ArticleAnnals of neurology2015
Fyn inhibition rescues established memory and synapse loss in Alzheimer mice.
Article in Annals of neurology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 186 papers.
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Who cites it
186 citing papers in PubMed, 308 citations in OpenAlex.
- A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer's disease.Alzheimer's research & therapy · 2024Trial
- Fyn kinase: a key mechanistic regulator and therapeutic target in tauopathy and neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Current review on inducible nitric oxide synthase and Src tyrosine kinase inhibitors as disease-modifiers in preclinical models of epilepsy.Histology and histopathology · 2026Review
- Native PLGA nanoparticles attenuate disease pathology via multiple pathways in 5xFAD Alzheimer's model.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Functional sQTLs regulating PTK2B exon 31 splicing uncover an RNA-dependent modulation of its kinase activity and cellular phenotype.Cell communication and signaling : CCS · 2026Article
- Alzheimer's disease: from molecular pathways to therapies.Molecular biomedicine · 2026Review
- Protein kinases as therapeutic targets in Alzheimer's disease: challenges, insights, and new frontiers.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Review
- Polydopamine Modified with Brain Targeting Peptide Rabies Virus Glycoprotein for Treatment of Alzheimer's Disease by Inhibiting Oxidative Stress and Inflammatory Response.International journal of nanomedicine · 2026Article
- Astrocytic Igfbp2 Promotes Spontaneous Seizures in a Mouse Model of Mesial Temporal Lobe Epilepsy.Glia · 2026Article
- Src and Abl as Therapeutic Targets in Lung Cancer: Opportunities for Drug Repurposing.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Exploration of the Neuromodulatory Properties of Fyn and GSK-3β Kinases Exploiting 7-Azaindole-Based Inhibitors.Journal of medicinal chemistry · 2025Article
- Diet-incorporated saracatinib, a Src tyrosine kinase inhibitor, counteracts diisopropylfluorophosphate (DFP)-induced chronic neurotoxicity in the rat model.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Article
- Fyn-dependent Tau microcluster formation seeds and boosts extensive Tau pathology.Acta neuropathologica · 2025Article
- Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery.Signal transduction and targeted therapy · 2025Review
- A 3D human iPSC-derived multi-cell type neurosphere system to model cellular responses to chronic amyloidosis.Journal of neuroinflammation · 2025Article
- Intramuscular delivery of recombinant AAV expressing EpoR76E improves memory and is neuroprotective in 5xFAD transgenics.Research square · 2025Article
- Therapeutic modulation of neurogenesis to improve hippocampal plasticity and cognition in aging and Alzheimer's disease.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- Inhibition of Src signaling induces autophagic killing of Toxoplasma gondii via PTEN-mediated deactivation of Akt.PLoS pathogens · 2025Article
- Unraveling the neuroprotective mechanisms of elephant black garlic extract against beta amyloid peptide-induced neurotoxicity.Frontiers in nutrition · 2025Article
- Repetitive Mild Closed-Head Injury Induced Synapse Loss and Increased Local BOLD-fMRI Signal Homogeneity.Journal of neurotrauma · 2024Article
126 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
objectiveCurrently no effective disease-modifying agents exist for the treatment of Alzheimer disease (AD). The Fyn tyrosine kinase is implicated in AD pathology triggered by amyloid-ß oligomers (Aßo) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncology compound, AZD0530, for AD.
methodsThe pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Aßo signaling to Fyn, Pyk2, and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild-type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, amyloid precursor protein (APP) metabolism, synaptic markers (SV2 and PSD-95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochemistry and by immunoblotting.
resultsAZD0530 potently inhibits Fyn and prevents both Aßo-induced Fyn signaling and downstream phosphorylation of the AD risk gene product Pyk2, and of NR2B Glu receptors in brain slices. After 4 weeks of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Aß metabolism. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity.
interpretationTargeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse density loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy 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.