Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer’s disease

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Publication Details

Journal
Molecular Psychiatry
Published
2026-09-01
DOI
https://doi.org/10.1038/s41380-026-03852-5
Citations
2
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
10.93

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article

Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer’s disease

Michael J. Beckstead, Brittany S. Pate, Amanda L. Sharpe, Christina C. Ramelow et al.
2 citations
Molecular Psychiatry
Alzheimer's disease research and treatments
10.93
article

Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer’s disease

Michael J. Beckstead, Brittany S. Pate, Amanda L. Sharpe, Christina C. Ramelow, Wooyoung Eric Jang, Upasna Srivastava, Korey Kam, David Weinshenker, L Cameron Liles, Margaret M Tish, Upsana Srivastava, Korey Kam, Wooyoung Eric Jang, Bernard Mulvey, Claudia Espinosa-Garcia, Anu Korukonda, Ronit Witztum, Andrew Varga, Harris E Blankenship, Michael J Beckstead, Jake Atallah, David J Weinshenker, Amanda L Sharpe, Linyue Lu, Dilpreet Kour, Keri Martinowich, Brittany S Pate, Christina C Ramelow, Srikant Rangaraju, Eugene Guo
article en
2 citations

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.

Molecular Psychiatry
Johns Hopkins University (US), Emory University (US), Johns Hopkins Medicine (US), Oklahoma Medical Research Foundation (US), Yale University (US), Lieber Institute for Brain Development (US), Icahn School of Medicine at Mount Sinai (US)
Alzheimer's Association, National Institute on Aging, National Institute on Drug Abuse, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences
Good health and well-being
Openalex Percentile: Top 3%
Alzheimer's disease research and treatments
10.93
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