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An early pathological feature is the accumulation of hyperphosphorylated \u201cpretangle\u201d tau (pTau) in the locus coeruleus (LC), the brain\u2019s primary source of norepinephrine (NE). While clinical studies link LC pTau burden to behavioral abnormalities, causal mechanisms remain unclear. We developed a translationally-relevant mouse model that recapitulates the \u2018LC-first\u2019 phenomenon using cell type-specific viral expression of pathogenic P364S mutant human tau in LC neurons. Three months post-infusion, pTau accumulation induced anxiety-and compulsive-like behaviors and reduced sleep spindles without altering overall sleep architecture. Consistent with the behavioral phenotypes, electrophysiological recordings revealed significant increases in spontaneous and evoked firing of LC neurons, accompanied by robust astrocytic reactivity with no apparent cell death. Transcriptomic analysis identified upregulation of\n                  <jats:italic>Hcn2<\/jats:italic>\n                  and downregulation of\n                  <jats:italic>Clic6<\/jats:italic>\n                  , suggesting changes in neuronal excitability. To further define molecular mechanisms, we developed a cell type-specific proteomics approach, which showed synaptic and metabolic alterations associated with LC-specific tau pathology. Early anxiety-like behaviors observed at 3 months diminished at later timepoints (6-9 months) and were replaced by anxiolytic characteristics. These findings demonstrate that pTau triggers phenotypes reflective of LC-NE hyperactivity in the early stages of AD pathogenesis, laying the foundation for the development of LC-based disease-modifying therapies to address neuropsychiatric manifestations.\n                <\/jats:p>","DOI":"10.64898\/2026.01.30.702923","type":"posted-content","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T06:50:18Z","timestamp":1770015018000},"source":"Crossref","is-referenced-by-count":3,"title":["Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"given":"Anu","family":"Korukonda","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harris E.","family":"Blankenship","sequence":"additional","affiliation":[{"name":"Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Korey","family":"Kam","sequence":"additional","affiliation":[{"name":"David M. 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