Epigallocatechin-3-gallate enhances clearance of phosphorylated tau in primary neurons

Abstract

In this study, we show that EGCG enhances the clearance of AD-relevant phosphorylated tau species in primary neurons. Interestingly, this result appears to be independent of both Nrf2 activation and enhanced autophagy - two previously reported mechanisms of phytochemical-induced tau clearance. EGCG did significantly increase expression of two autophagy adaptor proteins. Taken together, these results demonstrate that EGCG has the ability to increase the clearance of phosphorylated tau species in a highly specific manner, likely through increasing adaptor protein expression.

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).…”

“…Epigallocatechin gallate (EGCG), a small molecule natural product in green tea, inhibits aggregation of numerous amyloid proteins and, despite their tremendous stability, disaggregates fibrils of some amyloids into smaller units. [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.…”

“…Amyloid fibrils are disaggregated biologically by the aid of specific chaperones proteins, [24][25][26][27] and/or the autophagosome 16 . Amyloid disaggregation is an attractive potential therapeutic mechanism of action.…”

The Additive Effects of Low Dose Intake of Ferulic Acid, Phosphatidylserine and Curcumin, Not Alone, Improve Cognitive Function in APPswe/PS1dE9 Transgenic Mice

“…Catechin and its analogs are flavonoid polyphenols that are abundant in green tea. Among them, epigallocatechin gallate (EGCG) reportedly inhibits Aβ production via α-secretase activation 52) and β-secretase inhibition, 53) inhibits Aβ aggregation, 54) promotes Aβ 55) and phosphorylated tau 56) clearance via autophagy, 55) inhibits tau aggregation, 57) protects neural cells from oxidative stress and Aβ-induced neurotoxicity, 58,59) inhibits AChE activity, 60) and promotes neurogenesis. 61,62) In addition, more than 10 clinical trials have been conducted on EGCG or green tea, 63) and some have shown efficacy in improving cognitive function.…”

The efficacy of Epigallocatechin-3-gallate (green tea) in the treatment of Alzheimer’s disease: an overview of pre-clinical studies and translational perspectives in clinical practice

“…In another study, Bieschke et al showed that EGCG converted the large mature Aβ fibrils into smaller forms with no toxicity for mammalian cell [26]. A recent study conducted by Chesser et al , proved that EGCG in DIV8 primary rat cortical neurons, was able to enhance the clearance of AD-relevant phosphorylated tau species, indicating that EGCG could be used as an adjuvant agent for AD’s treatment [27]. Similar findings were obtained by Chang et al The authors demonstrated that EGCG reduced β-amyloid (Aβ) accumulation in M146 L and CHO cells [28].…”