A green tea polyphenol Epigallocatechin-3-gallate modulates Tau Post-translational modifications and cytoskeletal network

Abstract

Background: Alzheimer's disease is a type of dementia denoted by progressive neuronal death due to the accumulation of proteinaceous aggregates of Tau. Post-translational modifications like hyperphosphorylation, truncation, glycation, etc. play a pivotal role in Tau pathogenesis. Glycation of Tau aids in paired helical filament formation and abates its microtubule-binding function. The chemical modulators of Tau PTMs, such as kinase inhibitors and antibody-based therapeutics, have been developed, but natural compounds, as modulators of Tau PTMs are not much explored. Methods: We applied biophysical and biophysical techniques like fluorescence kinetics, SDS-PAGE, western blot analysis and transmission electron microscopy to investigate the impact of EGCG on Tau glycation in vitro. The effect of glycation on cytoskeleton instability and its EGCG-mediated rescue were studied by immunofluorescence in neuroblastoma cells.

CryoEM reveals how the small molecule EGCG binds to Alzheimer’s brain-derived tau fibrils and initiates fibril disaggregation

“…To confirm that EGCG binds to amyloid fibrils of tau, and that inhibition of tau by EGCG is not the result of indirect effects, [16][17][18] we confirmed binding of EGCG to recombinant fibrils of tau by ITC ( Fig. 1a).…”

“…[11][12][13][14][15] Evidence suggesting that EGCG disaggregates fibrils of tau includes studies in primary rat neurons showing that EGCG enhances clearance of phosphorylated tau, 16 although the reported effects of EGCG are somewhat pleiotropic and range from the inhibition aggregation to altered post-translational modification. 17,18 Here, we sought to illuminate the effects direct binding of EGCG to AD-tau by single-particle cryoEM structure determination. The challenge is to obtain a picture of the kinetic intermediate of pathogenic tau fibrils bound to EGCG, yet prior to the subsequent disaggregated state.…”