ArticleeLife2025
Chronic stress impairs autoinhibition in neurons of the locus coeruleus to increase asparagine endopeptidase activity.
Article in eLife, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- The Effect of Low-Dose Dexmedetomidine Nasal Spray on Anxiety Levels in Gynaecological Patients on the Day of Surgery: A Randomised Controlled Study.Drug design, development and therapy · 2026Trial
- The Oral-Brain Axis: A Unified Framework Linking Trigeminal Sensorimotor Dysfunction, Chronic Stress, Neuroinflammation, and Neurodegeneration.International journal of molecular sciences · 2026Review
- Stress, stress systems, and Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- Preclinical Catecholaminergic Biomarkers of Central Lewy Body Diseases.Journal of clinical neurology (Seoul, Korea) · 2026Review
- Chronic stress-induced LC-NE dysfunction: cellular and axonal mechanisms underlying impaired neuromodulation.Frontiers in neuroscience · 2026Review
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Authors and funding
7 authors.
Funding
Abstract
Impairments of locus coeruleus (LC) are implicated in anxiety/depression and Alzheimer's disease (AD). Increases in cytosolic noradrenaline (NA) concentration and monoamine oxidase A (MAO-A) activity initiate the LC impairment through production of NA metabolite, 3,4-dihydroxyphenyl-glycolaldehyde (DOPEGAL), by MAO-A. However, how NA accumulates in soma/dendritic cytosol of LC neurons has never been addressed despite the fact that NA is virtually absent in cytosol while NA is produced exclusively in cytoplasmic vesicles from dopamine by dopamine-β-hydroxylase. Since reuptake of autocrine-released NA following spike activity is the major source of NA accumulation, we investigated whether and how chronic stress can increase the spike activity accompanied by NA autocrine. Overexcitation of LC neurons is normally prevented by the autoinhibition mediated by activation of α2A-adrenergic receptor (AR)-coupled inwardly rectifying potassium-current (GIRK-I) with autocrine-released NA. Patch-clamp study revealed that NA-induced GIRK-I in LC neurons was decreased in chronic restraint stress (RS) mice, while a similar decrease was gradually caused by repeated excitation. Chronic RS caused internalization of α2A-ARs expressed in cell membrane in LC neurons and decreased protein/mRNA levels of α2A-ARs/GIRKs in membrane fraction. Subsequently, chronic RS increased the protein levels of MAO-A, DOPEGAL-induced asparagine endopeptidase (AEP), and tau N368. These results suggest that chronic RS-induced overexcitation due to the internalization of α2A-ARs/GIRK is accompanied by [Ca
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