ArticleProceedings of the National Academy of Sciences of the United States of America2014
Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer's disease.
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 114 papers, 3 of them syntheses that pooled it.
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Who cites it
114 citing papers in PubMed, 3 syntheses or guidelines pooled it, 199 citations in OpenAlex.
- The Role of c-Abl in Alzheimer's Disease: Guilty or not Guilty?Cellular and molecular neurobiology · 2025Pooled it
- Finding memo: versatile interactions of the VPS10p-Domain receptors in Alzheimer's disease.Molecular neurodegeneration · 2022Pooled it
- Meta-analysis of synaptic pathology in Alzheimer's disease reveals selective molecular vesicular machinery vulnerability.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2016Pooled it
- lncRNAs: key player in Aβ deposition.RNA biology · 2026Review
- Targeting receptor tyrosine kinases: from molecular mechanisms to clinical therapeutics.Signal transduction and targeted therapy · 2026Review
- Natural Products and Neuroregeneration: Rethinking Discovery Beyond Bioavailability Through Pseudo-Natural Product Design.Biomedicines · 2026Review
- Repurposing trazodone for Alzheimer's disease to modulate soluble ST2 levels and alleviate Alzheimer's pathology.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Neurexins, Ephrin receptors, and N-cadherin signaling as emerging mechanisms in synaptic dysfunction and neurodegenerative diseases.Communications biology · 2026Review
- Neuronal guidance signaling in neurodegenerative diseases: Key regulators that function at neuron-glia and neuroimmune interfaces.Neural regeneration research · 2026Article
- The Eph-ephrin system in neuropsychiatric and neurodevelopmental disorders.Journal of psychiatry & neuroscience : JPN · 2026Review
- A chromosome-level Mitragyna parvifolia genome unveils spirooxindole alkaloid diversification and mitraphylline biosynthesis.The Plant cell · 2025Article
- Analysis of changes in intercellular communications in Alzheimer's disease reveals conserved changes in glutamatergic transmission in mice and humans.Scientific reports · 2025Article
- Rhynchophylline alleviates cognitive deficits in multiple transgenic mouse models of Alzheimer's disease via modulating neuropathology and gut microbiota.Acta pharmacologica Sinica · 2025Article
- Interrogating mediators of single-cell transcriptional changes in the acute damaged cerebral cortex: Insights into endothelial-astrocyte interactions.Molecular and cellular neurosciences · 2025Article
- tRFAlzheimer's research & therapy · 2025Article
- Astrocytic EphA4 signaling is important for the elimination of excitatory synapses in Alzheimer's disease.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Chemerin-9 is neuroprotective in APP/PS1 transgenic mice by inhibiting NLRP3 inflammasome and promoting microglial clearance of Aβ.Journal of neuroinflammation · 2025Article
- Impact of hyaluronic acid-modified hafnium metalorganic frameworks containing rhynchophylline on Alzheimer's disease.Open life sciences · 2025Article
- Multichannel 3D-Printed Bioactive Scaffold Combined with Small Interfering RNA Delivery to Promote Neurological Recovery after Spinal Cord Injury.Research (Washington, D.C.) · 2025Article
- Constrained β-Hairpins Targeting the EphA4 Ligand Binding Domain.Journal of medicinal chemistry · 2024Article
54 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 2 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Alzheimer's disease (AD), characterized by cognitive decline, has emerged as a disease of synaptic failure. The present study reveals an unanticipated role of erythropoietin-producing hepatocellular A4 (EphA4) in mediating hippocampal synaptic dysfunctions in AD and demonstrates that blockade of the ligand-binding domain of EphA4 reverses synaptic impairment in AD mouse models. Enhanced EphA4 signaling was observed in the hippocampus of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD, whereas soluble amyloid-β oligomers (Aβ), which contribute to synaptic loss in AD, induced EphA4 activation in rat hippocampal slices. EphA4 depletion in the CA1 region or interference with EphA4 function reversed the suppression of hippocampal long-term potentiation in APP/PS1 transgenic mice, suggesting that the postsynaptic EphA4 is responsible for mediating synaptic plasticity impairment in AD. Importantly, we identified a small-molecule rhynchophylline as a novel EphA4 inhibitor based on molecular docking studies. Rhynchophylline effectively blocked the EphA4-dependent signaling in hippocampal neurons, and oral administration of rhynchophylline reduced the EphA4 activity effectively in the hippocampus of APP/PS1 transgenic mice. More importantly, rhynchophylline administration restored the impaired long-term potentiation in transgenic mouse models of AD. These findings reveal a previously unidentified role of EphA4 in mediating AD-associated synaptic dysfunctions, suggesting that it is a new therapeutic target for this disease.
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