biostudies-literatureUnknown9Faris STauopathies are neurodegenerative diseases characterized by intracellular abnormal tau deposits in the brain. Tau aggregates can propagate from one neuron to another in a prion-like manner, mediated by the interaction between tau and cell surface heparan sulfate proteoglycans. We developed an AlphaScreen assay, with His-tagged tau and biotinylated heparin, to represent the tau-HS interface to target the tau-glycan interface. Using our AlphaScreen assay, with a Z-factor of 0.65, we screened ∼300 compounds and discovered a small-molecule compound (herein referred to as A9), which can disrupt the tau-heparin interaction with micromolar efficacy. A9 also effectively inhibited heparin-induced tau aggregation in Thioflavin T fluorescence assays and attenuated tau internalization by H4 neurogliomFrontiers in molecular biosciences1083225https://www.ebi.ac.uk/biostudies/studies/S-EPMC9798536biostudies-literatureSmall-molecule compound from AlphaScreen disrupts tau-glycan interface.PMC9798536Murray AZhang FJin WSmith NFaris SWang CGibson JLinhardt RHe PfalseSmall-molecule compound from AlphaScreen disrupts tau-glycan interface.Tauopathies are neurodegenerative diseases characterized by intracellular abnormal tau deposits in the brain. Tau aggregates can propagate from one neuron to another in a prion-like manner, mediated by the interaction between tau and cell surface heparan sulfate proteoglycans. We developed an AlphaScreen assay, with His-tagged tau and biotinylated heparin, to represent the tau-HS interface to target the tau-glycan interface. Using our AlphaScreen assay, with a Z-factor of 0.65, we screened ∼300 compounds and discovered a small-molecule compound (herein referred to as A9), which can disrupt the tau-heparin interaction with micromolar efficacy. A9 also effectively inhibited heparin-induced tau aggregation in Thioflavin T fluorescence assays and attenuated tau internalization by H4 neurogliom2022-01-01T00:00:00Z20222025-04-18T22:24:09.297Z2025-04-07T10:07:37.945ZS-EPMC97985363658924210.3389/fmolb.2022.1083225