{
  "abstract": "Alzheimer's disease (AD), though defined as a cognitive disorder, often presents neuropsychiatric symptoms such as anxiety, depression, agitation, and sleep disruptions years before the onset of frank memory impairment. An early pathological feature is the accumulation of hyperphosphorylated \"pretangle\" tau (pTau) in the locus coeruleus (LC), the brain's primary source of norepinephrine (NE). While clinical studies link LC pTau burden to behavioral abnormalities, mechanisms underlying these phenomena remain unclear. We developed a translationally-relevant mouse model that recapitulates the 'LC-first' pattern 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 Hcn2 and downregulation of Clic6, 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. While pTau burden persisted at 6 and 9 months after viral infusion, the anxiety-like behaviors observed at 3 months abated at these later timepoints. These findings demonstrate that pTau triggers phenotypes reflective of LC-NE hyperactivity in the early stages of AD pathogenesis, with implications for future noradrenergic-based interventions to address neuropsychiatric manifestations.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA",
    "Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA",
    "David M. Rapoport Sleep Research Laboratory, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA",
    "Department of Neurology, Yale University, New Haven, CT, USA",
    "Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA",
    "Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA",
    "Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK, USA",
    "Department of Neurology, Emory University, Atlanta, GA, USA",
    "Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA. dweinsh@emory.edu"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 22,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Anu Korukonda",
      "orcid": "0000-0002-5068-4717"
    },
    {
      "affs": [
        1
      ],
      "name": "Harris E. Blankenship",
      "orcid": "0000-0001-7570-4895"
    },
    {
      "affs": [
        2
      ],
      "name": "Korey Kam",
      "orcid": "0000-0001-7011-9080"
    },
    {
      "affs": [
        3
      ],
      "name": "Dilpreet Kour",
      "orcid": "0009-0006-4865-2376"
    },
    {
      "affs": [
        3
      ],
      "name": "Claudia Espinosa‐García",
      "orcid": "0000-0002-9909-9092"
    },
    {
      "affs": [
        3
      ],
      "name": "Wooyoung Eric Jang",
      "orcid": "0000-0001-9700-5366"
    },
    {
      "affs": [
        3
      ],
      "name": "Upasna Srivastava",
      "orcid": "0000-0003-4096-9257"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Bernard Mulvey",
      "orcid": "0000-0003-0815-0436"
    },
    {
      "affs": [
        0
      ],
      "name": "Margaret M. Tish",
      "orcid": "0000-0002-8954-1983"
    },
    {
      "affs": [
        2
      ],
      "name": "Ronit Witztum",
      "orcid": "0009-0004-8987-1458"
    },
    {
      "affs": [
        6
      ],
      "name": "Christina C. Ramelow",
      "orcid": "0000-0001-5443-1074"
    },
    {
      "affs": [
        0
      ],
      "name": "Brittany S. Pate",
      "orcid": "0000-0002-3711-5229"
    },
    {
      "affs": [
        0
      ],
      "name": "Larry Cameron Liles"
    },
    {
      "affs": [
        0
      ],
      "name": "Linyue Lu"
    },
    {
      "affs": [
        0
      ],
      "name": "Jake Atallah"
    },
    {
      "affs": [
        0
      ],
      "name": "Eugene Guo"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Keri Martinowich",
      "orcid": "0000-0002-5237-0789"
    },
    {
      "affs": [
        1
      ],
      "name": "Amanda Lea Sharpe",
      "orcid": "0000-0003-3971-5946"
    },
    {
      "affs": [
        2
      ],
      "name": "Andrew W. Varga",
      "orcid": "0000-0002-3668-3371"
    },
    {
      "affs": [
        7,
        3
      ],
      "name": "Srikant Rangaraju",
      "orcid": "0000-0003-2765-1500"
    },
    {
      "affs": [
        1,
        6
      ],
      "name": "Michael J. Beckstead",
      "orcid": "0000-0002-1574-530X"
    },
    {
      "affs": [
        8
      ],
      "name": "David Weinshenker",
      "orcid": "0000-0002-3678-6215"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cxtkgs3apetq5.bib",
  "cited_by": 5,
  "doi": "10.1038/s41380-026-03852-5",
  "fulltext_url": null,
  "id": "cxtkgs3apetq5",
  "issns": [
    "1359-4184",
    "1476-5578"
  ],
  "landing_url": "https://doi.org/10.1038/s41380-026-03852-5",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2804|Alzheimer's disease research and treatments"
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  "openalex": "W7127056418",
  "pdf_url": "https://www.nature.com/articles/s41380-026-03852-5.pdf",
  "pmcid": "PMC12873788",
  "pmid": "41659445",
  "published": "2026-09-01",
  "publisher": "Springer Nature",
  "ris": "https://research.draconitic.com/paper/cxtkgs3apetq5.ris",
  "sources": [
    {
      "first_seen": "2026-11-11T13:20:32Z",
      "native_id": "W7127056418",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41380-026-03852-5"
    }
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Alzheimer's disease research and treatments",
      "subfield": "neuroscience"
    }
  ],
  "title": "Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer’s disease",
  "title_text": "Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer’s disease",
  "type": "peer-reviewed",
  "updated_at": "2026-11-13T13:21:09Z",
  "url": "https://research.draconitic.com/paper/cxtkgs3apetq5",
  "venue": "Molecular Psychiatry",
  "versions": []
}