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An In Vitro Model for Studying Tau Aggregation Using Lentiviral-mediated Transduction of Human Neurons
Published on: May 23, 2019
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Small-molecule compound from AlphaScreen disrupts tau-glycan interface.
Shannon Faris1,2, Weihua Jin3, James Gibson2
1Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY, United States.
Frontiers in Molecular Biosciences
|January 2, 2023
Summary
Researchers discovered A9, a compound that disrupts the tau-heparan sulfate proteoglycan interaction, a key step in tauopathy progression. This finding offers a promising therapeutic strategy for neurodegenerative diseases like Alzheimer's disease.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Tauopathies are neurodegenerative diseases marked by abnormal tau protein deposits.
- Tau pathology spreads between neurons via interaction with cell surface heparan sulfate proteoglycans (HSPGs).
Purpose of the Study:
- To develop a screening assay targeting the tau-HSPG interface.
- To identify small molecules that disrupt tau-HSPG interactions for potential therapeutic intervention in tauopathies.
Main Methods:
- Development of an AlphaScreen assay to model the tau-heparin interface.
- Screening approximately 300 compounds using the AlphaScreen assay.
- Validation of compound efficacy using Thioflavin T assays, cell internalization assays, nuclear magnetic resonance (NMR), and surface plasmon resonance (SPR).
Main Results:
- A novel small-molecule compound, A9, was identified that disrupts tau-heparin interactions with micromolar efficacy.
- A9 inhibited heparin-induced tau aggregation and attenuated tau internalization into cells.
- A9 binds to heparin, blocking tau binding sites, and demonstrates micromolar binding affinity.
Conclusions:
- The AlphaScreen assay is an effective tool for targeting the tau-glycan interface in drug discovery.
- Compound A9 shows promise as a lead therapeutic candidate for tauopathies, including Alzheimer's disease.
