ArticleProceedings of the National Academy of Sciences of the United States of America2014
α(2A) adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 80 citations in OpenAlex.
- Testing effects of paced breathing on plasma Aβ and brain perivascular spaces.International journal of psychophysiology : official journal of the International Organization of Psychophysiology · 2026Trial
- A Randomized Clinical Trial Reveals Effects of Mindfulness and Slow Breathing on Plasma Amyloid Beta Levels.Psychophysiology · 2025Trial
- Beta 2-adrenergic pathway combats Alzheimer's disease: Restoring cognition and synaptic integrity.Neural regeneration research · 2026Article
- The neuromodulatory fragility hypothesis of Alzheimer's disease pathogenesis.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Decoding GPCR signaling in living cells to advance early therapeutic discovery for neurological disorders.Frontiers in molecular neuroscience · 2026Review
- Pleiotropic prodrugs for both symptomatic and disease-modifying treatment of Alzheimer's disease.Acta pharmaceutica Sinica. B · 2025Article
- The interaction between neurotransmitter receptor activity and amyloid-β pathology in Alzheimer's disease.Journal of Alzheimer's disease : JAD · 2025Review
- The PKCι-β-arrestin2 axis disrupts SORLA retrograde trafficking, driving its degradation and amyloid pathology in Alzheimer's disease.Molecular neurodegeneration · 2025Article
- Autonomic dysfunction in neurodegenerative disease.Nature reviews. Neuroscience · 2025Review
- An Expanded Narrative Review of Neurotransmitters on Alzheimer's Disease: The Role of Therapeutic Interventions on Neurotransmission.Molecular neurobiology · 2025Review
- Monoamine alterations in Alzheimer's disease and their implications in comorbid neuropsychiatric symptoms.GeroScience · 2025Review
- Deciphering the Role of Adrenergic Receptors in Alzheimer's Disease: Paving the Way for Innovative Therapies.Biomolecules · 2025Review
- Noradrenergic therapies in neurodegenerative disease: from symptomatic to disease modifying therapy?Brain communications · 2025Review
- Monoamine signaling and neuroinflammation: mechanistic connections and implications for neuropsychiatric disorders.Frontiers in immunology · 2025Review
- Mechanism of Metal Complexes in Alzheimer's Disease.International journal of molecular sciences · 2024Review
- Endo-Lysosomal Network Disorder Reprograms Energy Metabolism in SorL1-Null Rat Hippocampus.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Androgen deprivation therapy exacerbates Alzheimer's-associated cognitive decline via increased brain immune cell infiltration.Science advances · 2024Article
- Systematic characterization of multi-omics landscape between gut microbial metabolites and GPCRome in Alzheimer's disease.Cell reports · 2024Article
- Adrenoceptor Desensitization: Current Understanding of Mechanisms.Pharmacological reviews · 2024Review
- Dual-specificity protein phosphatase 6 (DUSP6) overexpression reduces amyloid load and improves memory deficits in male 5xFAD mice.Frontiers in aging neuroscience · 2024Article
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Accumulation of amyloid β (Aβ) peptides in the brain is the key pathogenic factor driving Alzheimer's disease (AD). Endocytic sorting of amyloid precursor protein (APP) mediated by the vacuolar protein sorting (Vps10) family of receptors plays a decisive role in controlling the outcome of APP proteolytic processing and Aβ generation. Here we report for the first time to our knowledge that this process is regulated by a G protein-coupled receptor, the α(2A) adrenergic receptor (α(2A)AR). Genetic deficiency of the α(2A)AR significantly reduces, whereas stimulation of this receptor enhances, Aβ generation and AD-related pathology. Activation of α(2A)AR signaling disrupts APP interaction with a Vps10 family receptor, sorting-related receptor with A repeat (SorLA), in cells and in the mouse brain. As a consequence, activation of α(2A)AR reduces Golgi localization of APP and concurrently promotes APP distribution in endosomes and cleavage by β secretase. The α(2A)AR is a key component of the brain noradrenergic system. Profound noradrenergic dysfunction occurs consistently in patients at the early stages of AD. α(2A)AR-promoted Aβ generation provides a novel mechanism underlying the connection between noradrenergic dysfunction and AD. Our study also suggests α(2A)AR as a previously unappreciated therapeutic target for AD. Significantly, pharmacological blockade of the α(2A)AR by a clinically used antagonist reduces AD-related pathology and ameliorates cognitive deficits in an AD transgenic model, suggesting that repurposing clinical α(2A)R antagonists would be an effective therapeutic strategy for AD.
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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.