timestamp":1789170771899,"version":"build-2803163510"},"reference-count":45,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T00:00:00Z","timestamp":1732579200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["RS\u20102020\u2010KH106747"],"award-info":[{"award-number":["RS\u20102020\u2010KH106747"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Alzheimer's disease (AD) is marked by the presence of intraneuronal neurofibrillary tangles (NFTs), which are primarily composed of hyperphosphorylated tau protein. The locus coeruleus (LC), the brain's main source of norepinephrine (NE), is one of the earliest regions to develop NFTs and experience neurodegeneration in AD. While LC\u2010derived NE plays beneficial roles in cognition, emotion, locomotion, and the sleep\u2013wake cycle, its impact on tau pathology is unclear. To explore this relationship, we administered intraperitoneal injections of either N\u2010(2\u2010chloroethyl)\u2010N\u2010ethyl\u20102\u2010bromobenzylamine (DSP4), a selective neurotoxin for noradrenergic neurons, or reboxetine (RBX), a norepinephrine reuptake inhibitor, to decrease or increase NE levels, respectively, in early tau transgenic mice expressing mutant human P301L tau (ADLP<jats:sup>Tau<\/jats:sup>) for two months. Only the RBX\u2010treated mice exhibited cognitive deficits, as evidenced by their performance in the Y\u2010maze, novel object recognition, and contextual fear conditioning tests. Immunohistochemical analysis revealed increased hyperphosphorylated tau aggregates in the LC and hippocampus of the RBX\u2010treated mice. Furthermore, neuronal apoptosis was observed in the hippocampal CA1 region of these mice. Western blotting showed that RBX injections led to the overactivation of tau kinases PKA and GSK3\u03b2, resulting in hyperphosphorylated tau, neuronal loss, and cognitive impairments. Consistent with these findings, human brain organoids exposed to higher NE concentrations also displayed elevated hyperphosphorylated tau and increased activity of the same tau kinases. These findings suggest that excessive NE exposure accelerates tau pathology by overactivating the tau kinases. Thus, modulating NE levels in the brain via the LC\u2010NE system could be a potential therapeutic strategy for tau\u2010related AD.<\/jats:p>","DOI":"10.1111\/acel.14420","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T04:35:01Z","timestamp":1732682101000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Long\u2010term exposure to excessive norepinephrine in the brain induces tau aggregation, neuronal death, and cognitive deficits in early tau transgenic mice"],"prefix":"10.1111","volume":"24","author":[{"given":"June\u2010Hyun","family":"Jeong","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biomedical Sciences, College of Medicine Seoul National University  Seoul Korea"},{"name":"Convergence Dementia Research Center, College of Medicine Seoul National University  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong 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