Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer’s disease
9 affiliations
- 1Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
- 2Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
- 3David 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
- 4Department of Neurology, Yale University, New Haven, CT, USA
- 5Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA
- 6Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
- 7Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK, USA
- 8Department of Neurology, Emory University, Atlanta, GA, USA
- 9Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA. [email protected]
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.
Related
- Dissection of neuropsychiatric-relevant behavioral and structural phenotypes utilizing neuron type-specific ablation of the Bassoon gene in mice
- Cis-Attenuation of Pathogenic Scn8a Variant Causing Childhood Epilepsy Reveals Opposing Transcriptional Programs Driving NaV1.6 Gain and Loss of Function Phenotypes
- Novel Compound Heterozygous RECQL4 Pathogenic Variants and Associated Phenotypes in a Chinese Patient With Rothmund-Thomson Syndrome: Case Report and Literature Review.
- The Spectrum of Neurologic Phenotypes Associated With NUS1 Pathogenic Variants: A Comprehensive Case Series
- Spinal Noradrenergic Overdrive Promotes Reversible Motor Unit Aging and Sarcopenia
BibTeX
@article{korukonda2026pathogenic,
title = {{Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer’s disease}},
author = {Anu Korukonda and Harris E. Blankenship and Korey Kam and Dilpreet Kour and Claudia Espinosa‐García and Wooyoung Eric Jang and Upasna Srivastava and Bernard Mulvey and Margaret M. Tish and Ronit Witztum and Christina C. Ramelow and Brittany S. Pate and Larry Cameron Liles and Linyue Lu and Jake Atallah and Eugene Guo and Keri Martinowich and Amanda Lea Sharpe and Andrew W. Varga and Srikant Rangaraju and Michael J. Beckstead and David Weinshenker},
journal = {Molecular Psychiatry},
year = {2026},
month = sep,
doi = {10.1038/s41380-026-03852-5},
url = {https://doi.org/10.1038/s41380-026-03852-5},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer’s disease
AU - Anu Korukonda
AU - Harris E. Blankenship
AU - Korey Kam
AU - Dilpreet Kour
AU - Claudia Espinosa‐García
AU - Wooyoung Eric Jang
AU - Upasna Srivastava
AU - Bernard Mulvey
AU - Margaret M. Tish
AU - Ronit Witztum
AU - Christina C. Ramelow
AU - Brittany S. Pate
AU - Larry Cameron Liles
AU - Linyue Lu
AU - Jake Atallah
AU - Eugene Guo
AU - Keri Martinowich
AU - Amanda Lea Sharpe
AU - Andrew W. Varga
AU - Srikant Rangaraju
AU - Michael J. Beckstead
AU - David Weinshenker
PY - 2026
DA - 2026/09/01
JO - Molecular Psychiatry
DO - 10.1038/s41380-026-03852-5
UR - https://doi.org/10.1038/s41380-026-03852-5
AB - 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.
SN - 1359-4184
SN - 1476-5578
ER -