Distinguishing the Effect on the Rate and Yield of Aβ42 Aggregation by Green Tea Polyphenol EGCG

Abstract

Deposition of Aβ42 aggregates in the form of amyloid plaques is a pathological hallmark of Alzheimer’s disease. A desired avenue of intervention is the inhibition of Aβ42 aggregation. Epigallocatechin gallate (EGCG), the main polyphenol in green tea, has been generally considered an inhibitor of Aβ aggregation. However, previous experiments focused on the reduction of the amount of Aβ42 aggregates, while the effect of EGCG on the rate of Aβ42 aggregation was not critically analyzed. Here we performed an experimental evaluation of Aβ42 aggregation kinetics in the absence and presence of EGCG at a wide range of concentrations. We found that EGCG reduced thioflavin T fluorescence in an EGCG concentration-dependent manner, suggesting that EGCG reduced the amount of Aβ42 fibrils. The effect of EGCG on the rate of Aβ42 aggregation appears to be bimodal. We found that higher EGCG-to-Aβ42 ratios promoted the rate of Aβ42 aggregation, while lower EGCG-to-Aβ42 ratios inhibited the aggregation rate. To confirm that the reduction of thioflavin T fluorescence is due to the lowered aggregate quantity, but not due to perturbation of thioflavin T binding to Aβ42 fibrils, we probed the effect of EGCG on Aβ42 aggregation using site-directed spin labeling. Electron paramagnetic resonance of spin-labeled Aβ42 aggregates suggests that high EGCG-to-Aβ42 ratios led to a greatly reduced amount of Aβ42 fibrils, and these aggregates adopt similar structures as the fibrils in the no-EGCG sample. Potential implications of this work in designing prevention or therapeutic strategies using EGCG are discussed.

Design of Self-Assembled Nanoparticles as a Potent Inhibitor and Fluorescent Probe for β-Amyloid Fibrillization

“…Due to the synergistic effects of the hydration layer and positive charges on the surface of the copolymer, 52 pCG (0.54 mg/mL) shortened the lag time to 1.83 h, but the final fluorescence intensity of Aβ 40 remained unchanged. LC8-pCG and LC8-pCG-fLC8 not only accelerated the nucleation of Aβ 40 , potentially avoiding the generation of neurotoxic oligomers, 66,67 but also noticeably reduced the final ThT fluorescence intensity. Specifically, low concentrations of LC8-pCG and LC8-pCG-fLC8 nanoparticles could lead to the local enrichment of Aβ 40 on their surface, acting as "seeds" to accelerate the nucleation and ultimately shorten the lag time of Aβ 40 .…”

Inhibition of Islet Amyloid Polypeptide Fibrillation by Structurally Diverse Phenolic Compounds and Fibril Disaggregation Potential of Rutin and Quercetin

“…29 Similar results were reported for epigallocatechin gallate where the promotion of Aβ 42 aggregation was observed at increasing molar ratios, equally characterized by a decrease in lag time. 30 Naringenin was previously reported as potentially antidiabetic as its intake was associated with significantly lower T2D risk in humans, and it also inhibited IAPP fibrillation in vitro. 31,32 Conversely, molar ratio-dependent increase in inhibitor potency was observed when IAPP was incubated with sinapinic acid, with minimal deviation in IAPP fibrillation, compared to the control at the lowest inhibitor molar ratio (Supporting Information, Figure S1a).…”

Dual effect of epigallocatechine gallate on the pathology of Alzheimer s: Cholinesterases and amyloidogenesis

“…EGCG also inhibited the amyloid fibril aggregation in a time course manner. Previous studies report [26] the destabilizing effect of EGCG on Ab42 fibrillation but we investigated all types of fibrillation processes. All types of fibril formations was observed to increase by the two hours of experiment and EGCG destabilized the fibrillation from fourth hours.…”