ArticleThe Journal of clinical investigation2020
Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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Who cites it
81 citing papers in PubMed, 118 citations in OpenAlex.
- A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment.Brain : a journal of neurology · 2022Trial
- 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
- Locus Coeruleus as a Master Regulator of Diverse Functions in the Central Nervous System: Its Relevance in Ageing and Neurodegenerative Disorders.Annals of neurosciences · 2026Review
- Stress, stress systems, and Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- Neurotransmitter Systems in Alzheimer's Disease.Current issues in molecular biology · 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
- Reboxetine Treatment Reduces Hippocampal Gliosis in the P301S Tauopathy Mouse Model.ASN neuro · 2026Article
- Research progress on the role of the locus coeruleus in cognitive function.Frontiers in human neuroscience · 2026Review
- A locus coeruleus-centric framework for novelty, salience, and gamma oscillations: implications for neurostimulation, aging, and disease.Frontiers in aging neuroscience · 2026Article
- Chronic stress-induced LC-NE dysfunction: cellular and axonal mechanisms underlying impaired neuromodulation.Frontiers in neuroscience · 2026Review
- Tau protein: Physiological functions and multifaceted roles in neurodegenerative and psychiatric disorders.Genomic psychiatry : advancing science from genes to society · 2025Article
- Long-term Locus Coeruleus Stimulation Exacerbates Tau Pathology in PS19 Mice.bioRxiv : the preprint server for biology · 2025Article
- Impact of Alzheimer's disease risk factors and local neuromelanin content on the transcriptomic landscape of the human locus coeruleus.bioRxiv : the preprint server for biology · 2025Article
- Article
- Alcohol consumption during early adulthood increases the vulnerability of locus coeruleus neurons and amyloid beta pathology in female APP/PS1 mice.Alcohol (Fayetteville, N.Y.) · 2025Article
- Not 'Inactive' After All: Cardiotoxic Mechanisms of Catecholamine Metabolism by Monoamine Oxidase.Cardiovascular toxicology · 2025Review
- Regenerating Locus Coeruleus-Norepinephrine (LC-NE) Function: A Novel Approach for Neurodegenerative Diseases.Cell proliferation · 2025Review
- Disease-specific neuropathological alterations of the locus coeruleus in Alzheimer's disease, Down syndrome, and Parkinson's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Immunotherapy against tau fragment diminishes AD pathology, improving synaptic function and cognition.Molecular neurodegeneration · 2025Article
21 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Aberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer's disease-like (AD-like) neuropathology in the human brain. However, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here, we show that 3,4-dihydroxyphenylglycolaldehyde, which is produced exclusively in noradrenergic neurons by monoamine oxidase A metabolism of norepinephrine, activated asparagine endopeptidase that cleaved Tau at residue N368 into aggregation- and propagation-prone forms, thus leading to LC degeneration and the spread of Tau pathology. Activation of asparagine endopeptidase-cleaved Tau aggregation in vitro and in intact cells was triggered by 3,4-dihydroxyphenylglycolaldehyde, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal that norepinephrine metabolism and Tau cleavage represent the specific molecular mechanism underlying the selective vulnerability of LC neurons in AD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.