ArticleActa physiologica (Oxford, England)2025
Early signs of neuron autonomous and non-autonomous hyperexcitability in locus coeruleus noradrenergic neurons of a mouse model of tauopathy and Alzheimer's disease.
Article in Acta physiologica (Oxford, England), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- A new hope: locus coeruleus-norepinephrine system at the nexus of neuropsychiatric symptoms.Molecular psychiatry · 2026Review
- Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer's disease.Molecular psychiatry · 2026Article
- The monoaminergic systems as drivers of Alzheimer's disease pathophysiology and symptomatology.Current opinion in neurology · 2026Review
- Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer's disease.bioRxiv : the preprint server for biology · 2026Article
- Vagus nerve stimulation alters task-evoked pupillary responses in older but not younger adults: A single-blind active sham-controlled crossover trial.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Sleep and stress as modifiable drivers of Alzheimer's disease.NPJ dementia · 2026Review
- Tyrosinase-induced neuromelanin accumulation triggers rapid dysregulation and degeneration of the mouse locus coeruleus.bioRxiv : the preprint server for biology · 2025Article
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Abstract
aimThe locus coeruleus (LC) is one of the earliest brain regions affected by phosphorylated tau (p-tau) in Alzheimer's disease (AD). Using the P301S mouse model, we investigated the temporal progression of tau pathology and its functional consequences.
methodsImmunohistochemistry was used to assess p-tau deposition in LC noradrenergic neurons at 2-3 and 5-6 months. Electrophysiological recordings evaluated neuronal hyperexcitability, measuring membrane potential, rheobase, and spontaneous action potential (AP) frequency in P301S and wild-type (WT) mice. Fast-scan cyclic voltammetry (FSCV) was used to measure norepinephrine (NE) release. GABA(A) receptor subunit expression was analyzed via immunoblotting.
resultsP-tau was detected in LC neurons as early as 2-3 months, with a rostral-to-caudal gradient, and by 5-6 months, nearly all LC neurons exhibited p-tau immunoreactivity. P301S neurons showed hyperexcitability, characterized by depolarized membrane potentials, a more negative rheobase, and increased spontaneous AP frequency. Synaptic blockade elicited a reduced increase in AP frequency, suggesting diminished inhibitory tone. GABA(A) α2 subunit expression significantly declined with age in P301S mice, whereas α3 remained unchanged. FSCV showed significantly elevated NE release in P301S mice at 3 and 6 months compared to WT.
conclusionThe findings highlight early LC dysfunction in tauopathies, characterized by increased excitability, reduced inhibitory tone, and exaggerated NE release. This hyperactivity may contribute to excitotoxicity and downstream dysfunction in LC-regulated brain regions. Targeting LC hyperactivity and restoring inhibitory signaling could be promising therapeutic strategies for mitigating AD progression.
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