ArticleNeurobiology of disease2020
A peptide inhibitor of Tau-SH3 interactions ameliorates amyloid-β toxicity.
Article in Neurobiology of disease, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 30 citations in OpenAlex.
- 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
- Cholecalciferol (vitamin D3) is an agonist of the Alzheimer's disease-associated immune receptor TREM2.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Amyloid-β and Tau in Alzheimer's disease: pathogenesis, mechanisms, and interplay.Cell death & disease · 2026Review
- Multiple and Alternative Sites Make Tau Protein an Adaptable Sticky Surface for the SH3 Domain of Fyn Kinase.Angewandte Chemie (International ed. in English) · 2025Article
- The Effects of NeuronalCells · 2025Article
- Fyn Kinase in Alzheimer's Disease: Unraveling Molecular Mechanisms and Therapeutic Implications.Molecular neurobiology · 2025Review
- Enhanced Fyn-tau and NR2B-PSD95 interactions in epileptic foci in experimental models and human epilepsy.Brain communications · 2024Article
- Development of small-molecule Tau-SH3 interaction inhibitors that prevent amyloid-β toxicity and network hyperexcitability.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Article
- Fyn, an important molecule in the brain, is a potential therapeutic target for brain tumours.Frontiers in pharmacology · 2024Review
- Fyn nanoclustering requires switching to an open conformation and is enhanced by FTLD-Tau biomolecular condensates.Molecular psychiatry · 2023Article
- Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance inFrontiers in aging neuroscience · 2023Article
- Article
- Tau Acts in Concert With Kinase/Phosphatase Underlying Synaptic Dysfunction.Frontiers in aging neuroscience · 2022Review
- Fyn Kinase Activity and Its Role in Neurodegenerative Disease Pathology: a Potential Universal Target?Molecular neurobiology · 2021Review
- Tau and Membranes: Interactions That Promote Folding and Condensation.Frontiers in cell and developmental biology · 2021Review
- Beyond Neuronal Microtubule Stabilization: MAP6 and CRMPS, Two Converging Stories.Frontiers in molecular neuroscience · 2021Article
- Generation of Functional Mouse Hippocampal Neurons.Bio-protocol · 2020Article
- Fyn depletion ameliorates tauActa neuropathologica communications · 2020Article
- Alzheimer's disease risk geneeLife · 2020Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The microtubule-associated protein Tau is strongly implicated in Alzheimer's disease (AD) and aggregates into neurofibrillary tangles in AD. Genetic reduction of Tau is protective in several animal models of AD and cell culture models of amyloid-β (Aβ) toxicity, making it an exciting therapeutic target for treating AD. A variety of evidence indicates that Tau's interactions with Fyn kinase and other SH3 domain-containing proteins, which bind to PxxP motifs in Tau's proline-rich domain, may contribute to AD deficits and Aβ toxicity. Thus, we sought to determine if inhibiting Tau-SH3 interactions ameliorates Aβ toxicity. We developed a peptide inhibitor of Tau-SH3 interactions and a proximity ligation assay (PLA)-based target engagement assay. Then, we used membrane trafficking and neurite degeneration assays to determine if inhibiting Tau-SH3 interactions ameliorated Aβ oligomer (Aβo)-induced toxicity in primary hippocampal neurons from rats. We verified that Tau reduction ameliorated Aβo toxicity in neurons. Using PLA, we identified a peptide inhibitor that reduced Tau-SH3 interactions in HEK-293 cells and primary neurons. This peptide reduced Tau phosphorylation by Fyn without affecting Fyn's kinase activity state. In primary neurons, endogenous Tau-Fyn interaction was present primarily in neurites and was reduced by the peptide inhibitor, from which we inferred target engagement. Reducing Tau-SH3 interactions in neurons ameliorated Aβo toxicity by multiple outcome measures, namely Aβo-induced membrane trafficking abnormalities and neurite degeneration. Our results indicate that Tau-SH3 interactions are critical for Aβo toxicity and that inhibiting them is a promising therapeutic target for 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.