The green tea polyphenol (−)‐epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios

Abstract

The accumulation of amyloid-beta (Aβ) and tau aggregates is a pathological hallmark of Alzheimer's disease. Both polypeptides form fibrillar deposits, but several lines of evidence indicate that Aβ and tau form toxic oligomeric aggregation intermediates. Depleting such structures could thus be a powerful therapeutic strategy. We generated a fragment of tau (His-K18ΔK280) that forms stable, toxic, oligomeric tau aggregates in vitro. We show that (−)-epigallocatechin gallate (EGCG), a green tea polyphenol that was previously found to reduce Aβ aggregation, inhibits the aggregation of tau K18ΔK280 into toxic oligomers at ten- to hundred-fold substoichiometric concentrations, thereby rescuing toxicity in neuronal model cells.

The Effect of (−)-Epigallo-catechin-(3)-gallate on Amyloidogenic Proteins Suggests a Common Mechanism

“…EGCG treatment reduced cytotoxicity of Aβ (Levites et al 2003; Ehrnhoefer et al 2008; Bieschke et al 2010) [see also Table 7.1], Htt (Ehrnhoefer et al 2006), α-Syn (Ehrnhoefer et al 2008; Bieschke et al 2010; Lorenzen et al 2014), IAPP (Meng et al 2010) and tau (Wobst et al 2015) in cellular models. Experiments probing the effect of EGCG on TTR toxicity in cell culture were inconclusive (Miyata et al 2010).…”

“…This was observed for Htt (Ehrnhoefer et al 2006), Aβ (Ehrnhoefer et al 2008; Lopez del Amo et al 2012), α-Syn (Bieschke et al 2010; Suzuki et al 2012), the HIV-mediating SEVI (Hauber et al 2009; Popovych et al 2012), IAPP (Meng et al 2010; Suzuki et al 2012), and Insulin (Wang et al 2012a). EGCG was on the other hand unable to prevent fibril formation by β2m (Woods et al 2011), the prion protein (Rambold et al 2008), or heparin-induced fibril formation of tau (Wobst et al 2015). However, EGCG completely prevented the formation of β-sheet rich aggregates of an aggregation-prone mutant tau (His-K18ΔK280) in the absence of heparin (Wobst et al 2015).…”

“…EGCG was on the other hand unable to prevent fibril formation by β2m (Woods et al 2011), the prion protein (Rambold et al 2008), or heparin-induced fibril formation of tau (Wobst et al 2015). However, EGCG completely prevented the formation of β-sheet rich aggregates of an aggregation-prone mutant tau (His-K18ΔK280) in the absence of heparin (Wobst et al 2015). The crucial rate limiting step in TTR-amyloid formation involves monomerization of the TTR tetramer (Hammarstrom et al 2003).…”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…Thus, therapeutic strategies for AD, PD, and FTD might require reducing the synthesis, preventing the aggregation and/or enhancing the clearance of Aβ, tau, or α-syn. Numerous strategies directed at reducing the accumulation of these proteins have been developed, including the use of small interfering RNA, antisense RNA [39][40][41][42][43], degrading enzymes (e.g., cathepsin D, neurosin, neprilysin) [44][45][46], chaperonelike molecules that modulate aggregation state (e.g., Hsp70, β-syn) [47][48][49][50], anti-aggregation compounds (e.g., polyphenols) [51][52][53], and immunotherapy (passive, active, and Tcell-based) [54]. Moreover, the recent discovery that toxic oligomeric forms of α-syn and tau accumulate in the plasma membrane and are secreted to the extracellular environment has provided further rationale for the development of immunotherapeutic approaches for PD, DLB, MSA, FTD, and other neurodegenerative disorders characterized by the abnormal accumulation of these proteins [24,26,[55][56][57][58].…”

Inhibitors of protein aggregates as novel drugs in neurodegenerative diseases

“…In the last decade, different classes of tau aggregation inhibitors (TAIs) have been reported, including polyphenols [31], porphyrins [32], phenothiazines such as Methylene blue [32], benzothiazoles/cyanines such as N744 and Riluzole [33], thioxothiazolidinones (rhodanines), phenylthiazolehydrazides, anthraquinones, and aminothienopyridazines (ATPZs) [30,33] (Table 2).…”