(−)-Epigallocatechin-3-gallate, a Polyphenol from Green Tea, Regulates the Liquid–Liquid Phase Separation of Alzheimer’s-Related Protein Tau

Abstract

The microtubule-associated protein tau is involved in Alzheimer’s disease and other tauopathies. Recently, tau has been shown to undergo liquid–liquid phase separation (LLPS), which is implicated in the physiological function and pathological aggregation of tau. In this report, we demonstrate that the green tea polyphenol (−)-epigallocatechin-3-gallate (EGCG) promotes the formation of liquid tau droplets at neutral pH by creating a network of hydrophobic interactions and hydrogen bonds, mainly with the proline-rich domain of tau. We further show that EGCG oxidation, tau phosphorylation, and the chemical structure of the polyphenol influence the efficacy of EGCG in facilitating tau LLPS. Complementary to the inhibitory activity of EGCG in tau fibrillization, our findings provide novel insights into the biological activity of EGCG and offer new clues for future studies on the molecular mechanism by which EGCG alleviates neurodegenerative diseases.

Biphasic modulation of tau liquid–liquid phase separation by polyphenols

“…26 EGCG was shown to promote tau LLPS mainly by binding to its proline-rich domain. 9 Suramin was found to induce tau LLPS to reduce the formation of heparin-induced tau aggregates. 27 We have developed a cyclic dipeptide derivative that effectively inhibits and dissolves Zn-mediated tau condensates preventing the tau condensate-to-fibril transition.…”

“…4,6,7 Natural phenols, including (À)-epigallocatechin-3-gallate (EGCG), tannic acid (TA), myricetin, oleocanthal, curcumin, and rosmarinic acid have been shown to inhibit toxic tau aggregation. [8][9][10] Thiophene-based small molecules that modulate both amyloid-b (Ab) and tau aggregation and effectively protect neuronal cells have been identified. 11 Methylene blue (MB) and leucomethylthioninium (LMTM), bis(hydromethanesulphonate) were found to inhibit tau aggregation, however, their poor results in phase III clinical trials underscore the need for further investigation into tau aggregation mechanisms for the development of effective tau-targeted therapeutics.…”

“…Pyrogallol (PG), structurally similar to GA, could not modulate tau LLPS, emphasizing the intrinsic role of molecular variations in LLPS modulation. 9,30,31 Furthermore, a GA dose-dependent turbidity assay and DIC imaging indicated a biphasic nature (Fig. 2A).…”

“…S7A and B, ESI†). 9,22,27 However, the GA-induced tau condensates were sensitive to both HD and NaCl, but not to DMF (Fig. 3A and Fig.…”

“…1B). 9 To confirm, DIC imaging was conducted after incubating tau (5 μM) with SP (10 μM) for 30 minutes (Fig. 1C and Fig.…”