Disodium cromoglycate restricts human tau hyperphosphorylation and manifestation of associated phenotypes by inhibiting GSK3β activity in Drosophila disease models

BACKGROUND: Tauopathies include a group of neurodegenerative disorders characterized by the aggregation of hyperphosphorylated Tau Protein in brain. An imbalance between tau-specific kinases and phosphatases has been implicated in the pathogenesis of tauopathies. The glycogen synthase kinase 3β (GSK3β), a key tau kinase, has emerged as a promising therapeutic target. We evaluated whether Disodium Cromoglycate (DSCG), a recognized GSK3β inhibitor, restricts pathogenic tau hyperphosphorylation and manifestation of associated phenotypes in Drosophila. METHODS AND RESULTS: Human tauopathies in Drosophila was modelled by expressing pathogenic tau transgene in tissue specific manner by GAL4/UAS binary genetic tool. DSCG was administered orally to age-appropriate Drosophila of suitable genotypes at the specified concentrations. Preliminary screening, focused on establishing the relative ability to inhibit tau aggregation, identified 2 µM and 5 µM DSCG as the effective concentrations, which were then used in subsequent experiments. Various experiments such as brain sectioning, Mushroom body staining, cell death assay, behavioural assays etc. consistently suggested that effective dosages of DSCG efficiently restricts tau mediated neurodegeneration and the associated phenotypes. Immunostaining and western blot analysis subsequently suggested that DSCG treatment restricts tau hyperphosphorylation at the specific pathogenic site by increasing the inactive cellular pool of GSK3β in tau-expressing Drosophila tissues. CONCLUSION: Our study suggests that DSCG treatment efficiently restricts pathogenic hyperphosphorylation of human tau and limits the manifestation of associated phenotypes in Drosophila. Given the functional conservation of GSK3β and its associated cellular mechanisms between humans and Drosophila, our findings emphasize the potential of DSCG as a therapeutic strategy for tauopathies.

Drosophila; Disodium Cromoglycate (DSCG); GSK3β; Tauopathies; Treatment.